The information used for this section was from other HTAs, evidence-based guidelines and the manufacturers’ websites.

Treatment of primary breast cancer usually involves surgery to remove the breast tumour and any involved lymph nodes, followed by adjuvant therapy to reduce the risk of breast cancer recurrence. Recurrence can occur when some cancer cells remain after surgery or when previously unidentified cancer cells have spread to areas around the breast or other areas of the body {1}.

Breast cancer does not recur in all cases and therefore, some patients may experience harmful side-effects of adjuvant therapy unnecessarily {2}. The uPA/PAI-1, MammaPrint and Oncotype DX tests are intended to predict the likelihood of breast cancer recurrence in women and to support the tailoring of treatment to the individual patient.

Specifically,

• The uPA/PAI-1 test is intended for women with newly diagnosed lymph node-negative breast cancer {3}.
• MammaPrint is intended for women {4}:

• • with lymph node-negative and lymph node-positive breast cancer with a tumour size of 5 cm or less or for women
  • who are 61 years of age or less, with oestrogen receptor- positive or oestrogen receptor-negative, lymph node-negative breast cancer.
• The Oncotype DX assay is intended for women with newly diagnosed lymph node-negative or lymph node-positive, oestrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative invasive breast cancer {5}.

The information used for this section was from other HTAs, a government agency website and cancer research charity websites.

The condition is breast cancer. ICD-10 code: C50

Stage of breast cancer

After breast cancer has been diagnosed, various tests are performed to find out if the cancer has spread and to determine the stage of the disease. The stage of the breast cancer can inform decisions on the most appropriate treatment and help predict the prognosis of the patient.

Two systems can be used to describe the stage of the breast cancer, the numerical system {6} and the TNM classification system {7}.

The numerical system describes the cancer stage based on four characteristics {8}:

• size of the tumour
• whether the cancer is invasive or non-invasive
• whether the cancer is in the lymph nodes
• whether the cancer has spread to other parts of the body beyond the breast

Stage 0

Stage 0 is used to describe non-invasive breast cancers, such as ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS). There is no evidence of cancer cells or pre-cancerous cells invading the surrounding healthy breast tissue.

Stage I

Stage I describes invasive breast cancer. There is evidence of cancer cells invading the surrounding healthy breast tissue. Stage I is divided into subcategories known as IA and IB:

• Stage IA describes invasive breast cancer in which the tumour measures up to 2 cm and the cancer has not spread outside the breast.
• Stage IB describes invasive breast cancer in which there are small groups of cancer cells (0.2–2 mm) found in the lymph nodes in combination with no breast tumour or a tumour less than 2 cm in size.

Stage II

Stage II is also divided into two subcategories.

• Stage IIA describes invasive breast cancer in which either:
  • there is no breast tumour but cancer cells are found in the axillary lymph nodes; or
  • there is a breast tumour of 2 cm or smaller and cancer cells are found in the axillary lymph nodes; or
  • there is a breast tumour 2–5 cm in size but there are no cancer cells in the axillary lymph nodes
• Stage IIB describes invasive breast cancer in which either:
  • there is a breast tumour 2–5 cm in size and cancer cells are found in the axillary lymph nodes; or
  • there is a breast tumour larger than 5 cm but there are no cancer cells in the axillary lymph nodes

Stage III

Stage III is divided into three subcategories.

• Stage IIIA describes invasive breast cancer in which either:
  • there is no breast tumour but cancer cells are found in the axillary lymph nodes that are attached to each other or other structures, or cancer cells are found in the lymph nodes near the breastbone; or
  • there is a breast tumour (of any size) and cancer cells are found in the axillary lymph nodes that are attached to each other or other structures, or cancer cells are found in the lymph nodes near the breastbone
• Stage IIIB describes invasive breast cancer in which the tumour can be of any size and cancer:
  • has spread to the chest wall and/or skin of the breast; and
  • may have spread to axillary lymph nodes that are attached to each other or other structures, or cancer cells are found in the lymph nodes near the breastbone

Cancer that has spread to the skin of the breast is inflammatory breast cancer and is considered at least stage IIIB.

• Stage IIIC describes invasive breast cancer in which there is no breast tumour or, if there is a tumour, it can be of any size and cancer:
  • may have spread to the chest wall and/or the skin of the breast; and
  • the cancer has spread to lymph nodes above or below the collarbone; and
  • the cancer may have spread to axillary lymph nodes or to lymph nodes near the breastbone

Stage IIIC breast cancer is divided into operable and inoperable stage IIIC.

• Operable stage IIIC describes stage IIIC invasive breast cancer in which either:
  • cancer is found in ten or more axillary lymph nodes; or
  • cancer is found in lymph nodes below the collarbone; or
  • cancer is found in axillary lymph nodes and in lymph nodes near the breastbone
• Inoperable stage IIIC describes stage IIIC invasive breast cancer in which the cancer has spread to the lymph nodes above the collarbone

Stage IV

Stage IV is used to describe invasive breast cancer that has spread beyond the breast and nearby lymph nodes to other organs of the body, such as the lungs, distant lymph nodes, skin, bones, liver, or brain {6, 8}.

The TNM classification system describes the cancer stage based on three characteristics:

• size of the tumour (T),
• whether the cancer is in the lymph nodes (N)
• whether the cancer has metastasised, or spread to other parts of the body beyond the breast (M)

The T (size) category describes the primary tumour:

• TX: primary tumour cannot be assessed
• T0: no evidence of primary tumour
• Tis: non-invasive breast cancers; DCIS, LCIS
• T1: tumour is no more than 2 cm across
  • T1mic: cancer cells have spread no more than 0.1 cm into surrounding tissue (microinvasion)
  • T1a: tumour is 0.1–0.5 cm across
  • T1b: tumour is 0.5–1.0 cm across
  • T1c: tumour is 1–2 cm across
• T2: tumour is 2–5 cm across
• T3: tumour is more than 5 cm across
• T4: tumour of any size that has spread into the (a) chest wall or (b) skin
  • T4a: tumour has spread into the chest wall
  • T4b: tumour has spread into the skin
  • T4c: tumour is fixed to both the skin and the chest wall
  • T4d: inflammatory carcinoma. The overlying skin of the cancer is red, swollen and painful to touch

The higher the T number, the larger the tumour and the more it may have grown into the breast tissue.

The N (lymph node involvement) category describes whether or not the cancer has spread to the lymph nodes:

• NX: lymph nodes cannot be assessed
• N0: no evidence of cancer cells in lymph nodes
• N1: cancer cells in the axillary lymph nodes but the nodes are not attached to surrounding tissues
• N2 is divided into two subcategories:
  • N2a: cancer cells in the axillary lymph nodes that are attached to each other and other structures
  • N2b: no cancer cells in the axillary lymph nodes but cancer cells are present in the lymph nodes near the breastbone.
• N3 is divided into three subcategories:
  • N3a: cancer cells in lymph nodes below the collarbone
  • N3b: cancer cells in the axillary lymph nodes and the lymph nodes near the breastbone
  • N3c: cancer cells in the lymph nodes above the collarbone

The higher the N number, the greater the extent of the lymph node involvement.

The M (metastasis) category describes whether or not the cancer has spread to other parts of the body:

• MX: metastasis cannot be assessed
• M0: no evidence of distant metastasis
• M: distant metastasis is present {9, 10}

Tumour grade

In addition to the stage of the cancer, another factor that is considered when making treatment decisions is the tumour grade.

The tumour grade describes the appearance of cancer cells when compared with healthy breast cells under the microscope.

Grade 1 (low grade)

Grade 1 is used to describe a tumour in which the cancer cells grow very slowly and appear similar to healthy breast cells.

Grade 2 (moderate or intermediate grade)

Grade 2 is used to describe a tumour in which the cancer cells appear abnormal and are faster growing

Grade 3 (high grade)

Grade 3 is used to describe a tumour in which the cancer cells grow rapidly and appear very different to healthy breast cells

High grade tumours are likely to be metastatic and are treated more aggressively than low grade tumours {11}.

Receptor status

The receptor status of the cancer will also be determined to inform decisions about the most appropriate treatment for the patient and the risk of breast cancer recurrence.

Some breast cancers have receptors for the hormones oestrogen and progesterone. Breast cancers that express high levels of the oestrogen receptor are considered oestrogen receptor-positive (ER+) and those that do not express the receptor are considered oestrogen receptor-negative (ER-). Generally, ER+ cancers are sensitive to treatment with hormone (endocrine) therapies.

Some breast cancers have receptors for the HER2 (human epidermal growth factor 2) protein. Those cancers expressing high levels of the HER2 receptor are considered HER2-positive (HER2+) and are sensitive to treatment with trastuzumab (Herceptin) {12}.

The information used for this section was from cancer research charity websites.

The known risk factors that affect the incidence of breast cancer include:

• Age

Age is the strongest risk factor for breast cancer (after gender): the older the woman, the higher the risk.

• Reproductive history
  • Age at menarche: Early age at menarche has been consistently associated with an increased risk of breast cancer.
  • Age at first birth: The younger the woman, the lower the risk of breast cancer.
  • Parity: Childbearing reduces the risk of breast cancer. The higher the number of full-term pregnancies, the lower the risk.
  • Breastfeeding: Women who breastfeed have a lower risk of breast cancer compared with women who do not breastfeed.
  • Age at menopause: Late menopause increases the risk of breast cancer.
  • Oral contraceptives: The use of oral contraceptives increases the risk of breast cancer. There is no increased risk 10 years after stopping the use of oral contraceptives.
  • Hormone replacement therapy (HRT): Women who take HRT have an increased risk of breast cancer compared with those who do not. The risk increase is temporary and diminishes within 5 years of stopping the use of oral contraceptives.
• Previous breast disease

Women with a history of benign breast disease and women who have received treatment with radiation therapy to the breast or chest can have an increased risk of breast cancer. Women with a previous diagnosis of breast cancer have an increased risk of developing a second primary breast tumour.

• Family history

Breast cancer is higher among women whose close relatives have, or have previously had, breast cancer. Having a first-degree relative (mother or sister) with breast cancer approximately doubles a woman’s risk.

It is estimated that 5–10% of breast cancers are hereditary, resulting from gene mutations inherited from a parent. Inherited mutations in the BRCA1 and BRCA2 genes are the most common cause of hereditary breast cancer. Women with a mutation in either gene are at high risk of developing breast cancer in their lifetime, often at a younger age and in both breasts compared with women without a BRCA mutation.  

• Lifestyle factors                                                      
  • Being overweight or obese: Women with a high body mass index (BMI) have an increased risk of breast cancer, particularly post-menopausal women.
  • Physical activity: Evidence is developing that exercise reduces the risk of breast cancer, with the strongest association shown for post-menopausal women.
  • Alcohol consumption: The consumption of alcohol is linked to an increased risk of developing breast cancer and the risk increases with the amount consumed.
  • Diet: There is some evidence that a high intake of saturated fat is linked to an increased risk of developing breast cancer.

{13, 14}

The information used for this section was from an evidence-based guideline and cancer research charity websites.

Cancer begins when a cell or a group of cells start to grow and divide uncontrollably. This abnormal cell growth can occur when there are mutations in genes that are involved in cell growth or cell repair. Genes are segments of genetic code that provide the basic instructions that influence a cell’s behaviour. In healthy cells, when there is a gene mutation the cell repairs the mutation or dies. In cancer, cell repair and cell death do not occur so, as the cancer cell divides, the gene mutation(s) are passed on to the cell progeny. Some mutated genes are inherited (e.g. BRCA gene) but most mutations occur when cells divide or are created by environmental factors such as cigarette smoke {2}.

The natural progression of breast cancer differs greatly between patients. The two main categories of early breast cancer are in situ disease and invasive cancer. Breast cancer that is in situ is typically confined to the lobules (milk-producing glands) or ducts (tubes that carry the milk from the lobule to the nipple) of the breast. However, breast cancer in situ can progress from non-invasive (in situ) to invasive breast cancer and spread from the ducts or lobules, invading the surrounding tissues in the breast or other parts of the body {15}.

The main ways in which breast cancer can spread are by local spread to nearby tissues, or by regional or distant spread through the circulatory system or through the lymphatic system. In order for cancer to spread, cancer cells must become detached from the main tumour and be carried in the lymph to the lymph nodes or travel in the circulating blood until they get stuck in a capillary and invade the nearby tissue. When cancer cells spread and start to grow elsewhere in the body, the tumours are known as secondary tumours.

Circulating cancer cells can go undetected until a tumour starts to form and this is one of the reasons cancer can recur after the initial treatment. Another reason for cancer recurring is if cancer cells remain after the primary tumour has been removed.

The degree to which cancer has spread determines the stage of the disease and subsequent treatment. Typically, the more extensive the spread of cancer in the body then the more aggressive the treatment and the worse the patient’s prognosis {16}.

The information used for this section was from a cancer research charity website.

The symptoms of breast cancer are:

• a lump, swelling or thickening in an area of the breast
• a change in the size or shape of a breast
• dimpling or irritation of the skin
• a change in the shape of the nipple, particularly if it turns in, sinks into the breast or becomes irregular in shape
• a blood stained discharge from the nipple
• a rash on a nipple or surrounding area
• a swelling or lump in the armpit
• pain in either of the breasts or armpits

{17, 18}

The information for this section was from the basic literature search and health organisation websites.

Breast cancer is one of the most common causes of death from cancer in women.

The treatment of cancer can cause many side-effects including significant pain, persistent fatigue, osteoporosis and a reduction in fertility. Emotionally, a diagnosis of breast cancer and subsequent treatment can cause long-term anxiety, depression and isolation in both the individual and their relatives. Hair loss and changes to the body from a mastectomy for example, are associated with a social stigma and can significantly impact on quality of life and reduce self-esteem.

Lymphoedema is swelling caused by a build-up of lymph fluid in the tissues of the body. This can occur after breast cancer treatment because of damage to the lymphatic system as a result of lymph node surgery or radiotherapy. Lymphoedema does not affect all those who undergo lymph node surgery but in some people it can develop soon after treatment or years later. The most common symptom is swelling of the arm, hands and fingers on the side of the body that was operated on. Swelling can also affect the breast, chest and shoulder {19}.

Axillary (armpit) lymph node surgery results in complications for 80% of women. These can include limited mobility, arm oedema and numbness or sensory loss {20}.

The information for this section was from an international cancer research agency website and an international organisation report.

Breast cancer is one of the most commonly occurring cancers with an estimated 1.38 million women diagnosed worldwide in 2008. This accounts for nearly a quarter of all cancers diagnosed in women {21}. One in nine women will acquire breast cancer at some point in her life and one in thirty will die from the disease {22}. In 2008, the highest estimated European age-standardised rates of incidence among women was in Belgium (145 cases per 100,000) and the lowest rates were in Greece (57 cases per 100,000). In men, the rates were less than 1 per 100,000. The highest rate of breast cancer is in women aged over 70 years. Globally, incidence rates in developed countries are four or five times higher than those in developing countries. The highest incidence of breast cancer is in northern Europe, northern America, Australia and New Zealand, and the lowest incidence of breast cancer is in South Central Asia and, middle and eastern Africa {21}.

Information about the number of women with specific subtypes of breast cancer is limited. However, it is estimated that 70% of breast cancers are ER+ and that one in five women with breast cancer will have tumours that are HER2+ {12}. The receptor status of a tumour can indicate the risk of breast cancer recurrence and inform the patient prognosis.

The information for this section was from cancer research charity websites and an international organisation report.

In 2008, it was estimated that breast cancer was the cause of 139,000 deaths in Europe and 458,000 deaths worldwide. Globally, the range of mortality rates is less than the range of incidence rates because survival rates are higher in high-incidence regions (developed countries). The Organisation for Economic Co-operation and Development (OECD) reports 5-year breast cancer survival rates of over 80% in developed countries. The most important prognostic variable is the stage of the cancer at diagnosis. Survival rates are highest in women diagnosed with breast cancer at an early stage before it has spread {22, 23}.

Breast cancer is associated with high morbidity and the treatment of breast cancer can cause significant pain, osteoporosis, a reduction in fertility and long-term anxiety and depression, which can significantly impact on quality of life {19}.

The information used for this section was from other HTAs, evidence-based guidelines and the manufacturers’ websites.

Treatment of primary breast cancer usually involves surgery to remove the breast tumour and any involved lymph nodes, followed by adjuvant therapy to reduce the risk of breast cancer recurrence. Recurrence can occur when some cancer cells remain after surgery or when previously unidentified cancer cells have spread to areas around the breast or to other areas of the body {1}.

Breast cancer does not recur in all cases and, therefore, some patients may experience harmful side-effects of chemotherapy unnecessarily {2}. The uPA/PAI-1, MammaPrint and Oncotype DX tests are intended to predict the likelihood of breast cancer recurrence in women and to support the tailoring of treatment to the individual patient. Therefore, the use of these tests may reduce the number of women receiving chemotherapy and experiencing the associated side-effects unnecessarily, or increase survival rates by helping to identify patients who are at high risk of recurrence and, therefore, may need to receive more aggressive adjuvant therapy {3,4,5}.

The information used for this section was from guidelines, manufacturer’s websites and, surveys or questions sent to European healthcare agencies, clinicians and manufacturers.

According to the manufacturer, MammaPrint is currently marketed in all European countries and the test is most widely used in Spain, the Netherlands and Italy {Appendix COL-1}. Results from the survey of healthcare agencies suggest the test is also used in Germany, Slovenia and the UK {Appendix COL-3}.

Results from the manufacturer survey reported that the FEMTELLE uPA/PAI-1test is marketed in Germany, Spain, Slovenia, France and Italy and is most widely used in France and Germany. It is estimated that 7000 patients in Germany and 2000 patients in France are routinely tested each year {Appendix COL-1}. Results from the survey of healthcare agencies reported that the FEMTELLE uPA/PAI-1test is used in Germany and Slovenia and not used in Latvia, Norway, Spain and the UK {Appendix COL-3}.

Results from the manufacturer survey reported that the Oncotype DX test is marketed in Germany, UK, France, Spain, Greece, Hungary and Ireland. The test is most widely used in UK, Germany, Spain and Ireland {Appendix COL-1}. Results from the survey of healthcare agencies reported that the Oncotype DX test is used in Germany, Ireland, Italy, Slovenia, Spain and the UK {Appendix COL-3}.

The survey from clinicians suggested that all three tests are in use in Europe and that Oncotype DX is the most widely used. However, only seven clinicians responded to the survey and this low response rate may be at least in part due to the low use of the tests in European countries {Appendix COL-2}.

The Oncotype DX assay is included in three clinical guidelines from the National Comprehensive Cancer Network (NCCN) {24}, the American Society of Clinical Oncology (ASCO) {25}, and the St Gallen Consensus guidelines {26}. All three guidelines have included the Oncotype DX assay as a test to predict the patient benefit from chemotherapy.

The FEMTELLE uPA/PAI-1 test has been recommended in clinical guidelines from the ASCO {25}, the German Working Group of Gynecological Oncology (AGO) {27} and the German Breast Cancer Society for therapy decisions in node-negative breast cancer {28}. The National Academy of Clinical Biochemistry laboratory medicine practice guidelines include the FEMTELLE uPA/PAI-1 test for use of tumour markers in breast cancer {29}.

The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found insufficient evidence to recommend for or against the use of tumour gene expression profiles (Oncotype DX and MammaPrint). It considered that until more evidence was available the use of these prognostic tests should be decided by the clinician on a case by case basis {30}.

From the evidence and surveys it is unclear how much the prognostic tests are being used in Europe. It is likely that the low survey response rate is likely at least in part due to the low use of the tests in Europe although the recommendations for the use of MammaPrint in clinical guidelines in Germany suggest that the uptake of the MammaPrint test in Germany may be higher than the evidence and surveys indicate. The use of the Oncotype DX and MammaPrint prognostic tests is recommended in a number of clinical guidelines in the USA and, therefore, it is likely that the use of these prognostic tests is higher in the USA than in Europe.

The information used for this section was from the responses received from the multiple choice survey that was sent to European healthcare agencies.

Information received from European healthcare agencies reported current clinical practice for assessing the risk of breast cancer recurrence. Ten healthcare agencies responded and described the type of information that is used:

• Germany
  • Age of patient, tumour size, lymph node status.
• Ireland
  • Clinical observations (e.g. age, menopausal status), pathological (tumour size, tumour grade) and molecular (ER, HER2) parameters. Oncotype DX used for lymph node-negative, ER+, early-stage breast cancer.
• Latvia
  • Results of histological examinations (G, ER, PR, HER, Ki67, parameters of lympho-vascular invasion).
• Spain
  • TNM classification, immunohistochemistry tests, age and general condition of patient are the most used parameters to assess breast cancer recurrence.
• UK
  • A range of guidelines are used. Most often, local guidance, based on the Nottingham Prognostic Index and on Adjuvant! Online, has been developed to help clinicians understand the risk of breast cancer recurrence and to decide the benefits of adjuvant therapy for a particular patient.
• Austria
  • TNM classification, stage, molecular parameters (ER, HER2), clinical observations.
• Norway
  • Mammography (no PTBCRs).
• Italy
  • Accurate classification of primary lesions, familiarity, genetic profile.
• Slovenia
  • The risk of breast cancer is assessed with pathohistology (size of tumour, nodal status, tumour grade, lymphovascular invasion) oestrogen and progesterone receptors, HER2 status (both Herceptest and FISH), and MIB1(ki-67). In some cases of luminal B tumours, additional tests are used.
• Portugal
  • Each institution (hospital) has its own methods of assessing risk of breast cancer recurrence.

{Appendix COL-3}

The information used for this section was from evidence-based guidelines.

In the UK, histological examination of the breast tumour and lymph nodes following surgery provides prognostic information such as tumour grade, tumour size and nodal status. The receptor status of the tumour is also considered to predict response to specific targeted therapies. These prognostic factors, together with patient characteristics, are considered by a breast cancer multidisciplinary team when planning the treatment strategy and determining the likelihood of breast cancer recurrence.

A number of tools are used to assess prognosis and aid decisions on treatment planning. The two algorithms used in the UK are the Nottingham Prognostic Index (NPI) and Adjuvant! Online.

The NPI is used to predict survival following surgery for breast cancer. The NPI value is calculated using the size and grade of the tumour or lesion and the number of involved lymph nodes. An NPI score of greater than 5.4 indicates a poor prognosis and an NPI value less than 2.4 indicates an excellent prognosis.

The Adjuvant! Online software is designed to provide estimates of the risk of recurrence and the benefits of systemic adjuvant therapy. The estimates are based on individual patient characteristics and histological data on the tumour and lymph nodes. The software provides an estimate of the baseline risk of mortality or recurrence for patients if they do not receive adjuvant therapy {1}.

The American Society of Clinical Oncology recommends that the receptor status (e.g. HER2, ER) of the tumour, and the FEMTELLE uPA/PAI-1 and Oncotype DX tests are used to detect tumour markers and predict the risk of recurrence of breast cancer {25}.

The St. Gallen 2011 recommendations also included the receptor status of the tumour for indicating prognosis, and identified the Oncotype DX assay as potentially useful for predicting the need for adjuvant therapy in cases where other factors such as the receptor status do not help {26}.

The information used for this section was from evidence-based guidelines and other HTAs. The responses from surveys sent to clinicians and healthcare agencies were also reviewed.

Usually, the first treatment option for invasive breast cancer is surgery to remove the tumour or breast and any involved lymph nodes. Following surgery, histological examination of the tissues removed during surgery provides prognostic information including tumour grade, nodal status and tumour size. Receptor status (e.g. ER, HER2) is also determined to predict the response to specific targeted therapies. Patient characteristics and these prognostic and predictive factors are considered by a breast cancer multidisciplinary team to assess the risk of breast cancer recurrence and determine a plan of treatment.

Most patients with early breast cancer will require treatment that involves adjuvant therapy in addition to surgery. Adjuvant therapy typically consists of radiotherapy (typically for individuals with large tumours or many involved lymph nodes), chemotherapy (for individuals at high risk of poor outcome) or endocrine therapy (for individuals with tumours that are ER+) and many patients will require a combination of these. The purpose of adjuvant systemic therapy is to reduce the risk of breast cancer recurring because circulating cancer cells (occult metastatic disease) can often go undetected at the time of diagnosis and, therefore, breast cancer can recur at a later date. Planning adjuvant therapy is complex and mostly dependent on clinical decisions, the risk of recurrence, patient choice, the availability of drugs or therapies, and the licensed indications and side-effect profiles of individual drugs or therapies {1, 2}. The availability of different drugs and therapies may vary between countries and local healthcare authorities.

One of the challenges associated with the management of breast cancer is the decision about whether or not to use adjuvant chemotherapy. The likelihood of breast cancer recurrence and death is less for individuals who receive adjuvant chemotherapy so many individuals with early-stage breast cancer are advised to undergo chemotherapy. However, chemotherapy can have severe adverse effects and not all individuals will benefit from receiving it. Some, especially those with small tumours, may remain free of breast cancer recurrence at 10 years without chemotherapy.  

There are a number of algorithms and decision making tools to help clinicians assess the risk of breast cancer recurrence {2}. The prognostic tests, uPA/PAI-1 [FEMTELLE], MammaPrint and Oncotype DX are used in some countries to detect known predictive genetic or protein markers to help clinicians predict the likelihood of breast cancer recurrence in women and to support the tailoring of treatment to the individual patient.

The responses from the surveys did not indicate that the current management of breast cancer is different to published guidelines although the surveys were primarily focussed on the use of the prognostic tests not on the management of breast cancer.

The information used for this section was from evidence-based guidelines.

There was no evidence to suggest that current management described in CUR14 (and below) differed from the published guidelines.

Usually, the first treatment option for invasive breast cancer is surgery to remove the tumour or breast and any involved lymph nodes. Following surgery, histological examination of the tissues removed during surgery provides prognostic information including tumour grade, nodal status and tumour size. Receptor status (e.g. ER, HER2) is also determined to predict the response to specific targeted therapies. Patient characteristics and these prognostic and predictive factors are considered by a breast cancer multidisciplinary team to assess the risk of breast cancer recurrence and determine a plan of treatment.

Most patients with early breast cancer will require treatment that involves adjuvant therapy in addition to surgery. Adjuvant therapy typically consists of radiotherapy (typically for individuals with large tumours or many involved lymph nodes), chemotherapy (for individuals at high risk of poor outcome) or endocrine therapy (for individuals with tumours that are ER+) and many patients will require a combination of these. The purpose of adjuvant systemic therapy is to reduce the risk of breast cancer recurring because circulating cancer cells (occult metastatic disease) can often go undetected at the time of diagnosis and therefore, breast cancer can recur at a later date. Planning adjuvant therapy is complex and mostly dependent on clinical decisions, the risk of recurrence, patient choice, the availability of drugs or therapies and, the licensed indications and side-effect profiles of individual drugs or therapies {1, 2}. The availability of different drugs and therapies may vary between countries and local healthcare authorities.

One of the challenges associated with the management of breast cancer is the decision about whether or not to use adjuvant chemotherapy. The likelihood of breast cancer recurrence and death is less for individuals who receive adjuvant chemotherapy so many individuals with early-stage breast cancer are advised to undergo chemotherapy. However, chemotherapy can have severe adverse effects and not all individuals will benefit from receiving it. Some, especially those with small tumours, may remain free of breast cancer recurrence at 10 years without chemotherapy.  

There are a number of algorithms and decision making tools to help clinicians assess the risk of breast cancer recurrence {2}. The prognostic tests, FEMTELLE (uPA/PAI-1), MammaPrint and Oncotype DX are used in some countries to detect known predictive genetic or protein markers to help clinicians predict the likelihood of breast cancer recurrence in women and to support the tailoring of treatment to the individual patient.

The information used for this section was from the manufacturer’s websites and web-based searches.

The FEMTELLE test is manufactured by American Diagnostica Inc. (member of Sekisui Group) and has received the CE mark for use in Europe {3}.

MammaPrint is manufactured by Agendia and has received the CE mark for use in Europe. It is also approved for use by the US Food and Drug Administration (FDA) {4}.

The Oncotype DX assay is manufactured by Genomic Health and has received the CE mark for use in Europe. The assay is offered as a laboratory developed test and therefore, does not require FDA approval at this time {5}.

Please refer to the TEC domain for further details.

The manufacturer’s website and direct questions to the manufacturer were used to develop this assessment element.

FEMTELLE is a test (classified as an in vitro diagnostic device [IVD]) manufactured by American Diagnostica Inc. (Sekisui Diagnostics LLC from April 2012). It is a prognostic test for primary breast cancer that allows a quantitative determination of the two prognostic factors uPA and its inhibitor PAI-1 in tumour tissue by ELISA technology. The test helps to determine the risk of disease recurrence and to predict the likely benefit from chemotherapy in breast cancer patients. The breast cancer tumour tissue is surgically removed. The specimen is transported fresh (unfixed) to the pathologist who proceeds with the removal of a representative piece of tumour tissue (> 50 mg). The uPA and PAI-1 are extracted and the FEMTELLE test performed by ELISA {2}. If the patient samples need to be shipped to another clinical centre or diagnostic laboratory (Institute of Pathology, laboratories at breast cancer centres or private diagnostic laboratories – decentralised testing) for testing, the frozen samples must be shipped on dry ice. The results are communicated within 3–4 days after receiving the sample. The patient samples have to be kept frozen (-20°C or colder) until test performance. Before shipping of the samples, they can be stored (-20°C or colder) for up to 3 weeks {Appendix COL-2}. More information on FEMTELLE is available in the Appendix “Characteristics of the tests assessed” {TEC-1}.

The manufacturer’s website and direct questions to the manufacturer were used to develop this assessment element.

MammaPrint is a qualitative in vitro diagnostic test service that was commercially developed by Agendia BV. MammaPrint is not a commercially available IVD device; it is a testing service provided at the manufacturer’s laboratories. MammaPrint uses the gene expression profile of fresh/fresh frozen or FFPE breast cancer tissue samples to assess a patient’s risk of distant metastasis. The MammaPrint result is indicated for use by physicians as a prognostic marker only, along with all the other clinicopathological factors {Appendix COL-2}. The analysis is based on several sequential processes: isolation of RNA from FFPE tumour tissue sections, DNase treatment of isolated RNA, linear amplification and labelling of DNase-treated RNA, cRNA purification, hybridisation of the cRNA to the MammaPrint microarray, scanning the MammaPrint microarray and data acquisition (feature extraction), calculation and determination of the risk of recurrence in breast cancer patients. The MammaPrint analysis is designed to determine the gene activity of specific genes in a tissue sample compared with a reference standard. The result is an expression profile, or fingerprint, of the sample. The correlation of the sample expression profile with a template (the mean expression profile of 44 tumours with known good clinical outcome) is calculated and the molecular profile of the sample is determined (low risk, high risk) {Appendix COL-2}. The specimen (FFPE tissue taken from a surgical specimen) has to be shipped according to a specific protocol provided by the manufacturer. Once the specimen arrives at the manufacturer’s laboratory, results will be available within 10 working days (by email, fax, hard copy and/or secure intranet account) to the requesting physician {3}. FFPE samples can be sent at room temperature (the manufacturer receives the sample the day after shipment) {Appendix COL-2}. More information on MammaPrint is available in the Appendix “Characteristics of the tests assessed” {TEC-1}.

The manufacturer’s website was used to develop this assessment element.

Oncotype DX Breast Cancer Test (Oncotype DX) is multi-gene diagnostic assay that predicts the likelihood of benefit from adjuvant chemotherapy in a subset of breast cancer patients. This is not a commercially available IVD device; it is a testing service provided at the manufacturer’s laboratory {Appendix COL-2}. Oncotype DX quantifies gene expression for 21 genes (16 cancer-related genes and 5 reference genes) in breast cancer tissue by reverse transcriptase-polymerase chain reaction (RT-PCR). First, RNA is extracted from the breast cancer tumour specimen and purified. The RNA is then analysed by real-time RT-PCR. Finally, the recurrence score (RS, corresponding to a point estimate of the 10-year risk of distant recurrence with a 95% CI for an individual patient) is calculated from the gene expression results {4} {5}. To quantify gene expression, RNA is extracted from FFPE tumour tissue and subjected to DNase I treatment. Total RNA content is measured and the absence of DNA contamination is verified. Reverse transcription is performed and is followed by quantitative TaqMan (Roche Molecular Systems, Inc.) RT-PCR reactions in 384-well plates. The expression of each of 16 cancer genes is measured in triplicate and then normalised relative to a set of 5 reference genes {4}. The specimen (tissue block or slides) has to be shipped according to a specific protocol provided by the manufacturer. Once the specimen arrives at the manufacturer’s laboratory, typical processing time for the test to be completed is 7–10 days. The result is sent (by secure intranet account or fax) to the requesting physician {6}. Shipping of the sample is organised via FedEx in priority and takes a maximum of 3 days {Appendix COL-2}. More information on Oncotype DX is available in the Appendix “Characteristics of the tests assessed” {TEC-1}.

The manufacturers’ websites as well as the results from the basic search were used to develop this assessment element.

The intended use of the three tests (FEMTELLE, MammaPrint, and Oncotype DX) is prognostic (likelihood of breast cancer recurrence) and the results need to be considered together with all the other clinical and pathological factors.

FEMTELLE assesses the likelihood of breast cancer recurrence in women with newly diagnosed, lymph node-negative (LN-) breast cancer. FEMTELLE quantitatively determines the uPA  and PAI-1 levels in tumour tissue extracts, allowing the identification of patients with a high (uPA and/or PAI-1 high) or low (uPA and PAI-1 low) risk of recurrence {7}. The timeframe within which such risk recurrence applies is not clearly stated.

MammaPrint has different indications for Europe and the USA:

• In Europe, it is intended as a prognostic test for women of all ages, with LN- and LN+ breast cancer (up to 3 nodes positive) with a tumour size ≤ 5.0 cm {8}.
• In the USA, it is intended as a prognostic test for women ≤ 61 years with primary invasive, oestrogen receptor-positive (ER+), or oestrogen receptor-negative (ER-) LN- breast cancer {9}{Appendix COL-2}. It assesses a patient’s risk for distant metastasis (up to 10 years for patients less than 61 years old, up to 5 years for patients 61 years). The test is indicated for breast cancer patients with Stage I or Stage II disease, with a tumour size of ≤ 5.0 cm and LN-.

Oncotype DX is intended to predict the likelihood of recurrence in women of all ages with newly diagnosed Stage I or II, ER+LN- breast cancer treated with tamoxifen {8}. The test assigns the breast cancer a recurrence score. The test also looks at the expression of hormone receptor genes, both the ER and progesterone receptor (PR), and can provide an indication of how responsive the cancer is likely to be to hormonal therapy {8}.

The manufacturers’ websites, the results from the basic search and regulatory authorities’ websites were used to develop this assessment element. Information obtained by free internet searches and snowballing references from relevant documents were integrated.

FEMTELLE received the CE mark in 2004 {10} and currently awaits FDA licensing {11}. FEMTELLE is not registered in the FDA database {12}.

MammaPrint received the CE mark in November 2005. The company voluntarily submitted MammaPrint to the US Food and Drug Administration for approval under proposed new guidelines for such tests: approval was granted in February 2007 {9}. MammaPrint is registered in the FDA database {12}.

Oncotype DX collection kit received the CE mark in 2007 (October) {13}. Oncotype DX has not received FDA approval {14} but the laboratory that performs the Oncotype DX test has been certified by the Clinical Laboratory Improvement Amendments (CLIA) to perform the test for clinical use {15}.

The manufacturers’ websites and direct questions to the manufacturer were used to develop this assessment element.

The FEMTELLE uPA/PAI-1 test can be performed at any laboratory that has access to a tissue homogeniser, ELISA reader and cooled centrifuge (16,000 g) {Appendix COL-2}. Detailed information about the FEMTELLE test and technical procedure can be obtained by contacting the manufacturer directly {16}. Alternatively, the sample can be shipped to any laboratory qualified to perform ELISA testing. However, the manufacturer has indicated a list of “recommended laboratories” (based in France and Germany) that have experience in performing the test and that take part in regular quality assessment rounds {Appendix COL-2}. The list of “recommended laboratories” is available from the manufacturer.

The MammaPrint test is performed in the manufacturer’s two laboratories: in Irvine, California (USA) or in Amsterdam, The Netherlands (Europe). The specimen (fresh/fresh frozen or FFPE tissue from a surgical specimen) has to be shipped according to a specific protocol provided by the manufacturer {3}.

The Oncotype DX test is performed in the manufacturer’s laboratories in California (USA) after the specimen (FFPE tissue block or slides) has been shipped according to a specific protocol provided by the manufacturer {6}.

The manufacturer’s website and direct questions to manufacturers were used to develop this assessment element.

The three tests (FEMTELLE, MammaPrint, and Oncotype DX) are add-on tests (not replacing any existing tests) to provide additional information in the tertiary care setting (i.e. specialised consultative healthcare facilities). The tissue samples are collected during breast cancer surgery. The information provided by the tests will be used by the multidisciplinary cancer team to supplement the other clinical and pathological information to determine whether or not the patient should receive adjuvant therapy.

Free internet searches were used to develop this assessment element.

The technology itself is not characterised by a fast rate of development; the working principles of the tests have been known for a number of years and no breakthroughs are anticipated. However, given the research activities in the field of cancer genetics and genomics, it is likely that new applications of the same technology will be proposed in the future {19}.

The manufacturers’ websites as well as the results from the basic search were used to develop this assessment element.

The results of the FEMTELLE uPA/PAI-1 assay are reported as absolute protein concentrations of uPA and PAI-1 in the patient’s tumour tissue. The uPA and PAI-1 values refer to the respective total protein concentrations {16}. The results help to identify those node-negative patients who have a low risk of disease recurrence and those patients who have a high risk of disease recurrence after surgery.

Cut off values are:

• uPA = 3 ng/mg total protein
• PAI-1 = 14 ng/mg total protein

Patients with low uPA and low PAI-1 values (below the cut off) are predicted to have a low risk of disease recurrence. The risk value, intended as percentage of recurrence within a timeframe without further adjuvant therapy, is not stated. Patients with high uPA and/or high PAI-1 values (above the cut off) are predicted to have an increased risk of disease recurrence {20}. The risk value, intended as percentage of recurrence within a timeframe without further adjuvant therapy, is not stated.

The results of the MammaPrint test are used for risk-group assignment on the basis of a dichotomised value only (i.e., high or low risk). A tumour is defined as having a low-risk gene signature if the cosine correlation coefficient for the expression of the 70-gene profile in that tumour with the previously established classifier is above 0.4, which is the cut-off point used in the original study by van’t Veer {9} {21}. A “low risk” result means that a patient has a 10% chance that her cancer will recur within 10 years without additional adjuvant treatment, either hormonal therapy or chemotherapy. A “high risk” result means that a patient has a 29% chance that her cancer will recur within 10 years without any additional adjuvant treatment, either hormonal therapy or chemotherapy {9}.

The results of the Oncotype DX are used to calculate the 10-year risk of distant recurrence as a continuous function of the RS. Three risk groups have been defined: low risk (RS ≤17), intermediate risk (18 ≤RS ≤30), and high risk (RS ≥ 31) {9}.

A previous result card (RC-TEC8) and direct questions to manufacturers were used to develop the present assessment element.

The three tests assessed either must be performed exclusively by the manufacturer’s laboratories (MammaPrint and Oncotype DX), or, in the case of FEMTELLE, are generally done by the laboratories indicated by the manufacturer, so no material investment, equipment or supplies are needed within the centres other than those required for specimen preparation. The equipment and supplies required for  specimen preparation are commonly available in cancer centres and hospitals across the EU. The procedures for sample preparation are already established.

The FEMTELLE test can be also performed in any laboratory equipped with: a tissue homogeniser (e.g. dismembrator) to homogenise the tumour tissue, a cooled laboratory centrifuge (16,000 g), and an ELISA plate reader, and following the indication of the manufacturer. This equipment is available as routine laboratory equipment at many routine diagnostic laboratories {Appendix COL-2}. After a routine inspection of the excised tumour tissue, a representative piece of tissue must be removed by the pathologist from the unfixed tumour tissue. After freezing at -20 °C the tissue can be stored at -20 °C for up to 3 weeks. The frozen samples can be shipped on dry ice to any laboratory that performs the FEMTELLE test.

This assessment element has been integrated with TEC12 “What equipment and supplies are needed to use genetic tests for cancer?” The resulting assessment element is the following “What material investments, equipment, and supplies are needed to use FEMTELLE, MammaPrint, and Oncotype DX?”

Direct questions to the manufacturers were used to develop this assessment element.

As the three tests are provided or recommended as testing services (to be performed exclusively by the manufacturer’s laboratories or, in the case of FEMTELLE, by other laboratories as recommended by the manufacturer) no special staff, training or other human resources are needed within the centres to perform the tests. Specimen preparation is the only key issue and needs to be performed by the pathologist, following specific instructions provided by the manufacturer. In particular, FEMTELLE requires fresh/fresh-frozen tumour tissue while MammaPrint can be performed using either fresh/fresh-frozen tumour samples or FFPE samples, and Oncotype DX functions with FFPE samples. For this reason, qualification, training and quality assurance related to the sample preparation strongly depend on the specific local context and on familiarity with the various sample preparation techniques.

Laboratories that want to establish FEMTELLE testing at their site need specific training. For this purpose the technicians involved receive detailed technical training at selected laboratories. The training is usually planned for 3 days. Participants are trained on the whole technical procedure (tissue homogenisation, protein extraction, ELISA testing, total protein determination and calculation of the results). American Diagnostica usually supports the new attendees {Appendix COL-2}.

For Oncotype DX only the manufacturer (Genomic Health) has established guidelines on how to select slides (to ensure that the slide contains sufficient tumour material and that the diagnosis is correct). No further training is needed for a local pathologist. At Genomic Health, all slides are reviewed by board-certified pathologists to ensure the correct diagnosis and if necessary they perform micro-dissection to select material for analysis {Appendix COL-2}.

Other domains results (ORG, SOC, ETH, LEG) were used to develop the present assessment element.

The three tests (FEMTELLE, MammaPrint, and Oncotype DX) are being used in women who have already been diagnosed as having breast cancer to determine their risk of recurrence and to determine whether they can avoid potentially unnecessary additional adjuvant therapy or receive potentially beneficial treatment. Clinicians should advise patients on the availability of tests within their own territory. As stated in RC-ORG3, different studies using patient interviews and questionnaires have shown that, given the level of knowledge on prognostic tests for cancer recurrence, there is room for improvement in the patient information {17}. Healthcare organisations should provide patients with counselling and educational materials to inform them about the potential benefits and harms associated with testing, and should discuss with patients whether the test results are likely to change their decision about therapy {18}. It may also be worthwhile to consider informed patient consent, since the decision to test usually rests with clinicians (see RC-ORG7). See also SOC domain (RC-SOC5) and LEG domain (RC-LEG1) for more details about information activities for patients.

A previous results card (RC-TEC14) was used to develop the present assessment element.

No additional information is required for patients or individuals outside the target group concerning  indications/contraindications, the procedure, and role of test in the diagnostic/therapeutic pathway. In the case of the test results, confidentiality is a major concern; no other people apart from the patient need to be informed about them.

Other domain results (ORG) were used to develop the present assessment element.

Training in sample collection and preparation is very important to avoid sample failure and to achieve an appropriate balance so that there are enough tumour cells but not too much stromal tissue; this may affect the effectiveness of the tests as well as the management of the patient because if the specimens are of poor quality the biopsy and the test may need to be repeated (see RC-ORG2 for more details).

In addition to the basic search, a search was done in PubMed by IP on 15 March 2012 using search string

• 3 (safety[Title/Abstract]) AND #2 >18 studies
• 2 (surgical pathology[Title/Abstract]) AND #1 246
• 1 quality[Title/Abstract] 449032

A questionnaire was sent to the manufacturers asking

• What are the safety standards that the technology must follow?
• What is the statistical, percentage of sampling error?
• What systems are used to minimise or eliminate the risk of the sample contamination?

As there is no separate sampling needed for the three tests in this HTA, we did not evaluate the harms related to invasive sampling (surgery or core biopsy). Instead we looked at some general safety concerns of surgical tissue sample diagnostics, such as sample contamination, delays in transfer, incorrect labelling, and other features which may affect the reliability of the result and thus patient safety.

T = any surgical tissue analysis

I = NA

C = NA

O = errors and quality issues that affect safety

The tissue sample is cut up and prepared in the surgical theatre, moved to the further preparations gross room or the pathological laboratory, and finally sent to the manufacturer’s own laboratory or those recommended by the manufacturers for analysis. Several factors, both process dependent and operator dependent, contribute to error in this chain. The reported frequency of diagnostic errors in oncologic pathology depends on definitions and detection methods, and ranges from 1% to 15%. The large majority of diagnostic errors do not result in severe harm, although mild to moderate harm in the form of additional testing or diagnostic delays occurs in up to 50% of errors (1).

Pathology laboratories traditionally have considered two types of error: errors of accuracy and errors of precision of the test itself (2). Accuracy is the closeness of a measure to its true value, and precision is the degree to which repeated measures show the same results. But, there are additional process- and operator-dependent related errors that may affect patient safety, such as identification errors, specimen defects or contamination, and delays. In a study where surgical pathology amendment reports were analysed in a university hospital in the USA it was noticed that amendments (changes, corrections) were made to approximately five reports out of 1000. About one fifth of them were due to misidentifications (e.g. attribution of specimens to the wrong patient), one out of ten were due to specimen defects (e.g. lost or inadequate size of specimen), a quarter were due to misinterpretation (e.g. false negative), and almost half were due to reporting defects (e.g. dates, diagnostic codes) (3).

Misidentification

In summary, approximately 1/1000 patients and 2–4/1000 surgical pathology specimens end up being misidentified or having incorrect labels in the report.

Studies: Anecdotal evidence indicated that identification errors are frequent (4). Identification errors were studied in a prospective study including 136 laboratories from several countries (5). Of the 427 255 cases reviewed, 1811 had some type of mislabelling (0.4%). The entire case was mislabelled in 1.1/1000 (490) cases, 1/1000 specimens were mislabelled (796 specimens of 358 cases), 1.7/1000 blocks were mislabelled (2172 blocks in 461 cases) and  1/1000 slides were mislabelled  (2509 slides in 502 cases). Misidentification of cases and specimens occurred most often at collection or at accessioning (i.e. when specimens are received, sorted, and entered in the laboratory). In 1751 out of the 1811 mislabelled cases (97%) the mislabelling was corrected without any additional consequences. In 59 cases (3%) a correction report was issued, and in 24 cases (1%) patient care was affected some way. Another retrospective study examined quality control records for an 18-month period and identified mislabelled surgical specimens. Out of 29 500 specimens 2.5/1000 were mislabelled (6). A prospective cohort study with 21 300 surgical specimens noted that 4.3/1000 specimens were incorrectly labelled. Reasons were, in order of frequency: not labelled at all, empty container, laterality incorrect, incorrect tissue site, incorrect patient, no patient name, and no tissue site (7). The majority of routine practices for identification and labelling probably underestimate the frequency of occurrence of errors, and many errors probably go undetected (4). Errors detected before patient harm or inconvenience has occurred are often called near misses.

Contamination

Significant and worrisome levels of contamination of non-primate genome assemblies with human DNA sequences have been noted (8).

Information has been published on psychological harms related to prognostic genetic tests that estimate the predisposition of healthy individuals to become cancer patients. But, as the three tests in this HTA are part of the cancer management pathway, and are diagnostic aids for physicians to select the best treatment, and the time lag from testing to treatment (adjuvant chemotherapy) is short, it is less likely that these tests have similarly significant psychological consequences for patients. We looked for evidence of psychological outcomes from the effectiveness studies of this report, and identified further studies from the basic search.

In the USA, 78 women who were tested with Oncotype DX and treated for early-stage breast cancer in one clinic between 2004and 2009 were sent a questionnaire assessing their knowledge of breast cancer their experiences of testing (9). Approximately 26% (17 of 65) of women agreed or strongly agreed that getting the Oncotype DX test result made them worried and anxious. Greater endorsement of test-related distress was associated with higher actual recurrence risk based on the test, as the majority of women who experienced test related distress had intermediate or high recurrence risks based on their test results (low = 18%, 6 of 33; intermediate = 30%, 7 of 23; high = 44%, 4 of 9). Stronger feelings of distress were also related to having chemotherapy, rather than radiation, and having more frequent worries about breast cancer recurrence.

The emotions of patients receiving MammaPrint were examined in the Netherlands (10). Patients who received a concordant high-risk result from both tests, i.e. clinical and gene tests, and patients who received a discordant low-risk result in clinical tests and a high-risk result from the gene test showed significantly more negative emotions than patients who received concordant low risk results from both tests or discordant high-risk results from clinical tests and a low-risk result from the gene test.

A search was done in PubMed by IP on 21 February 2012. Search strategy

• 23 Add Search (#22) AND #21 35
• 22 Add Search hospital[Title/Abstract] 550947
• 21 Add Search (#20) AND #17 1505
• 20 Add Search (#19) OR #18 546515
• 19 Add Search work[Title/Abstract] 483270
• 18 Add Search occupational[Title/Abstract] 79830
• 17 Add Search (#16) OR #15 39041 04:41:15
• 16 Add Search formaldehyde[Title/Abstract] 14641
• 15 Add Search formalin[Title/Abstract] 24748

The search yielded 35 articles {Appendix SAF-3}. The National Toxicology Program Final Report on Carcinogens 2010 was taken as the basis for carcinogenicity information. As there are sufficient EU sources for safety epidemiology and safety management, all guidelines prepared for non-European contexts were excluded.

Information was also retrieved from web pages of manufacturers, from the European Agency for Safety and Health at Work (EU-OSHA), the draft NICE report 2012, the European Commission Joint Research Centre’s European Chemical Substances Information System (ESIS), and the WHO International Programme on Chemical Safety (IPCS). As there is no free database for Material Safety Data Sheets (MSDS), the best way to find the data sheets is to Google for MSDS and formaldehyde.

T = all surgical tissue sample preparation methods using formalin

I = NA

C = NA

O = occupational risks

Preparation of the tissues samples for each of the three tests under review is different. Before sending the test kit to the manufacturers’ laboratories (or recommended laboratory) preparation of samples for Oncotype DX requires formalin fixation (11). In MammaPrint this is optional; as of January 2012, the manufacturer accepts formalin-fixed paraffin-embedded samples (12). In uPA/PAI-1 formalin fixation is not used.

Risks of formalin fixation

The concentrated water solution (37–40%) of formaldehyde (CAS registry number 50-00-0) is known as formalin (its German trade name). In laboratory practice, 10% and 4% formaldehyde water solutions are used. Formaldehyde evaporates easily from the formalin surface. Formaldehyde (HCHO, methanal) is a colourless gas, which has a short half-life in air due to its decomposition in light. Due to its high solubility in water formaldehyde is fast absorbed in the mucus of the upper respiratory tract, predominantly in the nasal cavity and sinuses, where it can damage the cilia (13). It does not reach the pharynx under non-extreme exposure. Formaldehyde exposure can occur locally, at the place of the initial contact (respiratory or digestive tract, skin etc) and generally, as a result of absorption (14).

Formaldehyde concentrations that have been associated with various toxic effects in humans show wide inter-individual variability and are route dependent. Symptoms are rare at concentrations below 0.5 ppm; however, upper airway and eye irritation, changes in odour threshold, and neurophysiological effects (e.g., insomnia, memory loss, mood alterations, nausea, fatigue) have been reported at concentrations ≤ 0.1 ppm. The odour threshold is 0.8–1 ppm. The most commonly reported effects include eye, nose, throat, and skin irritation. Other effects include allergic contact dermatitis, histopathological abnormalities (e.g., hyperplasia, squamous metaplasia, and mild dysplasia) of the nasal mucosa, occupational asthma, reduced lung function, altered immune response, and haemotoxicity (15).

Formalin has been used for decades and the amounts used in hospitals and laboratories are substantial. Concerns about carcinogenicity and other health hazards have changed its use in past years. Pre-filled containers are used for small biopsies that need to be opened only for a short time, just to remove the specimen, exhaust devices have been developed and formaldehyde exposure is monitored. It has been noted that hospital workers underestimate their levels of exposure to formaldehyde (16).

Carcinogenicity of formaldehyde

The International Agency for Research on Cancer (IARC) concluded in 2006 that there is sufficient evidence of the carcinogenicity of formaldehyde in humans, and placed formaldehyde in Group I—known carcinogens, along with asbestos and benzene (15). This was reinforced in the eleventh Report of Carcinogens based on limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in laboratory animals (13).

A large number of epidemiological studies have been conducted to evaluate the relationship between formaldehyde exposure and carcinogenicity in humans. There are cohort studies and nested case-control studies of health professionals, including physicians, pathologists and laboratory nurses. They generally report mortality or incidence of cancer for ever-exposed workers in analyses using standardised mortality ratios or proportionate mortality ratios. Some of the studies attempted indirect measures of exposure, such as length of professional membership as a proxy for exposure duration.

Cancer risk in healthcare workers exposed to formaldehyde (13):

• cancers of the buccal cavity and pharynx: elevated but statistically non-significant risk (based on three cohort studies: Hayes 1990; Walrath 1983, 1984)
• lung cancer: no association observed in six cohort studies (Hall 1991, Hayes 1990, Stroup 1986, Levine 1984, Walrath 1983 and 1984)
• lymphohaematopoietic cancers: elevated mortality risk based on six cohort studies (Hall 1991, Hayes 1990, Stroup 1986, Levine 1984, Walrath 1983 and 1984);statistically significant risk: RR 1.31 (1.16, 1.47)(Bosettti 2008)
• leukaemia: RR 1.39 (1.15, 1.68)
• brain and central nervous cancers: meta-analysis by Bosetti 2008 reported statistically significant increase in risk, RR 1.56 (1.24, 1.96); excessive mortality reported in six cohort studies, with statistically significant difference in three studies: SMRs/PMRs 1.94 to 2.7 (Stroup 1986, Walrath 1983, 1984)
• pancreatic cancer: two meta-analyses identified borderline significant increase among pathologists and anatomists (Ojajärvi 2000, Collins 2001)

Other medical problems related to formaldehyde exposure

Eye irritation, tears and sensation of odour are common in most individuals. There can be an adverse reaction of hypersensitivity, even at low concentrations. It has been suggested that long- term inhalation of formaldehyde may trigger classic immunoglobulin E-mediated nasal allergy in atopic individuals (17). Clinical data has revealed dermatitis and skin sensitisation among histotechnologists after chronic exposure to formalin (18). A group of 15 histology technicians had subclinical statistically significant differences in nasal resistance. EU directives list sensitising substances. Respiratory sensitizers are required to be labelled with their R-phrases. Formaldehyde has an R-phrase R43 which means that it may cause sensitisation by skin contact. Significantly elevated odds of work-related asthma have been observed for exposure to formalin/formaldehyde in hospitals (19). A study of 34 workers in an anatomy laboratory revealed decreased pulmonary function (FVC and FEV₃) at formaldehyde exposures in the range 0.07– 2.94 ppm. Another study with 280 non-smoker histotechnologists with formaldehyde exposure showed small differences in the reduction of vital capacity during 4 years compared with non-exposed controls (20).

In 1997 the Industrial Health Foundation experts’ panel identified the occupational exposure limit for formaldehyde that would prevent irritation. The panel concluded that there was sufficient evidence to show that persons with asthma do not respond differently from healthy individuals following exposure to concentrations of up to 3.0 ppm. The panel could not identify a group of people who were hypersensitive, nor was there evidence that anyone could be sensitised (develop an allergy) following inhalation exposure to formaldehyde. Although cancer risk did not receive exhaustive evaluation, the panel agreed with other scientific groups who have concluded that the cancer risk of formaldehyde is negligible at airborne concentrations that do not produce chronic irritation (21). More details about the occupational exposure limits are presented in {SAF11}.

Higher rates of spontaneous abortion and low birth weight have been reported among children of women occupationally exposed to formaldehyde (15, 22).

A relatively low threshold of response and the disagreeable, irritating pungent suffocating odour of formaldehyde prevent one from breathing intolerable amounts of gas. Although in rare massive acute exposures victims have suffered pulmonary oedema and even death, such a situation is unlikely in the surgical theatre or pathological laboratory due to the relatively limited amount of formalin that is used.

There is a discrepancy between epidemiological statistical data and clinical observations. Neither otolaryngology nor other manuals mention formaldehyde as a possible aetiological or contributing factor to cancer. Nevertheless, regulatory agencies assume that formaldehyde is a potential occupational carcinogen that requires appropriate regulations

The search results for {SAF7} were used as the basis for this section. IP performed additional searches in PubMed and Google (10 March 2012) using the search terms, environment, ground water, endocrine disruptor, developmental toxin, reproductive toxin and cholinesterase inhibitor, combined with formaldehyde. No pertinent results were identified.

Further information was searched from EU Chemical agencies web page and the REACH (Registration, Evaluation, Authorisation and Restriction of Chemical Substances) web page. Starting in the late nineties new horizontal chemicals legislation was developed, and in 2007, REACH came into force. REACH’s primary aim is “to ensure a high level of protection of human health and the environment”. In the coming decade, REACH will place the burden of proof on industry, which must collect or generate the data necessary to ensure the safe use of chemicals. This data will be publicly available through the central database held at the European Chemicals Agency and will help to close the current information gap on chemicals. REACH also provides rules for phasing out and substitution of the most dangerous chemicals.

Since little was found in the above-mentioned sources, IP screened several MSDS for information on the ecotoxicity of formaldehyde.

T = Any procedure using formaldehyde

I = NA

C = NA

O = Environmental hazards

Formaldehyde 10%:

• ecotoxicity: not available
• BOD5 and COD: not available
• biodegradation: possibly hazardous short term degradation products are not likely; however, long-term degradation products may arise
• toxicity of the products of biodegradation:  they are less toxic than the product itself

Source: http://www.sciencelab.com/msds.php?msdsId=9925911

Formaldehyde 4 %:

• ecotoxicity: 96 h LC₅₀ 134 mg/litre rainbow trout; bacterial toxicity threshold (Pseudomonas putina) 14 mg/litre
• biodegradation: biodegradable in water; degradation half-life in daylight 3 h
• bio-accumulation: not bio-accumulative

Source: http://www.bio-techsolutions.ltd.uk/PDF/BufForm.pdf

Regarding toxicity to the aquatic environment, the following guidance is given on the disposal of formaldehyde waste. Place formaldehyde waste in a chemically compatible container with a sealed lid and label clearly. Complete a hazardous waste tag and call EH&S (486 – 3613). All biological materials preserved in formaldehyde must also be disposed of in this manner, not in medical waste containers. Drain disposal of dilute aqueous solutions containing formaldehyde is permitted to the limit of 100 g of solute per laboratory per day (for example, 1 litre of 10%formalin, or 10 litres of 1% formalin). This limit applies only as long as no other hazardous chemical is present in the solution.

Source: http://www.ehs.uconn.edu/Word%20Docs/Formaldehyde%20Hazards%20and%20Precautions.pdf

A search was done in PubMed by IP on 15 March 2012 using search string

• 3 Add Search (safety[Title/Abstract]) AND #2 >18 studies
• 2 Add Search (surgical pathology[Title/Abstract]) AND #1 246
• 1 Add Search quality[Title/Abstract] 449032

See {Appendix SAF-4}

T = all surgical pathology activities

I = interventions which improve quality and safety

C = NR

O = patient safety

Clinical practitioners play an essential role in error reduction through several avenues such as effective test ordering, providing accurate and pertinent clinical information, procuring high quality specimens, providing timely follow-up on test results, effectively communicating on potentially discrepant diagnoses, and advocating second opinions on the pathology diagnosis in specific situations (1).

An important component of improving patient safety is reducing medical errors. A step towards reducing the errors is their identification. Mislabelling occurred significantly less in study laboratories with continuous individual-case (one by one) accessioning and in laboratories with formal, documented quality checks at accessioning (5). Systematic monitoring and subsequent evaluation of various aspects of hospital and laboratory practices is suggested (See TEC and/or ORG domain for quality assurance).

A search was done by IP on 21 February 2012 in PubMed. Search strategy

• 23 Add Search (#22) AND #21 35
• 22 Add Search hospital[Title/Abstract] 550947
• 21 Add Search (#20) AND #17 1505
• 20 Add Search (#19) OR #18 546515
• 19 Add Search work[Title/Abstract] 483270
• 18 Add Search occupational[Title/Abstract] 79830
• 17 Add Search (#16) OR #15 39041 04:41:15
• 16 Add Search formaldehyde[Title/Abstract] 14641
• 15 Add Search formalin[Title/Abstract] 24748

The search yielded 35 articles {Appendix SAF-3}. The National Toxicology Program Final Report on Carcinogens 2010 was taken as the basis for carcinogenicity information. As there are sufficient EU sources for safety epidemiology and safety management, all guidelines prepared for the non-European context were excluded.

Information was also retrieved from web pages of manufacturers, the EU-OSHA, the draft NICE report 2012, the European Commission Joint Research Centre’s European Chemical Substances Information System (ESIS), and the WHO IPCS. As there is no free database for MSDS, the best way to find the data sheets is to Google MSDS and formaldehyde.

T = Any tissue sample requiring formalin fixation

I = Staff in surgical theatres and pathological laboratories

C = Procedures by which formalin is eliminated or substituted

O = Cancers, respiratory symptoms

The concentrations of formaldehyde and its metabolite in blood or urine have proven to be inefficient measures of exposure (13). Occupational exposure limits (OELs) are the major control instruments for workers’ exposure assessment and management. There are two types of OELs: atmospheric and biological, and two main legal levels: constraining (binding) and indicative. More information about national exposure limits and monitoring regulation, as well as possible statutory health surveillance can be found through the national Focal Points of the European Agency for Safety and Health at Work, which are official government-nominated representatives of EU-OSHA (http://osha.europa.eu/en/oshnetwork/focal-points/index_html).

Minimum requirements for the protection of workers from risks to their safety and health arising, or likely to arise, from the effects of chemical agents that are present at the workplace or as a result of any work activity involving chemical agents are presented in Directive 98/24/EC—risks related to chemical agents at work (http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CELEX:31998L0024:EN:NOT)

EU regulations* define the preventive measures at work places:

• assess the risk
• eliminate or substitute the agent
• prevent exposure
• inform and train workers
• monitor exposure and health problems
• record the findings
• consult workers or their representatives

see details in OSHA Factsheet http://osha.europa.eu/en/publications/factsheets/39

• Council Directive 98/24/EC of 7 April 1998 on the protection of the health and safety of workers from the risks related to chemical agents at work and
• Directive 2000/54/EC of the European Parliament and of the Council of 18 September 2000 on the protection of workers from risks related to exposure to biological agents at work.

Checklist for laboratory accidents http://osha.europa.eu/en/publications/e-facts/efact20

Eliminating exposure:

Several attempts have been made to find a substitute for formalin in hospitals and laboratories but all alternatives have failed (23). Another approach has been to change the work flow so that no formalin is needed in the surgical theatre and the samples are transported to the pathological laboratory for formalin fixation. This would reduce exposure to formaldehyde in the surgical theatre where advanced preventive and exposure limiting solutions, such as hoovers, are missing. A system using cooling and pressure-vacuum sealing of the fresh tissue sample in the surgical theatre before moving it to the pathology laboratory for formalin fixation has been used in a hospital in Turin. According to one before–after study, the quality of tissue conservation improved and the odds of having respiratory symptoms in surgical staff who used formalin fixation in the theatre was 12 times as large as that among staff who use the vacuum sealing method (24, 25).

Preventing exposure:

Several countries have their own standards for limiting exposure to formalin and monitoring procedures. The Industrial Health Foundation experts’ panel identified in 1997 an OEL that would prevent irritation. The panel concluded that for most people, eye irritation that is clearly due to formaldehyde does not occur below at least 1.0 ppm. Information from controlled studies involving volunteers indicated that moderate to severe eye, nose, and throat irritation does not occur for most people until airborne concentrations exceed 2.0–3.0 ppm. The data indicated that below 1.0 ppm, if irritation occurs in some people, the effects rapidly subside due to "accommodation." Based on the weight of evidence from published studies, the panel found that those exposed to 0.3 ppm for 4–6 h in chamber studies generally reported eye irritation at a rate no different than that observed when people were exposed to clean air. It was noted that at a concentration of 0.5 ppm (8-h time-weighted average [TWA]) eye irritation was not observed in the majority of workers (about 80%) (21).

Formalin spills are not that rare and they require attention. Material safety data sheets present protocols for avoiding spills. They should be stated in the laboratory’s standard operating procedures. The amount of formaldehyde gas that evaporates depends on the surface area, not the volume spilled, so the aim should be to minimise the surface area of the spill. Cleaning should therefore start immediately. A dike made of wet paper can be used to prevent the surface area of the formalin from increasing. A spill kit should be reserved, with disposable gowns, gloves, and safety glasses. Goggles and a wet mask should be worn while cleaning up. The wet mask should be changed often while it gets saturated with formalin. Ventilation should be increased and water taps left running to increase the humidity in the room. For irritation of the throat, milk or alkaline drinks are optimal for immediate drinking and gargling. Eye washing for some minutes with cold water after formalin splashing is obligatory and every histology laboratory must have an eyewash fountain.

Checklist for laboratory accidents http://osha.europa.eu/en/publications/e-facts/efact20

No studies that addressed this question were identified.

Please see the answer provided for assessment element question EFF6 (D0021): Did the results in uPA/PAI, MammaPrint®, or Oncotype DX tests in women diagnosed with early stage invasive breast cancer lead to changes in the treatment choice with adjuvant therapy and/or further imaging compared to standard practice?

uPA/PAI-1 test

No studies were identified that addressed this question for uPA/PAI-1 tests.

Oncotype DX test

Eleven observational studies were found for Oncotype DX that addressed the part of the question relating to the treatment choice with adjuvant therapy. Two of these had a prospective design (Table 1 in Appendix 5). Only one study measured changes in the decisions made by patients {22}.

No studies were identified for Oncotype DX that addressed the part of the question relating to changes in further imaging.

Overall, Oncotype DX influenced the physicians’ adjuvant treatment recommendations in 19%–51% of patients.

Lo et al. 2010 {22} conducted a prospective observational study in which patients and physicians served as their own controls, with observations made before and after the RS assay {22}. 67 (75%) patients, and 16 (out of 17) medical oncologists completed the 12-month follow up questionnaire. Physicians changed their treatment recommendation and actual treatment in 28 patients (31.5%) after RS assay results compared with their decision using standard clinicopathological prognostic factors (41 physicians [46%] also used Adjuvant! Online). The greatest change was from a pre-test recommendation of chemotherapy plus hormonal therapy (CHT) to a post-test recommendation of hormonal therapy (HT), which occurred in 20 cases (22.5%). RS assay results increased the physicians’ confidence in their treatment recommendation in 68 cases (76%), 14 (88%) believed that RS assay results influenced their treatment recommendation and all the physicians would use the RS assay again.

According to this study, 24 (27%) patients changed their treatment decision on the basis of the results of the RS assay. The greatest change was from CHT to HT with 9 (10.1%) patients changing their treatment decision from CHT to HT.

Henry et al. 2009 {25} presented the results of a prospective single centre, small sample size USA study in lymph-node negative patients on changes between the initial recommendation for or against chemotherapy and the actual administration of chemotherapy based on RS assay, compared with clinicopathological data and Adjuvant! Online {25}. RS results changed the panel’s recommendation in 7 cases (24%). Prior to RS testing, the expert panel recommended chemotherapy in 12 patients (41%) and hormonal therapy only (no chemotherapy) in 17 (59%) patients. Five of 12 initial recommendations in favour of chemotherapy were changed to against and two of the 17 initial recommendations against chemotherapy were changed to favouring chemotherapy when the test results were known. RS results altered the plan for chemotherapy in 9 patients (31%); 7 patients (54%) initially recommended for chemotherapy did not receive it, and 2 (13%) received chemotherapy following initial recommendations against it.

Seven of the studies found (Oratz et al. 2007, Asad et al. 2008, Ademuyiwa et al. 2011, Partin et al. 2011, Rayhanabad et al. 2009, Joh et al. 2011 and Kamal et al. 2011 {26–32}) were retrospective chart reviews and cross-sectional studies on medical oncologists in the USA. These studies investigated the effect on changes in the decision to use chemotherapy of using the Oncotype DX test compared with standard clinicopathological factors, clinical guidelines, or prognostic tools such as Adjuvant! Online and the Nottingham Prognostic Index {26–32}. All but one {31} used test results in lymph node-negative patients while Joh et al. {31} used results in both node-negative and -positive early breast cancer patients.

In the Oratz et al. 2007 {26} study, the oncologists changed the adjuvant treatment recommendation in 14 (20%) patients when they knew the RS assay results, compared with their recommendation based on commonly used prognostic factors alone. Of 68 patients, 17 (25%) received a different adjuvant treatment (HT vs. chemotherapy [CT]) from that recommended without knowledge of the RS assay results. For three patients who eventually received CT, the original recommendation was HT. Two of these three patients had a high RS.

Asad et al. 2008 {27} assessed the affect of the RS assay results on the reccomendation about chemotherapy administration compared with a presumed treatment recommendation based on the 2007 NCCN guideline. RS influenced the recommendation concerning chemotherapy in 37 (44%) patients; 4 patients with tumours <1.0 cm in size were advised to have chemotherapy, and 33 patients with tumours ≥1.0 cm in size were advised to undergo hormone treatment only.

Ademuyiwa et al. 2011 {28} analysed the impact of Oncotype DX testing on physicians’ recommendations about adjuvant chemotherapy and on the receipt of chemotherapy, compared with clinicopathological characteristics, Adjuvant! Online and the Nottingham Prognostic Index. Knowledge of RS assay results led to a change in management for 38% of women. Of the 188 patients who did not receive chemotherapy, 71 had a recommendation favouring chemotherapy from an oncologist who was blinded to the RS score. Of the 88 patients who received chemotherapy, 34 did not have a chemotherapy recommendation when the oncologist did not know the RS assay result.

Partin et al. 2011 {29} analysed the change in the decision to administer chemotherapy compared with a presumed treatment recommendation based on the 2007 NCCN guideline, St. Gallen Consensus Recommendations 2007, and Adjuvant! Online. Knowledge of RS assay results led to a change in management for 27% to 74% of women, depending on the guidelines used for comparison. According NCCN guidelines, seven patients who were deemed low risk should have received HT but five of them received CHT. 162 patients who were deemed high risk by NCCN should have received chemotherapy but 124 (77%) received HT. According to the St. Gallen recommendations, 32 patients who were deemed low risk should have received HT but 5 received chemotherapy. According to Adjuvant! Online, 92 patients were deemed low risk and should have received HT, but 20 of them received chemotherapy (22%). Of 16 patients who were deemed high risk by Adjuvant! Online, chemotherapy was used in 44%.

Rayhanabad et al. 2009 {30} assessed the change in physician management, based on RS assay results, compared with using traditional NCCN guidelines; 15 of 58 women (26%) had a change in their breast cancer management based on the gene assay results (P<0.05).

Joh et al. 2011 {31} analysed the impact of Oncotype DX  compared with clinicopathological data on chemotherapy recommendations. Including Oncotype DX RS data led to a change in the treatment recommendation in 24.9% of cases.

Kamal et al. 2011 {32} similarly analysed the impact of Oncotype DX compared with clinicopathological data on chemotherapy recommendations. In this study the Oncotype DX results led to a change in the treatment recommendation in 19% of cases. Based on clinical data without the Oncotype DX results, five oncologists recommended chemotherapy in 16%–23% of the 31 cases and one oncologist recommended chemotherapy in 52% of cases. When given the Oncotype DX results, the same five oncologists recommended chemotherapy in 10%–19% of the 31 cases, and the other oncologist recommended chemotherapy in 58% of cases.

Geffen et al. 2011 {33} conducted an  observational study on medical oncologists in Israel, looking at their treatment recommendations for node-negative and node-positive patients, after Oncotype DX test results compared with using clinicopathological features and Adjuvant! Online alone {33}. In 34 patients (25.2%, 95% confidence interval (CI) 17.9% to 32.5%), the recommendation for chemotherapy was changed after obtaining the assay result. Most changes (70.6%) were from chemotherapy to no chemotherapy. For 24 (17.8%) patients (95% CI 11.3% to 24.2%), the treatment recommendation was changed after receiving the Oncotype DX test results to hormonal therapy; while only 10 (7.4%) patients (95% CI 2.9% to 11.8%) had a treatment recommendation changed to chemotherapy (P<0.0001). 16 (11.9%) patients, chose not to accept the recommendations after the Oncotype DX test results, with 2 (1.5%) requesting chemotherapy after being recommended hormonal therapy alone and 14 (10.4%) patients refusing recommended chemotherapy.

Oratz et al. 2011 {34} performed a cross-sectional web-based survey on physicians in the USA investigating their treatment recommendations, for lymph node-positive patients, after receiving the Oncotype DX test results, compared with using clinicopathological data alone {34}. Out of 1017 invited oncologists, 232 accessed the survey but only 160 (16%) completed it. Of these 160 medical oncologists, 70 (51%) changed their recommendations after receiving the Oncotype DX test results. In 33%, the recommended treatment intensity decreased from chemotherapy plus hormonal therapy to hormonal therapy alone. In 9%, the treatment intensity increased from hormonal therapy alone to chemotherapy plus hormonal therapy and in 8%, the treatment recommendation changed in a way that did not fit the definition of either increased or decreased intensity.

Two observational studies of Oncotype DX are currently ongoing, one in France {35} and one in Canada {36} (Table 2 in Appendix 5).

The French study http://prsinfo.clinicaltrial.gov/ct2/show/record/NCT01446185?id=NCT01446185&rank=1 {35} aims to independently evaluate the adoption of this test for decision making in France, in the context of the local treatment guidelines and practices, and to provide data that are meaningful to the French health system and medical community.

The Canadian study, http://prsinfo.clinicaltrial.gov/ct2/show/NCT01423890?id=NCT01423890&rank=1 {36} is a prospective population-based cohort that aims to evaluate the adoption of this test for decision making in Ontario; one thousand eligible consenting women will have their tumour tissue specimen sent to Genomic Health where the Oncotype DX assay will be performed. The estimated completion date is December 2012.

MammaPrint test

Two studies (one with a prospective design) were found that assessed whether the results of the MammaPrint tests in women diagnosed with early stage invasive breast cancer lead to changes in the choice of treatment with adjuvant therapy compared with standard practice (Table 3 in Appendix 5).

No studies were found that addressed whether the results in MammaPrint tests in women diagnosed with early stage invasive breast cancer lead to changes in additional imaging compared with standard practice.

Using MammaPrint would have resulted in altered treatment advice in 13% to 40% of patients. There are currently no ongoing studies in clinical trials registers.

Bueno-de-Mosquita et al. 2007 {37} conducted a prospective community-based observational study in the Netherlands to analyse the effect of the prognosis signature on the use of adjuvant systemic treatment. They studied both changes in the adjuvant therapy advice given (recommendation) and changes in the actual adjuvant therapy received, compared with using the Dutch CBO (Centraal BegeleidingsOrgaan - Institute for Healthcare Improvement) guidelines alone, in 427 lymph node-negative patients{37}. Adjuvant systemic treatment were advised in 56 (13%) additional patients (when the prognosis signature was used in combination with the Dutch CBO guidelines for adjuvant systemic treatment advice compared with using the Dutch CBO guidelines alone); chemotherapy in six (1%) additional patients, endocrine treatment in 40 (9%) additional patients, and both in ten (2%) additional patients. These increases were mainly because 12% (50) more patients  received endocrine treatment (54 [13%] had endocrine treatment added, and four [1%] had endocrine treatment withheld).

Chemotherapy was added in 35 (8%) patients and withheld in 19 (4%) patients (net 16 (4%) patients had more chemotherapy). 83 (19%) patients received another adjuvant systemic treatment (combined Dutch CBO guidelines, prognosis signature findings, and patient’s preference compared with treatment advice based only on the Dutch CBO guidelines).

Gevensleben et al. 2010 {38} performed a retrospective chart review and a cross-sectional study in Germany to investigate the change in treatment advice using MammaPrint test results, compared with the St. Gallen criteria and Adjuvant! Online, in 140 lymph node-negative and -positive, early invasive, breast cancer patients {38}. Using the MammaPrint test would have resulted in altered treatment advice in 40% of patients. In 59 out of 62 patients with a poor prognosis signature identified by MammaPrint, the clinical treatment was recorded. Of these 59 patients, 19 (32%)  did not receive any adjuvant systemic treatment other than endocrine therapy and were potentially under treated. Of 77 patients who were classified as having a good prognosis by MammaPrint, and for whom treatment was known, 35 (45%) received chemotherapy and were potentially over treated.

Only one observational study that assessed patient quality of life was identified {22}. This reported the impact of using the Oncotype DX test on quality of life, in parallel with its impact on patient satisfaction (Table 1, Appendix 3).

Lo et al. 2010 conducted a prospective observational study in which patients and physicians served as their own controls; observations were made before and after the RS assay {22}. A total of 67 (75%) patients and 16 (out of 17) medical oncologists completed the 12-month follow-up questionnaire. Outcomes considered relevant to this question were: change in patient quality of life; change in patient satisfaction with the choice of treatment; change in patient anxiety; and change in patient decisional conflict. Patient quality of life was assessed using the Functional Assessment of Cancer Therapy, FACT-B, FACT-G survey. This was administered before and 12 months after the RS assay. To assess the impact of using the RS assay on the patient’s perceived risk of recurrence and satisfaction with the adjuvant therapy decision, differences in the results of questionnaires administered before ordering the RS assay, after the RS results, and at 12-month follow- up were compared. Changes in patient satisfaction were assessed by comparing the results of the questionnaire administered immediately after the RS results, with that administered 12 months after the start of study. Changes in decisional conflict were assessed by comparing results of the Decisional Conflict Scale (DCS) administered before and immediately after the RS assay results. Changes in patient anxiety were assessed by comparing the results of the State—Trait Anxiety Inventory (STAI) administered: before, immediately after and 12 months after the RS assay results.

The results indicated that patient quality of life remained stable when assessed using the Functional Assessment of Cancer Therapy (FACT-B: pre-RS mean 112.2 (SD = 17.4), 12 months post-RS 114.3 (SD = 18.6) P = 0.55; and FACT-G: pre-RS mean 88.7 (SD = 12.3): 12 months post-RS 87.6 (SD = 14.9); P = 0.49) {22}. State or situational anxiety (STAI) mean scores significantly decreased over time; from 39.6 (SD = 14.5) to 36 (SD = 12.6) and 34 (SD = 11.5); P = 0.007, as did decisional conflict (statistically significant decrease immediately post-RS; from mean DCS 1.99 (SD = 0.62) to 1.69 (SD = 0.50); p < 0.001).

Patient satisfaction immediately after the RS assay was as follows: 78 (95%) were glad they took the RS assay test; 77 (87%) understood how the assay works; 79 (89%) felt that the results were easy to understand; and 74 (83%) indicated that the results of the RS assay influenced their decision making. At 12-months after the RS assay (67 (75%) completed the 12-month questionnaire), 62 (92.5%) continued to feel satisfied that they had used the RS assay; 64 (95.5%) were satisfied with their treatment decision; and 54 (80.6%) continued to believe that the results influenced their treatment decision. Those patients (n = 5) not satisfied noted a negative impact on quality of life, treatment side-effects including aches, hot flashes, pain and mood alteration, and a negative impact on self image.

No studies that addressed this question were identified.

This question could only be answered indirectly for the Oncotype DX test.

Please see the answers and evidence tables in assessment element questions: EFF3 (D0012): What is the effect of adjuvant therapy on the basis of uPA/PAI-1, MammaPrint®, or Oncotype DX test results on health-related quality of life compared to treatment on the basis of standard practice?; and EFF14 (D0018): Would the patient be willing to use the technology again?

According to the results from Lo et al. 2010 {22}, patient satisfaction immediately post-RS assay was as follows: 78 (95%) were glad they took the RS assay test; 77 (87%) understand how the assay works; 79 (89%) felt that the results were easy to understand; 74 (83%) indicated that the results of the RS assay influenced their decision making. At 12-months post-RS assay (67 (75%) completed the 12-month questionnaire) 62 (92.5%) continued to feel satisfied that they had used the RS assay; 64 (95.5%) were satisfied with their treatment decision and 54 (80.6%) continued to believe that the results influenced their treatment decision.

Those patients (n = 5) not satisfied noted a negative impact on quality of life, treatment side-effects including aches, hot flashes, pain, mood alteration, and negative impact on self image.

According to results from Tzeng et al. 2010 and Richman et al. 2011 {23,24} most women (96%, 74/77) reported that they would have the test again if they had to decide today, and 95%, 73/77 would recommend the test to other women. In Richman et al. 2011 {24} most outcome data are duplicates of the data reported in Tzeng et al. 2010 {23}.

Two published articles on Oncotype DX test addressed the question “Would the patient be willing to use the technology again?”

A multicentre cross-sectional study was performed in the Netherlands using a questionnaire, and supplemented by retrospective medical chart review; in Richman et al. 2011{24} most outcome data are duplicates of those reported in Tzeng et al. 2010 {23}. Of 104 invited women (mainly lymph node-negative), 78 completed the survey and 77 were analysed. Most women (96%, 74/77) reported that they would have the test again if they had to decide today, and 95%, 73/77 would recommend the test to other women (Table 1 in Appendix 4).

This question could only be answered for the Oncotype DX test, indirectly, through results from the Tzeng et al. 2010 and Richman et al. 2011 articles {23,24}. In Richman et al. 2011 {24}, most outcome data are duplicates of those reported in Tzeng et al. 2010 {23}.

Please see the answer and evidence table provided in assessment element question: EFF14 (D0018): Would the patient be willing to use the technology again?

According to results from Tzeng et al. 2010 and Richman et al. 2011 {23, 24}, 95%  of women (73/77) agreed that the Oncotype DX test gave them a better understanding of the chances of success with their treatment options. A few women had concerns about the test: 8% (6/77) reported that they had the test only because other family members wanted them to; 5% (4/77) reported that having the test had a negative effect on their family; and 3% (2/76) agreed that this information about one’s cancer is better left unknown.

According to Richman et al. 2011 {24}, approximately 26% (17/65) of women agreed or strongly agreed that receiving the Oncotype DX test result made them worried and anxious. Greater test-related distress was associated with higher recurrence risk based on the test, as the majority of women who experienced test-related distress had intermediate or high recurrence risks based on their test results (low  = 18% (6/33); intermediate  = 30% (7/23); high = 44% (4/9)). Stronger feelings of distress were also related to receiving chemotherapy, not receiving radiation, and having more frequent worries about breast cancer recurrence.

No RCTs or prospective cohort studies on uPA/PAI-1, MammaPrint and Oncotype DX tests were found that assessed whether using these three prognostic tests (each test compared with standard/current practice or direct (head to head) comparison) to guide the use of adjuvant chemotherapy effectively improves long term clinical outcomes such as overall survival and disease-specific survival (for example: disease-free, progression-free, or recurrence-free survival)?

A few studies were found that did not satisfy the inclusion criteria and are discussed in the Domain discussion section.

In clinical trials registries the following trials were found: one ongoing RCT, the NNBC3-Europe trial, on the uPA/PAI-1 test; two RCTs, the TAILORx Trial and the WSG Plan B trial on Oncotype DX test; and one RCT, the MINDACT trial, on the MammaPrint test (Tables 1–3 in Appendix 2).

The aim of the NNBC3-Europe trialhttp://prsinfo.clinicaltrial.gov/ct2/show/record/NCT01222052?id=NCT01222052&rank=1 {18} is to compare the biological risk assessment using the uPA/PAI-1 test with a clinicopathological algorithm in patients with newly diagnosed node-negative breast cancer and to investigate whether high-risk node-negative patients should receive adjuvant chemotherapy with or without taxanes. The type of risk assessment used will be decided by each centre. Patients found to be at low risk will be observed. High-risk patients were randomised to one of the two adjuvant chemotherapies. The estimated completion date is February 2019.

The TAILORx (Trial Assigning Individualized Options for Treatment) trial http://prsinfo.clinicaltrial.gov/ct2/show/NCT00310180?id=NCT00310180&rank=1 {19} is a prospective clinical trial in which all patients undergo an Oncotype DX assay; if the RS is <11 patients will receive hormonal therapy alone. If the RS is >25, patients will receive chemotherapy plus hormonal therapy. If the RS is between 11 and 25, patients will be randomised to receive chemotherapy plus hormonal therapy (the standard treatment arm) versus hormonal therapy alone (the experimental treatment arm). The choice of the hormonal therapy and chemotherapy regimens will be at the discretion of the treating physicians and must be consistent with one of several standard options. The RS ranges differ from those originally described as low <18, intermediate (18–30) and high risk >30 for the assay. The estimated primary outcome completion date is April 2014.

The WSG Plan B trial is a randomised comparison of adjuvant docetaxel/cyclophosphamide with sequential adjuvant EC/docetaxel chemotherapy in patients with HER2/Neu-negative early breast cancer, http://prsinfo.clinicaltrial.gov/ct2/show/NCT01049425?id=NCT01049425&rank=1 {20} Classification of patients will be by Oncotype DX test results (in addition, optional uPA/PAI-1 may be done). Low-risk patients, with RS≤11 will receive hormone therapy alone. High-risk (including intermediate) patients, RS>11, will be randomised to two chemotherapy arms: epirubicin/cyclophosphamide followed by docetaxel or docetaxel/cyclophosphamide. The estimated primary outcome completion date is October 2016.

The MINDACT (Microarray In Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy) trial http://prsinfo.clinicaltrial.gov/ct2/show/NCT00433589?id=NCT00433589&rank=1 {21} is the first prospective, randomised study comparing the 70-gene signature with the common clinicopathological criteria in selecting patients for adjuvant chemotherapy in breast cancer with 0 to 3 positive nodes. All eligible women undergo a MammaPrint assessment and a traditional clinicopathological risk assessment, performed using a modified version of Ajuvant! Online.

Women with both clinical and genomic high risks are offered adjuvant chemotherapy; women with both clinical and genomic low risks do not receive chemotherapy; women with discordant risk are randomised for the decision of adjuvant chemotherapy based on clinical or genomic risk. All patients are candidates for adjuvant chemotherapy and are offered a non-mandatory second randomisation between an anthracycline-based regimen and docetaxel/capecitabine therapy. All ER-positive women may be offered a non-mandatory endocrine therapy randomisation between 7 years of letrozole and 2 years of tamoxifen following 5 years of letrozole. The estimated primary outcome completion date is March 2019.

No RCTs or prospective cohort studies on uPA/PAI-1, MammaPrint and Oncotype DX  tests were found that addressed how does treatment with adjuvant therapy on the basis of the test results of uPA/PAI-1, MammaPrint and Oncotype DX compared with treatment on the basis of standard practice in women diagnosed with early stage invasive breast cancer modify the magnitude and frequency of morbidity.

Please see the answer provided in the Assessment element question: EFF9 (D0025): What is the effect of adjuvant therapy on the basis of uPA/PAI-1, MammaPrint, or Oncotype DX test compared to treatment on the basis of standard practice in women diagnosed with early stage invasive breast cancer on overall survival and disease specific survival (for example: disease-free-, progression free-, recurrence-free-survival)?

No RCTs or prospective cohort studies on uPA/PAI-1, MammaPrint  and Oncotype DX tests were found that addressed how treatment with adjuvant therapy on the basis of the test results of uPA/PAI-1, MammaPrint and Oncotype DX  tests compared with treatment on the basis of standard practice in women diagnosed with early stage invasive breast cancer improves patient morbidity.

Please see the answer provided in the Assessment element question:

EFF9 (D0025): What is the effect of adjuvant therapy on the basis of uPA/PAI-1, MammaPrint or Oncotype DX test compared to treatment on the basis of standard practice in women diagnosed with early stage invasive breast cancer on overall survival and disease specific survival (for example: disease-free-, progression free-, recurrence-free-survival)?

Studies extracted from the basic literature search were analysed. Data from eight studies {1; 2; 3; 4; 5; 7; 8; 9} were found to be relevant to this question. The ORG and TEC domains also provided information relevant to this question.

None

Taking into account the outcomes described in the scope, the resources to be included in the analysis extend beyond those used in the diagnostic process.

Depending on the patient’s risk of recurrence, early invasive breast cancer may be treated, after primary surgery, with adjuvant chemotherapy to prevent or delay distant recurrence {1; 2}. The introduction of prognostic tests that assess the likelihood of breast cancer recurrence {TEC domain} could change the probability of using adjuvant chemotherapy to treat invasive breast cancer. Thus the use of prognostic tests will change the costs associated with treatment and the downstream costs of dealing with any cancer recurrences. It is important to include all the resources used and their costs. The resources used were identified from four main studies {2; 3; 4; 5}.

According to Chen et al. {6} after patients are divided according to risk profiles, they can be assigned to different treatment scenarios: chemotherapy plus endocrine therapy for oestrogen (ER)-positive, high-risk patients; chemotherapy alone for ER-negative, high-risk patients; endocrine therapy alone for ER-positive, low-risk patients; and no adjuvant therapy for ER-negative, low-risk patients. Anti-HER2 (human epidermal growth factor receptor 2) agents (e.g trastuzumab) can be added to chemotherapy depending on the risk classification and HER2 status {3}.

Table 1. Resources identified

Since few studies have a well-described coverage of the costs included in the model, further information about the resources used in the treatment decisions and treatment of women diagnosed with early invasive breast cancer would be needed to provide an appropriate economic evaluation.

Selected studies extracted from the basic literature search were analysed. Eight studies {1; 2; 3; 4; 5; 7; 8; 9} were found to be relevant to this question.

The quantity of resources used, excluding the resources associated with the delivery of the prognostic tests, will be highly dependent on the distribution of patients over the risk profiles and on the distribution of the duration in each of the different health states. Thus the amount of resources used, after the risk of recurrence profile distribution (using the prognostic tests or standard of care), will need to be modelled separately for each of the treatment scenarios and patient health states.

A number of the studies selected and analysed describe the quantity of resources used in their models {2; 3; 4; 5}. These estimates of resource utilisation were based on different sources of information including treatment guidelines, observational studies, and retrospective studies leading to different estimates of overall resource utilisation in different studies.

This variability, based on the inconsistency of the data, could be reduced with further high quality evidence from randomised controlled trials (RCTs) as discussed in the EFF domain.

Due to the limitations referred to in the domain introduction, the objective here is to prepare a rough description of the structure of an economic evaluation. It was not considered appropriate to present the unit costs for each resource identified.

The studies selected and extracted from the basic literature search were analysed. Eight studies {1; 2; 3; 4; 5; 7; 8; 9} were found to be relevant to this question because they had a chapter dedicated to costs.

The majority of the studies that were found to be relevant did not present the unit costs by resource but instead provided only the total cost of the identified resource. Additionally, costs can vary from region to region and are not transferable to national HTA production.

Due to the limitations referred to in the domain introduction, the objective here is to prepare a rough description of the structure of an economic evaluation. It was not considered appropriate to present the unit costs for each resource identified.

Selected studies extracted from the basic literature search were analysed. Only two economic studies {1; 7} were found to be relevant to this question.

The study perspective selected in the scope—societal perspective—requires consideration of the inclusion of indirect costs in the model.

It is known that both chemotherapy treatment, mainly its adverse effects, and cancer recurrence can generate productivity loss in active women. Only two of the studies referred to indirect costs and they did not consider the inclusion of productivity losses due to the perspective adopted (payer’s perspective) {1; 7}.

The use of prognostic tests is expected to have a positive impact on indirect costs if, from its utilisation, there is a resulting decrease in the utilisation of chemotherapy and a decrease in cancer recurrence. There is not enough high quality evidence to assess this impact.

Further evidence development is needed to address this question.

Analysis of selected studies extracted from the basic literature search.

According to the EFF domain, there is insufficient high quality evidence to assess the effectiveness of the intervention. Without this information, it is not possible to calculate the incremental effects.

More information on this topic can be found in result cards RC-EFF9, RC-EFF10, RC-EFF11, RC-EFF13.

Further development of high quality evidence from RCTs on effectiveness is needed as discussed in the EFF domain.

An analysis of the selected studies extracted from the basic literature search was performed. Seven economic studies {1;2;3;4;5;6;9} were found to be relevant to this question.

The societal perspective was adopted. A decision analytic model followed by a Markov model was designed to evaluate the cost-effectiveness/cost-utility of prognostic tests compared with standard care as defined in the scope. The model was based on information included in the literature {1;2;3;4;5;6;9} and from the TEC domain.

The model addresses the evolution of early invasive breast cancer in women and compares the costs and outcomes in terms of QALYs (expected Quality Adjusted Life Years) for a patient’s lifetime. A simplified presentation of the decision model is shown in Figures 1 and 2.

The two initial branches of the decision tree represent a choice between the use of a prognostic test (uPA/PAI-1([FEMTELLE], Oncotype DX or MammaPrint) and the use of standard care (St Gallen consensus recommendations, NCCN, Adjuvant! Online or NPI) to stratify the women with early invasive breast cancer as at high or low risk of having distant recurrence. The probability distribution should be drawn from the literature, preferably from RCTs. The selection of treatment will also depend on ER status.

After this stratification there are four different treatment scenarios: chemotherapy plus endocrine therapy for patients who are ER-positive and at high-risk of recurrence; chemotherapy alone for ER-negative, high-risk patients; endocrine therapy alone for ER-positive, low-risk patients; and no adjuvant therapy for ER-negative, low-risk patients. Anti-HER2 agents can be added to chemotherapy depending on the risk classification and HER2 status {3}. Branches that include chemotherapy lead to subtree 1 via a chance node that considers the existence of toxicity associated with chemotherapy.

The Markov model shows the clinical after adjuvant therapy with 3 stages modelled. The structure of the Markov model is the same for all the “M” nodes but the transition probabilities and state utilities differ depending on each branch.

Figure 1 – Decision tree analysis

Figure 2 – Markov model

The objective here is only to present a rough description of the model. The necessary cost and outcome data were not collected and the model was not constructed or run. The quantity of resources used should be drawn from the literature, namely RCTs. The unit costs should be collected from national or regional data sources. The outcomes should also be drawn from the literature, namely RCTs.

It is necessary to investigate the impact of uncertainty in the model input parameter values. The most important values to explore on sensitivity analyses are the values of the probabilities used, mainly the ones related to the definition of high and low risk of recurrence. Also, the cost of adjuvant chemotherapy because these costs vary depending on the type of regimen used {8} and the utility values are important parameters to examine with sensitivity analysis.

Due to the lack of quality evidence to identify the effectiveness of the interventions {EFF domain} it was not possible to identify the cost-effectiveness ratio.

A rough description of an appropriate economic evaluation was created in case clinical effectiveness data becomes available in the future.

It is important to keep in mind that cost-effectiveness ratios are usually not directly transferable between countries because the values, in particular the cost values, included in the model may vary by nation or region. However, the model structure presented here could be used by changing the input data to reflect the situation locally.

uPA/PAI-1, Oncotype DX^®  and MammaPrint^® are prognostic tests for the prediction of risk of breast cancer recurrence and, thus, for treatment decision making. They are applied in the decision about chemotherapy in lymph node negative cancers. The effects of the tests on the clinical outcome can be either avoiding unnecessary chemotherapy as well as its side-effects or by employing it where it might not otherwise have been used, thereby reducing recurrence risk.

The presented tests aim to improve the risk stratification based on clinical and pathological factors but are currently experimental although commonly used in clinical practice by academic and community oncologists. So they would be an add-on to standard modes of diagnosis and care based on clinicopathological criteria (such as age, tumour size, type, grade, and histological characteristics, HER2 status, hormone receptor status, menopausal status and lymph node status), but we have found no direct evidence to suggest that, at the moment, these tests are actually an add-on to standard mode of diagnostic/care. The intended use of these three tests, and the data about their performance, are different. First of all, the data available relate mainly Oncotype DX and MammaPrint, while there are few data on uPA/PAI-1. In the absence of a gold standard or reference technology, no estimates are available for analytic false positive or false negative rates {2, 3, 4}.

The performance of all three of these assays as prognostic tests is very similar. Level 1 evidence has been achieved for the Oncotype DX and uPA-PAI-1 assays for their roles as predictive as well as prognostic tests. MammaPrint is the first FDA-approved gene-expression-based assay to be used as a prognostic test for women with node-negative breast cancers. Therefore these tests may be considered as an adjunct to clinical and pathological information and have been incorporated into clinical guidelines in the USA. Direct evidence from randomised clinical trials is lacking and therefore their clinical utility is mainly in risk prognostication while more data are needed to validate their predictive value for selecting the best adjuvant chemotherapy. Despite many gene-expression profiling studies in neo-adjuvant settings, no one has been able to develop a robust predictive marker for a specific chemotherapeutic agent or specific combination regimen. However this does not mean that gene expression profiles cannot be used to provide clinically useful guides for chemotherapy {4}. It is clear that these tests have the potential to change the prognostication and treatment options for patients with breast cancer.

Studies about changes in clinical management using these test (in practice for the Oncotype DX test only) are minimally informative, because they do not specify the information actually given to the patient or how clinicians combine test results with other risk factors to limit or expand therapeutic choices. Changes in adjuvant systemic chemotherapy recommendations have been demonstrated in 21–74% of cases with addition of the 21-gene recurrence score (Oncotype DX test) compared with standard guidelines alone (the NCCN guidelines, or the St.Gallen Consensus Statement or The Adjuvant! Online). In the majority of cases, the change in treatment recommendations included a shift from chemotherapy and hormonal therapy to hormonal therapy alone in patients with low 21-gene recurrence scores, irrespective of their categorisation by traditional guidelines {5,6, 7, 8, 9}. It is not possible to determine, however, whether documented changes in management are due to compliance with the physician recommendations, and weighing of risks and benefits, or reflect the effects of test marketing.

So, at this time, strong claims cannot be made about the clinical value of these assays and their potential superiority over standard clinico-pathological parameters alone {10, 11, 12, 13, 14, 15}.

These trials should provide clinicians with fundamental, probably definitive, information regarding the clinical utility of these tests.

Not applicable for specific ethical issues. For social arrangements, see the Social domain of this report.

Two points should be highlighted: firstly, from the justice point of view, there are ethical considerations because moving resources into unproven technologies such as these tests, which have a prognostic function (and the link between the test and both distant recurrence and overall survival are not well understood), may affect the access of other breast cancer patients to chemotherapy. Secondly, there may be opportunity costs for other breast cancer patients in terms of lost opportunities to develop other prognostic tests for this other patient group that might prove to be better. These tests could be diverting research resources and expertise away from other tests and treatments that may prove more useful.

These tests are applied for potentially “fragile” patients, if they are affected by breast cancer and the tests are used to evaluate the possible recurrence of the pathology. For the social impact of the patient’s vulnerability see also the Social domain of the Report.

It is possible that the harms associated with chemotherapy among women who will not have a distant recurrence outweigh the benefits of chemotherapy among women who are destined to have a distant recurrence. These recurrence risk tests may also correctly recategorise women who were determined to be at high risk using existing risk indicators as being at low risk for recurrence. It seems plausible that more women will benefit (i.e., avoid unnecessary chemotherapy), but there is the potential for significant harms among a small number of low or intermediate risk women (who might have benefited from chemotherapy), possibly resulting in breast cancer recurrence or death. There are currently insufficient data to confidently estimate these risks and benefits. In addition, it is difficult to determine what proportion of women with moderate to high risk, based on conventional risk assessments, will have “low enough” recurrence scores in the prognostic tests to affect their decision about chemotherapy.

It has been suggested, in a small retrospective study {16}, that a differential benefit may arise from chemotherapy in the low and moderate risk groups.  If this were substantiated by further evidence then the relative benefit for the low and moderate risk groups would be relevant in the ethical analysis.

Moreover, some data on the technical performance of assays were identified for Oncotype DX and MammaPrint tests (not sufficiently for the uPA/PAI-1 test), though estimates of analytic sensitivity and specificity [respectively the capacity that the test will be positive if the genetic variant is present and negative if it is absent {17}] could not be made. Based on the reported rates of testing failures related to sample quality, pre-analytic issues related to sample preparation, transport, and processing should be addressed in routine practice {18}.

In the absence of a gold standard or reference technology, no estimates are available for analytic false positive or false negative rates. Knowledge of the risks of the analytic false positive or false negative rates are fundamental for clinicians’ and patients’ decision making.

So, one big limitation of these new tests is that their biological basis and clinical implications for treatment are just now beginning to be well understood. In this initial stage of the introduction of the tests, which can span many years, patients and clinicians will face difficult decisions about how to integrate potentially discordant information from the standard methods for deriving information about patients and the new genomic tests. Some women may not fully understand and may be reluctant to forgo chemotherapy when genomic tests indicate low recurrence risk but standard criteria suggest high recurrence risk. Research is needed to find out how women understand and use the risk information and investigate tolerance levels for risk in decision making.

This highlights the potential need for clinicians to take added care in explaining the benefits and the risks of genomic testing for breast cancer recurrence risk, especially issues surrounding conflicting test results {19}.

The purpose of the tests being evaluated is to replace or supplement prognostic guidelines and tools in current use, such as Adjuvant! Online. These involve cut-off values for risk classification which provide a gateway to further treatment or advice. Cut-off values are based on scientific evidence but their implementation affects the stage at which patients access treatment, as well as the overall number being treated. They therefore involve normative concerns beyond the clinical evidence on which they are based that are rarely explained transparently to patients. Implementing a cut-off value in a new group of patients, or a new cut-off for an existing group, may change the traditional professional approach of clinical staff, for example by causing them to deny treatment to individual patients who do not fall into the right risk category.  

These new tests raise the question of the extent to which patients are prepared to participate in informed decision making about their care.

Information about the risk of breast cancer recurrence from these tests should play a significant role in women’s breast cancer treatment decisions. One study using data from existing risk indicators showed that reducing the risk of dying from breast cancer by even 0.5% to 1% would make adjuvant chemotherapy acceptable to patients {20}. Breast cancer patients often do not understand basic information about their prognosis, including their risk of recurrence {21}. Many women even have difficulty in understanding  their risk of breast cancer {22} even after risk counselling {23}. There are few studies that indicate whether patients understand genomic tests and their results adequately to be informed decision makers when using them.

In one study assessing interest in genomic tests to determine the risk of recurrence of breast cancer in women previously treated for early-stage breast cancer {24}, most participants indicated that they would have been interested in this genomic testing. The women stated that they preferred an active role in decision making about treatment and would have wanted the results incorporated into treatment planning. In this study a scenario, less likely to happen in practice, such as a physician’s recommendation to have chemotherapy in response to a test result that indicated a low risk of recurrence was also used to elicit participants’ reactions to a situation that presented conflicting information. The results underscore the considerable weight that participants placed on their physicians’ recommendations and the importance of patient education about how clinicians incorporate genomic risk of recurrence information into decision making about treatment. Indeed, the value placed on testing by the physician, and how this is conveyed, will likely be critical to patients’ decision-making processes.

However, among early-stage breast cancer patients who received Oncotype DX, it seems that there is low knowledge about many aspects of genomic recurrence risk testing. Few patients understood that the test shows the likelihood of metastasis assuming additional treatment and does not provide information about the familial risk of breast cancer {25}.

One potential reason for misunderstanding risk is low health literacy. The U.S. Department of Health and Human Services defines health literacy as “the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions” {26}. Some studies show that health literacy is fundamental to women’s understanding and capacity to learn about the new breast cancer recurrence risk genomic tests as well as their desire for active participation in medical care: women with lower health literacy recalled less of the information provided about the recurrence risk test than women with higher health literacy. Health literacy was not related to the amount of additional information women desired. Women with higher health literacy preferred to have a more active role in decisions about the test. Health literacy may affect women’s capacity to learn about the new genomic tests as well as their desire for informed participation in their medical care {27, 28}.

Given the possible misinterpretation of specific (genomic) terminology as well as less specific terminology (e.g. “not done”, “not interpretable”) {29}, it is imperative that more attention should be paid to information issues in this field. Studies show that most patients prefer to be involved in medical decisions that affect their care {30,31} and that patients who are active participants in their medical decisions are better adjusted psychologically; they report being more satisfied with their decisions, and are more likely to adhere to their treatment regimens {32, 33, 34}. These new tests raise important new issues for the clinicians about how to communicate with patients about their recurrence risks.

Acknowledgement by clinicians of the potential problems and subsequent clarification of any misconceptions should prevent or relieve patients’ anxieties and help them to cope with the situation.

Therefore, in addition to giving us insights into their understanding of this new procedure, the participants in a study also provided insights into the ways clinicians may be able to help them. Two specific points in particular that need to be improved in clinical practice emerge. Firstly, healthcare professionals should explain to patients the difference between genomic signatures and genetic testing, and should emphasise that the analysis focuses solely on the tumour genes and has nothing to do with whether or not the disease is hereditary. Secondly, the disclosure of “not done” and “not interpretable” results should be handled with care because of the potentially negative implications of these terms. Physicians should explain that these expressions refer to technical problems that have arisen, and not to the tumour itself. Improving the quality of the information with which patients are provided about these new methods – by taking more time to explain what they involve, favouring discussions and eliciting feedback from the patients – will enable them to play an active role in the decision-making process about their treatment and ensure that those who agree to have gene analysis performed on their tumours are satisfied with the procedure {26}.

These findings have practical implications. When communicating recurrence risk test information to patients, clinicians and others health professionals should pay attention to patient health literacy and numeracy, and perhaps adjust the delivery of and time spent on communication of risk information to patients.

Not Applicable.

Not applicable.

In this context, clinical utility is the likelihood that using a gene expression profiling test to guide management in patients with diagnosed early-stage breast cancer will significantly improve health-related outcomes. Clinical utility is assessed by investigating the balance of benefits (reduced adverse events due to low-risk women avoiding chemotherapy) and harms (cancer recurrence that might have been prevented) associated with the use of the test, compared with the use of alternative management strategies.

No direct evidence links use of the MammaPrint test to clinical outcomes.

No studies evaluated the capacity of MammaPrint to predict benefit from other treatments (e.g., chemotherapy).

No studies determined whether use of MammaPrint in place of, or in addition to, current clinicopathological approaches (e.g., Adjuvant! Online, St. Gallen) changes management, and/or improves outcomes based on management with clinicopathological markers alone.

Retrospective analysis of one arm of a prospective clinical trial showed that the chemotherapy benefit in ER-positive, node-negative patients, randomised to tamoxifen or to tamoxifen plus chemotherapy, was most convincing in women in the Oncotype DX RS high-risk category (27% reduction in 10-year recurrence rate) {35}.

Many persons would likely have been offered chemotherapy without testing, but test results may influence patient–clinician decision making. This study provided the strongest evidence available addressing the clinical utility of the Oncotype DX test, but the study design was not optimal and prospective confirmation of these findings is needed. Three quarters of Oncotype DX results are in the intermediate and low risk ranges, where estimates of recurrence risk have wide and overlapping confidence intervals, and evidence of benefit provided by chemotherapy is inadequate to make decisions. The TAILORx trial will focus on these result groups, {37} but results will not be known for some time.

No direct evidence was found that links the use of the uPA/PAI-1 test to clinical outcomes.

Direct evidence was not found linking any of the three tests to improved outcomes, but there are studies about the components of clinical utility that might provide indirect evidence for clinical utility. There is encouraging indirect evidence for Oncotype DX, and plausibility for potential use of MammaPrint and, possibly, the uPA/PAI-1 test {36, 37, 38, 39, 2, 4}.

It seems plausible that more women will benefit (i.e., avoid unnecessary chemotherapy), but there is the potential for significant harms among a small number of low or intermediate risk women (who might have benefitted from chemotherapy), possibly resulting in breast cancer recurrence or death. There are currently insufficient data to confidently estimate these risks and benefits. In addition, it is difficult to determine what proportion of women with moderate to high risk based on conventional risk assessments will have a “low enough” score to affect their decision about chemotherapy.

Not Applicable. See also the results of RC-ETH11.

Up to now, through the available studies, it is not possible to evaluate the consequences of using these tests on a large scale, within a healthcare system, because the clinical efficacy data are still insufficient and still heterogeneous for these three tests. In addition, the three tests so far have probably had different frequencies of use in the USA and Europe. Moreover, among the economic analyses that have been conducted on these assays, almost all of them involve the Oncotype DX test; only one study examined MammaPrint, and one study compared directly the cost-effectiveness of Oncotype DX and MammaPrint {40, 41, 42, 43, 44, 45, 46, 47, 48}. The use of these gene expression profiling tests for early-stage breast cancer may have significant effects on patient outcomes, medical services use, and costs. These tests may potentially contribute to higher quality, more efficient care and reduce rising healthcare expenditures. A key challenge for patients with breast cancer and their healthcare providers, while making treatment decisions, relates to the decision to use or forego adjuvant chemotherapy. Chemotherapy is expensive for payers and healthcare systems and it can produce significant side-effects (e.g., myelosuppression and permanent ovarian failure), which may have a substantial impact on quality of life. Thus, assessing the outcomes, use, and costs associated with these genomic diagnostic tests is critical for future clinical and health policy decision making as well as for future applications in healthcare systems.

The few available studies suggest that, although both Oncotype DX and MammaPrint are costly and have high incremental cost-effectiveness ratio (ICERs), it is reasonable to presume a willingness to pay for testing strategies that are likely to yield reduced expenditures for payers, health systems, patients, and society in the long term.

Unfortunately, however, these studies are at an early stage, so inconclusive.

From the point of view of justice within the healthcare system, it is not reasonable to deny resources to populations on the basis of unproven new treatments. In particular the uncertain correlation between these tests and both distant recurrence and overall survival, plus their relatively high ICER mean that other more effective treatments may need to be foregone in order for patients to access these tests.

Not Applicable.

Not Applicable.

We refer to the Legal domain of the present report.

The body of evidence on the three marketed gene expression tests for breast cancer prognosis show that these tests have considerable potential for improving prognostic and therapeutic prediction. It also provides valuable lessons about the complexity of evaluating such tests {1} . Because the role of the genes included in these tests in determining prognosis is not completely understood, it is often unclear which clinical or tumour characteristics are being measured. Intrinsic tumour aggressiveness, ability to metastasise, and responsiveness to treatment (hormonal, radiation, or chemotherapy) — each of which might involve different genes — could determine prognosis.

However, the characteristic to be assessed in a particular study must often be inferred from the treatment, tumour, and clinical characteristics of the study population. Results from populations that are clinically and therapeutically heterogeneous might not be optimal in determining the prognosis or risk for a particular woman. Endpoints also varied. Survival was defined in the studies as disease-free, distant recurrence-free, or overall, measured at 5 or 10 (or more) years. Predictive strength varied considerably depending on which endpoint the test was optimised for.

Finally, performance of the underlying gene signature is not necessarily identical to the marketed test, because many test procedures, including pretest sample preparation and transport, can differ. It is therefore critical to pay close attention to the test description, population, and endpoints for each study to understand which studies are mutually supportive, which are adding qualitatively different information, and to whom they apply {2} . Despite the clinical novelty of these tests, their development must follow the same principles and procedures as those for any multivariate clinical prediction rule. These principles are outlined in detail in the clinical literature {49,50} and have been agreed on in reporting guidelines {51} and articulated with respect to expression-based predictors in various review articles {52, 53} .

There is limited evidence about the laboratory procedures used for these tests, including information about their reproducibility {54, 55}. Concerns have been expressed about the potential influence of several factors on the performance of these tests, such as intra-tumour molecular heterogeneity, warm/cold ischaemia time, fixation and processing using formalin fixed tumour tissue, and influence of biopsy cavity {2, 3, 4}.

More studies are available that assess the analytic performance of the Oncotype DX and MammaPrint tests, though additional data on some points (e.g. impact of variability on risk classification) are needed. Since all three of the prognostic tests are proprietary (single clinical source), and external proficiency testing is not available at this time, reporting by the laboratories of quality control/ quality assessment protocols and analytic performance data would provide additional information for clinicians and patients {18}.

The domain methodology was used for this question (analysis of selected studies extracted from the basic literature search). Three articles were found to be relevant to this question. Information provided by the manufacturers to the HTA was also reviewed.

uPA/PAI-1 and FEMTELLE

For the purposes of this HTA, the uPA/PAI-1 test may be analysed in three ways:

1. The FEMTELLE test may be analysed in a laboratory recommended by the manufacturer.
2. The FEMTELLE test may be analysed in a laboratory that meets the quality standards recommended by the manufacturer.
3. A generic (“home brew”) uPA/PAI-1 test may be developed and analysed in a laboratory to its own standards.

All of the literature refers to the generic uPA/PAI-1 test rather than to the brand FEMTELLE. Unless specified otherwise, the information which follows therefore relates to the generic uPA/PAI-1 test and may not apply to FEMTELLE. It may also not apply consistently to the uPA/PAI-1 test since processes may differ from one laboratory to another.

Obtaining tissue samples

Tissue may be obtained from surgical specimens or from core needle biopsies for Oncotype DX® {1}, MammaPrint® {2} and uPA/PAI-1{3}. It is possible that the uPA/PAI-1 test can only reliably be carried out on tissue from surgery rather than core biopsy tissue {4}. Care must be taken in obtaining the samples in accordance with the manufacturer’s instructions (see RC-TEC13 for more details).

Preserving tissue samples

MammaPrint uses fresh-frozen tissue, tissue preserved in an RNA preservative solution, or formalin- fixed paraffin-embedded (FFPE) tissue. Oncotype DX uses FFPE  breast cancer tumour tissue. The uPA/PAI-1 test, including FEMTELLE, requires fresh-frozen tissue. {RC-TEC2, RC-TEC3, RC-TEC4}

If one particular tissue collection and preservation system is normally used in the clinical setting, use of a test that requires a different system will have an impact on work flows.

Impact on clinical communication and cooperation

Use of these tests may require some additional forms of communication and cooperation between hospital units, outpatient services and hospital structures. There is more detail on this in question ORG3 below.

Impact on patient flow

Tissue samples for Oncotype DX and MammaPrint must be sent to a central laboratory for processing. This may have implications for patient flow as the results are received in 10–14 days (Oncotype DX) or 7–10 days (MammaPrint). If the FEMTELLE test is analysed in house according to the manufacturer’s instructions, this takes two days. If it is sent to a designated laboratory for processing the results should be received in 3–4 days {COL-2}. There is no information in the literature about the time taken to process generic uPA/PAI-1 tests, but reasonably this could be variable.

There is more detail in question RC-ORG3 below about the impact on patient communication of introducing the tests.

The literature contains little information on the work flow and patient flow impact of using these tests. Some points that were made in the literature are summarised above. However, since quality criteria have not been applied to these studies (see domain methodology), the real impact of these points on work and patient flows is unknown.

Analysis of selected studies extracted from the basic literature search. Two articles were found to be relevant to this question.

MammaPrint

MammaPrint must be analysed exclusively by the manufacturer’s laboratory so no special staff, training or other human resources are needed within the centres, other than pathologists for the specimen preparation. Sample isolation and preparation must be performed by pathologists in the proper way, following the instructions of the manufacturer. Specimen preparation requires either fresh, fresh-frozen or FFPE tissue. {RC-TEC2, RC-TEC3, RC-TEC4}

In the logistics pilot study preceding the MINDACT trial {5} training activities were performed before introducing the 70-gene prognosis-signature into daily clinical practice. The study coordinator organised on-site instruction meetings in each participating hospital. These instruction meetings were attended by a multidisciplinary team, i.e. breast surgeons, medical oncologists, pathologists, data managers and research nurses. During this instruction visit, the logistical scheme was discussed and incorporated into the local standard procedures. Additionally, all study-specific standard procedures were explained in detail in a manual of operations and were summarised on provided pocket summaries, to support standardised procedures for tissue collection, freezing and shipment. The authors highlighted that training and repetition are very important to avoid sample failure and to achieve the balance between a sufficient amount of tumour cells and a limited amount of stromal tissue. {5}

Oncotype DX

Oncotype DX must be analysed exclusively by the manufacturer’s laboratory so no special staff, training or other human resources are needed within the centres, other than pathologists for the specimen preparation. Sample isolation and preparation must be performed by pathologists in the proper way, following the instructions of the manufacturer. The pathologist must be able to select the appropriate tumour block for Oncotype DX, given that results should reflect the invasive component of the tumour. Specimen preparation requires FFPE tissue. {6, RC-TEC4}

uPA/PAI-1 and FEMTELLE

If FEMTELLE is analysed in the centre’s own laboratory, the staff must be trained to an appropriate level (see RC-TEC13 or RC-ORG5 for more details). If the samples are sent to a laboratory recommended by the manufacturer, no special staff, training or other human resources are needed within the centres, other than pathologists for the specimen preparation. In both cases sample isolation and preparation must be performed by pathologists in the proper way, following the instructions of the manufacturer. Specimen preparation requires fresh-frozen tissue. {RC-TEC2}

No information was found about the staff, training or human resources requirements of using a generic (“home brew”) uPA/PAI-1 test.

If one particular tissue collection and preservation system (such as FFPE) is normally used in the clinical setting, use of a test which requires a different system (such as fresh-frozen) will have an impact on staff, training and human resource needs.

Analysis of selected studies extracted from the basic literature search and data from electronic clinician survey. Five articles were found to be relevant to this question. We found additional information by an internet search of grey literature performed on 20 March 2012 via the search engine Google. It was performed by one investigator using key words specific to the Organisational Aspects domain (“communication”, “cooperation”, “network”, “teamwork”, “multidisciplinary team”, “multiprofessional team”) combined with each test (uPA/PAI-1/ Oncotype DX/ MammaPrint). Two grey literature sources are referred to in these results.

All of the literature refers to the generic uPA/PAI-1 test rather than to the brand FEMTELLE.

Cooperation activities

Tissue collection and preservation

If one particular tissue collection and preservation system is normally used in the clinical setting, use of a test that requires a different system will have an impact on inter-departmental cooperation. For example, Mook S et al. (2007) found that the logistics for the collection of fresh-frozen tissue are complex and vary from hospital to hospital{7}.Therefore, performing microarray analysis, especially on a real-time basis, can cause some logistical problems such as insufficient freezing procedures, or transport-related issues. The authors concluded that close collaboration between pathologists, surgeons and oncologists is of paramount importance.

Cooperation between units compared with standard care

Compared with standard care, these tests may require some additional forms of cooperation between hospital units, outpatient services and hospital structures. For instance, the National Cancer Institute states that performing and evaluating these tests will need the implementation of an integrated process involving different units of the organisation, clinical participants and stakeholders. An integrated process of care presumes the standardisation of coordination and communication mechanisms among the different participants. Multidisciplinary teams of pathologists, surgeons and oncologists are the best suited to lead the evaluation of cancer recurrence risk with these tests. Interdisciplinary cooperation will likely affect current practice patterns. Modern practices require a more customised examination with more cooperation between those who order the test, those who perform it and those who interpret it. Genetic counsellors may have a role to play. These specially trained health professionals are skilled at supporting individuals when testing is being considered, when test results are received, and during the weeks and months afterwards {8}.

The electronic survey of clinicians showed that the relationship between those who prescribe the test, those who administer it and those who interpret the results is usually very close. Six out of eight respondents (75%) said that those who prescribe the test and those who administer it are part of the same team. One respondent (13%) stated that the prescribers and those who administer the test are linked by a relationship of “supply of services” and one respondent (13%) said the relationship was “professional advice”. A similar pattern is reported by respondents about those who administer the test and those who interpret the results: for five out of eight (63%) it is within the same team, for two (25%) it is a relationship of “professional advice” and for one (13%) it is a relationship of “supply of services”. The units within organisations that are in charge of administering the test vary: for four respondents (50%) it is a laboratory or pathology department, for three (38%) it is an oncological unit, for one (13%) the test is sent away to be performed and for one (13%) it is carried out in the private sector.

MammaPrint

In a prospective community-based feasibility study (RASTER) for the use of the 70-gene signature, hospitals that wanted to be enrolled had to have uniformly structured multidisciplinary breast cancer care that used standard operating procedures, and had to have at least one dedicated physician (surgeon, pathologist, or medical oncologist) as a local coordinator. The coordinator’s role was to encourage and guarantee adequate information and communication activities among professionals involved in the patient pathway {9}.

Communication activities

Compared with standard care, the decision to introduce the tests (uPA/PAI-1/ Oncotype DX/ MammaPrint) in the clinical pathways of women with invasive breast cancer may need additional communication to all professionals involved and to eligible patients. Findings from the electronic survey show that in 75% of cases (6 out of 8) the availability of the test was communicated to clinicians. They were told about the need for careful identification of appropriate patients to use the test on and its rationale, or that the test would be discussed with relevant patients. One respondent from Spain reported also that clinicians were told that the test helps to make therapeutic decisions in some cases. In some places administrative staff and nursing staff were told about the need for careful identification of eligible patients and the rationale for the tests. (See {COL-3} for the full survey results.)

With patients

On the basis of patient interviews and questionnaires, Retal et al. (2007) felt that, given the level of knowledge on prognostic tests for cancer recurrence, there is room for improvement in the patient information {10}. The EGAPP (Evaluation of Genomic Applications in Practice and Prevention) working group (Berg et al. 2009) recommended that healthcare organisations should provide patients with counselling and educational materials to inform them about the potential benefits and harms associated with testing, and should discuss with patients whether the test results are likely to change their decision about therapy {11}. (See the Social Aspects domain of this HTA for more details about training and information activities for patients.)

Among professionals involved in the patient pathway

The Breast Centres Network takes the view that communication among professionals is essential in order to ensure that all the information coming from the prognostic tests is available quickly and is correctly interpreted. They also highlight that a molecular geneticist should be accessible for consultation by the specialists in the clinic {12}.

The literature contains little information on the cooperation and communication requirements for using these tests. Some points that were made in the literature are summarised above. However, since quality criteria have not been applied to these studies (see domain methodology), the real impact of these points on cooperation and communication activities is unknown.

Analysis of selected studies extracted from the basic literature search. Three articles were found to be relevant to this question. The results of the Clinical Effectiveness domain of this HTA were also taken into account.

MammaPrint and Oncotype DX are currently offered as laboratory services subject to Clinical Laboratory Improvement Amendments (CLIA) general laboratory standards. Even if central laboratories offering the tests are certified and use reliable procedures, pre-analytic issues at the sending sites such as specimen acquisition and handling can potentially affect the results of the testing. Standardised protocols for sample processing, storage and preparation are important to ensure results {13}.

Marchionni L et al. (2007) have envisaged the potential for scale problems that may be faced in the future as a consequence of increased demand for these tests. They take the view that scientific or regulatory bodies should monitor whether the degree of accuracy seen in investigational settings can be maintained with increasing demands. Scaling up the tests could represent a challenge for the reproducibility and reliability of the tests in any setting, especially if more than one laboratory offers the assays, since procedures to ensure inter-laboratory reproducibility will be needed {13}.

The National Horizon Scanning Centre in the UK reported that the test could be taken in general, non-specialist hospitals (secondary care) or in highly specialist services or hospitals (tertiary care), but it did not recommend one setting over another {14}.

No information was found in the literature review about this question for either the generic uPA/PAI-1 test or the FEMTELLE brand.

The literature contains little information on the advantages and disadvantages of providing the tests centrally or locally. The potential impact on healthcare budgets or skill levels in hospital laboratories of the tests only being carried out at the company’s own laboratories was not discussed. The points made in the literature are summarised above. However, since quality criteria have not been applied to these studies (see domain methodology), the real impact of these points is unknown.

Analysis of selected studies extracted from the basic literature search. Five articles were found to be relevant to this question. Information provided by the manufacturers to the HTA was also reviewed.

In all cases, tissue must be extracted and handled with care, and appropriate staff must be available and trained to the appropriate level. {RC-TEC13}

MammaPrint

According to the manufacturer, centres that use fresh tissue can order MammaPrint Specimen Collection and Transportation Kits online, place the tumour biopsy specimens in RNARetain, a proprietary RNA stabilizing solution, and then courier it to Agendia in the Netherlands. FFPE tissue may also be sent. Results are delivered electronically within 10 days at a cost of $3200 {15}. In the EU the MammaPrint assay costs €2675 {COL-2}.

Oncotype DX

According to the manufacturer, the cost of the assay is $3450 (€3180 in the EU and £2580 in the UK) and the samples are processed by Genomic Health’s own laboratories. {COL-2}

Obtaining and preserving tissue samples does not require any additional investment in centres that handle FFPE tissue, as guidelines for selecting tissue samples for the Oncotype DX assay are consistent with those for selecting optimal tissue blocks for standard immunohistochemistry assays {16}.

uPA/PAI-1

The assay requires a substantial amount of fresh-frozen tissue sample. This will have an impact on costs in centres that normally use FFPE tissue.

The generic uPA/PAI-1 test costs approximately €150 {4, 17}.

FEMTELLE

According to the FEMTELLE manufacturer, in order to process the test, laboratories need the following equipment that is available as routine equipment at many diagnostic laboratories: homogeniser (e.g. dismembrator) to homogenise the tumour tissue; cooled laboratory centrifuge; enzyme-linked immunoassay (ELISA) plate reader. The laboratories that perform the test should be qualified to perform ELISA testing (e.g. private diagnostic laboratories, institutes of pathology, diagnostic laboratories at breast cancer centres etc.). Laboratories that want to establish FEMTELLE testing at their site must be trained in experienced ISO certified laboratories that have performed many FEMTELLE tests. To this end the technicians receive detailed technical training at selected laboratories. {COL-2}

The sample may also be shipped to any laboratory qualified to perform ELISA testing. The manufacturer has a list of recommended laboratories. {RC-TEC7}

The manufacturer supplies the FEMTELLE test kit to laboratories for approximately €300. {COL-2}

Analysis of selected studies extracted from the basic literature search and data from electronic clinician survey. Twelve articles were found to be relevant to this question. Information provided by the manufacturers to the HTA was also reviewed.

MammaPrint

Management problems

Until recently MammaPrint required fresh or fresh-frozen tumour samples to preserve the quality of the RNA. Some of the potential difficulties in the implementation of the test in daily clinical practice have been the required change in routine work-up for tissue handling in centres that do not usually handle fresh tissue. This includes the onsite availability of the pathologist {10}. Mook et al. (2007) found that the logistics for the collection of fresh-frozen tissue are complex and vary from hospital to hospital. Therefore, performing microarray analysis, especially on a real-time basis, can cause some logistical problems such as insufficient freezing procedures, or transport-related issues. The authors concluded that close collaboration between pathologists, surgeons and oncologists is of paramount importance {7}. Centres that normally use FFPE tissue no longer face these issues now that MammaPrint can be used on FFPE tissue. {RC-TEC3}

Retèl et al. (2009) reported organisational issues faced during the implementation of MammaPrint in daily clinical practice in some community hospitals in the Netherlands (15 of the 16 participating hospitals in the RASTER study). All hospitals succeeded in implementing the required tumour sampling logistics. The duration of the implementation, measured from patient consent to first patient inclusion, varied from 0.2 to 9.4 months (median 1.2). The two outliers (4.3 and 9.4 months) had start-up problems especially in the pathology process.

The change in routine work-up for tissue handling (fresh-frozen tissue versus paraffin embedding) and the onsite availability of the pathologist were most difficult to achieve. However, if those logistics were in place, no other major problems appeared {10}.

Retel et al. (2009) also found that a potential increase in chemotherapy prescription, which was the result in the RASTER study, should be taken into account even though the initial expectation among the researchers and professionals involved was for the opposite to be the case{10}.

In one study, where all samples were obtained by surgical resection, a failure rate (i.e. the test produced no usable result) of 18% was observed due to non-representative tumour tissue (<50% tumour cells) {5}.

Opportunities

The MammaPrint assay has a larger gene number (70 genes) and could provide a greater opportunity to assess additional pathways and potentially provide additional pharmacogenomic information than the 21-gene Oncotype DX assay. It also has a wider indication than Oncotype DX by including both oestrogen-positive(ER+) and ER- patients, which also allows for the inclusion of a greater number of younger patients {18}.

Microarray based gene-expression profiling has also been used to define cellular functions, biochemical pathways, cell proliferation activity, and regulatory mechanisms {19}.

According to Retel et al. (2009) the introduction of this technology in hospitals, if well managed, does not change the time between surgery and the start of radiotherapy or adjuvant systemic treatment {10}.

Oncotype DX

Management problems

Failure rates in the range of 2.7 to 44.9% (mean 20.3% and median 11.8%) have been noted, some of which is due to insufficient tumour samples. This may in part be due to the use of archive samples and may not necessarily reflect the full sample normally available at the time of diagnosis {1}.

According to some researchers, Oncotype DX is an expensive test but it may save downstream costs of treatment by limiting chemotherapy to patients with higher risks of recurrence who are most likely to benefit from this regimen. Therefore immediate savings are expected because of reduced  chemotherapy costs, supportive care costs, and management of adverse events per woman tested {20, 21}. This expectation have not been met in other contexts such as in Israel (Clalit Health Services, Tel Aviv, Israel) where testing 368 patients with ER+, lymph node negative (LN-), early stage breast cancer with Oncotype DX increased their health-care costs by $1,500,000. In the view of the study authors, these higher overall costs, relative to cost-savings that have been estimated for the USA, are likely to be a consequence of the higher expenditure per patient in Israel for adjuvant chemotherapy and its administration {22}.

uPA/PAI-1

Management problems

The uPA/PAI-1 assay requires a fresh-frozen tissue sample. The tissue-handling requirements make this assay challenging in current clinical practice if tissue is not normally collected and preserved in this way.

The prognostic significance of ELISA in small amounts of tissue, such as tissue collected by core biopsy, has not been confirmed {6}. Therefore, at present, this assay may not be practical for many women with small tumours, such as those who are detected by screening, for whom the decision about adjuvant chemotherapy is difficult {23}.

FEMTELLE: According to the manufacturer, training and quality assurance are needed for sample isolation. The pathologist should be trained to inspect breast cancer tumour tissue. Finally, the laboratories that perform the FEMTELLE test should participate in regular quality assurance rounds organised by a designated laboratory in Nijmegen in the Netherlands. {COL-2} These requirements could be considered a management problem.

Opportunities

FEMTELLE: The manufacturer states that FEMTELLE is performed in more than 30 centres in Europe (Germany, France, Spain, Slovenia) {24}. FEMTELLE can be also performed in any laboratory equipped with a tissue homogeniser, an ELISA reader, and a cooled centrifuge (16,000 g). {RC-TEC7} This could be considered a management opportunity. Laboratories that want to establish FEMTELLE testing at their site must be trained in experienced ISO certified laboratories that have performed many FEMTELLE tests. To this end the technicians receive detailed technical training at selected laboratories. {COL-2}

Potential for scale problems

Marchionni et al. (2007) have identified one problem that may be faced in the future: the consequences of an increase in demand for these tests. They consider that scientific or regulatory bodies should monitor whether the degree of accuracy seen in investigational settings can be maintained with increasing demands. Tissue sampling and processing may be a potential issue for broad implementation of testing {13}.

Possible need for databases

Marchionni et al. (2007) suggest that consideration should be given to developing databases with complete data on each patient tested with these and future tests. The data should include all the analyses performed, laboratory logs, the raw and processed data, and all the information about procedures and analyses that have been performed to produce a risk estimate from a tumour sample {13}.

Potential for problems with acceptability

The introduction of these tests in clinical practice could be hampered by some resistance of clinicians, nursing staff or administrative staff. As shown by the electronic survey of clinicians, resistance could be for economic and financial reasons (e.g. anxiety about offering a test to the patient that they would need to pay for). Moreover, the tests might not be strongly advocated by some clinicians because of their limited use or their cost. (See RC-ORG8 for more information about degree of acceptance of the tests.)

The literature contains little systematic information on the management problems and opportunities of using these tests. The main potential problems highlighted are: tissue-handling requirements (sample isolation, preparation, transport and processing); possible increase in chemotherapy costs; potentially high failure rates; possible challenges in scaling up use of the tests; and possible resistance to introduction of the tests. However, since quality criteria have not been applied to the studies used (see domain methodology), the real impact of these points on management problems and opportunities is unknown.

Analysis of selected studies extracted from the basic literature search and data from electronic clinician survey. Five articles were found to be relevant to this question. Well-conducted experimental and observational trials can give a picture of clinical decision-making and patient eligibility, which are too close to the ideal protocol. Results from the electronic survey give additional information from clinical practice.

Only anecdotal evidence was found in the literature.

The EGAPP working group (Berg et al. 2009) considered that, until more data are available, clinicians must decide on a case by case basis whether the use of a gene-expression profile test adds value beyond the use of the current prognostic markers (and how to weigh and combine these risks), and whether each test’s validation population is relevant to their patients’ age, disease status, and race/ethnicity {11}.

According to the European electronic survey, the folowing are responsible for deciding which women are eligible for the tests:

• 6 respondents (75%): clinicians
• 1 respondent (13%): national healthcare systems
• 1 respondent (13%): local healthcare systems
• 1 respondent (13%): insurance companies
• 1 respondent (13%): payers

Six different reasons were given (by one respondent each) as the basis for making the eligibility decision: (1) on the basis of availability, funding and potential clinical benefit; (2) on a case by case basis to women at intermediate risk of breast cancer who are struggling to make a decision around adjuvant chemotherapy; (3) on the basis of evidence; (4) if they meet the local authorities’ inclusion criteria; (5) if they had the characteristics required to be enrolled on the MINDACT trial; and (6) on the basis of evidence, cost analysis and resource allocation prioritisation.

Oncotype DX

In one study of 44,079 tumour specimens from early-stage, ER+ breast cancer patients, surgeons ordered the Oncotype DX assay more frequently for HER2+, whereas medical oncologists ordered it more often for node-positive patients {25}.

In a round table discussion, expert opinion suggested that, although there is no set policy or algorithm for determining who should receive an assay, the typical patient for whom they would most likely order the test is an ER-positive patient with a tumour measuring between 1 and 3 cm. The participants in the discussion said that the Oncotype DX assay is validated in larger tumours, and  is ordered for patients who have larger tumours, and athough it is by no means a universal practice, sometimes it was ordered for women with node-positive disease. The experts considered that  the assay may also be useful for patients with minimal nodal involvement and for whom the clinician would normally recommend chemotherapy but where the patient may be hesitant to receive chemotherapy {26}.

From a data review over the past 6 months for a single centre, it was found that nearly 15% of requests for the Oncotype DX assay were for patients who had micrometastases {26}.

There is little information in the literature about clinical decision-making and patient eligibility. In conjunction with the electronic survey, the data lead us to conclude that the decision to use the tests rests mainly with clinicians, and that in reality the tests may not be used on the indicated patient population. Centres may not have a set policy for determining who should have the tests. However, these conclusions are not robust.

Analysis of selected studies extracted from the basic literature search and data from electronic clinician survey. Seven articles were found to be relevant to this question.

The Clinical Effectiveness domain of this HTA has analysed the impact of use of the tests on clinicians’ decision-making. Here we consider only data about acceptance of the tests by clinicians.

All of the literature refers to the generic uPA/PAI-1 test rather than to the brand FEMTELLE.

The currently available literature suggests that risk stratification in breast cancer patients has not improved considerably over the past years. Clinicians still use tumour size, grade, and age, with the addition of biomarkers such as uPA/PAI-1, Oncotype DX or MammaPrint in some centres, to determine recurrence risk. Meanwhile, clinicians are eager to implement new techniques, including uPA/PAI-1 assessment, to better refine treatment decisions {4} but they tend to look for more confirmative data concerning the validity of the tests before implementing them in routine clinical practice. During a conference about the regular use of genetic assays in clinical practice in San Francisco in 2009, the audience members voted 50% in favour of regular use of multigene assays in low-risk, node-positive patients and 50% against. After the debate, the audience vote shifted away from regular use, with 33% in favour and 67% against {27}.

Results from the electronic survey show that clinicians and nursing staff have a good acceptance of the tests. (Seven out of eight respondents (88%) reported that both clinicians and nurses accepted or readily accepted the tests.) Nevertheless there was some resistance. Possible reasons for resistance were given by individual survey respondents as follows: lack of confidence in cost effectiveness; the fact the patient has to pay the cost of the test; lack of availability of patients (many are already involved in ongoing clinical trials on adjuvant therapy which do not use these tests); the desire to wait for published data from clinical trials (TailoRX, MINDACT) to define the role and necessity of these tests in therapeutic decision making. Some resistance comes also from administrative staff or nursing staff: some reported anxiety about offering a test to the patient that they would need to pay for or fear of an immediate cost increase due to a lack of confidence in the cost effectiveness of the tests. (See {COL-3} for the full survey results.)

Moreover, the uPA/PAI-1 assay and, until recently, MammaPrint require a fresh-frozen tissue sample, and there is some reluctance to adopt the tests in countries in which fresh-frozen tissue is not readily available after surgery. Core biopsy specimens are now more common and researchers are therefore trying to demonstrate that assays from core biopsies are reliable{4}.

Li et al. (2008) suggest that national or regional healthcare systems should develop supporting information systems that offer educational and consultation programmes for physicians and other healthcare providers, as well as for the general population, to guide the adoption and use of these tests {15}.

MammaPrint

A survey performed in 15 community hospitals (Retèl et al. 2009) showed that all the physicians interviewed expected that the MammaPrint signature will eventually become part of future regular diagnostics. Some expected the signature to be performed in all patients; others considered it as a complementary parameter especially in difficult cases. In general, the physicians rated the addition of the 70-gene signature as beneficial for patient management; however, several medical oncologists tended to look for more confirmative data concerning the validity of the signature {10}.

Oncotype DX

Some studies reported that the Oncotype DX Recurrence Score (RS) increased medical oncologists’ confidence in their treatment recommendation:

• Henry et al. (2009) investigated the impact of the assay on a panel of five breast oncology experts. RS results increased panel consensus by 10% but did not appear to increase the reported strength of panellists’ recommendations {28}.
• Lo et al. (2010) investigated physician satisfaction about the 21-gene RS assay through a prospective observational study. Results showed increased confidence of medical oncologists in their treatment recommendation in 68 cases (76%). When asked whether they would order the RS assay again, medical oncologists stated they would order it again in 97% of cases {29}.
• Oratz R et al. (2011) carried out a web-based survey, in the USA, of medical oncologists who ordered the 21-gene RS assay. The response rate was low (16%). Of the 160 respondents, 112 (70%) reported being mostly or completely satisfied with the data supporting the use of the 21-gene RS assay in postmenopausal patients with LN+, ER+ disease, and 75 (47%) reported the same level of satisfaction with the data regarding its use in premenopausal patients with LN+,ER+ disease {30}.

The quality of studies available is poor and the reliability of results, weak. Indeed, data on acceptance come from observational studies, surveys and expert opinions. Moreover, healthcare professionals who responded to the surveys may have had a systematically different impression of the clinical utility of the tests compared with non-respondents, so that acceptance results could be overestimates.

Analysis of selected studies extracted from the basic literature search and data from the electronic clinician survey. Two articles were found to be relevant to this question. A grey literature search was performed on 10 February 2012 via the search engine Google by one investigator using key words specific to the Organisational Aspects domain (“stakeholder”, “stakeholder involvement”, “genomic test”, “genetic test”) combined with each test (uPA/PAI-1/ Oncotype DX/ MammaPrint). One grey literature source is referred to in these results.

As highlighted in the electronic survey, all the relevant stakeholders within healthcare organisations usually work in close collaboration and as part of the same team. All those concerned are in charge of ordering, administering or interpreting the test and their decisions affect the spread of the tests in clinical practice. The electronic survey of clinicians showed that clinicians, and to a lesser extent also nursing staff and administrative staff, have a good acceptance of the tests. Nevertheless, some resistance was expressed because of economic and financial issues or the limited use of the tests. (See {COL-3} for the full survey results.)

Li et al. (2008) consider that cooperation is needed between third party payers and manufacturers, so that useful information and stronger evidence are produced or found by manufacturers in order to support the decision-making process. They suggest that manufacturers should develop supporting information systems that offer educational and advice programmes for physicians and other healthcare providers, as well as the general population, to spread knowledge and awareness about this kind of testing {15}.

In a review published by the American Society of Clinical Oncology in 2010 the authors examined the coverage policies of six private payers for the Oncotype DX 21-gene assay, highlighting that clinical evidence was the most important factor in decision making for all payers, even if they had different perceptions about the strength of evidence at the time of the coverage decision. Other factors influencing the decision about adoption were, for instance, physician adoption or medical society endorsement. Some payers reported that signs of broader adoption, such as increased number of claims, served as triggers for a closer policy review {31}.

The Institute of Medicine (2012) believes that stakeholders representing regulators, payers and providers should share their perspectives on evidence. More dialogue and coordination among stakeholders is needed to facilitate the development of the necessary evidence base. Test development and reimbursement need to focus on the clinical utility of the test and the net benefit to patients. Moreover, the analysis of evidence must be adapted to the clinical setting and to the evidence needed for that particular application {32}.

The literature provides some insight into the influence of stakeholders on the adoption and diffusion of the prognostic tests for breast cancer recurrence in clinical practice. The degree of acceptance of these tests by clinicians, nursing staff and administrative staff, as shown by the electronic survey, was considered in this assessment element as it could be a factor influencing their diffusion. Cooperation between third party payers, regulators, providers and manufacturers could facilitate the development of further clinical evidence to support coverage decisions.

The domain methodology was used for this question (analysis of selected studies extracted from the basic literature search).

According to literature review, the introduction of prognostic tests for breast cancer recurrence (PTBCRs) in clinical practice does not appear to have a direct impact on any of the social areas (e.g. working life, family life, social relations). Feelings of distress and anxiety are frequently reported and are related to the consequences of the tests on treatment decisions. It remains unclear whether and how these feelings affect the social areas of the patient.

Oncotype DX

According to Richman 2011 approximately 26% (17 of 65) of women agreed or strongly agreed that getting the test result made them worried and anxious. Greater endorsement of test-related distress was associated with higher actual recurrence risk based on the test, as the majority of women who experienced test-related distress had intermediate or high recurrence risks based on their test results (low  = 18%, 6 of 33; intermediate  = 30%, 7 of 23; high = 44%, 4 of 9). Stronger feelings of distress were also related to getting chemotherapy, not getting radiation, and having more frequent worries about breast cancer recurrence. {10}

Richman (2011) and Tzeng (2010), in their observational study on women’s experiences with genomic testing, reported that few women agreed that they had the test only because other family members wanted them to (8%); that the test had a negative effect on their family (5%); or that information about one’s cancer is better left unknown (3%). They did not report whether these experiences could affect the family life of patients. {10}, {11}

Lo et al. (2010) assessed the impact of Oncotype DX on total quality of life. The results showed that women’s quality of life remained stable over the year of diagnosis and treatment (P = 0.55) according to Functional Assessment of Cancer Therapy (FACT-B and FACT-G) surveys. Quality of life was assessed before the women obtained the results of the recurrence score (RS) assay (mean, 112.2; SD = 17.4) and 12 months after the assay (mean, 114.3; SD = 18.6). These data come from a questionnaire addressed to a small sample (89 patients) of American women with lymph-node-negative cancer. {6}

An indirect influence is due to the fact that genomic tests can help with making complex decisions about adjuvant treatment for cancer that, itself, has a strong impact on many of social areas. Following the tests, patients enrolled in the study by Lo et al. experienced reduced anxiety over their treatment decision and increased confidence in their choice of therapy. They reported significantly lower conflict about the decision about adjuvant treatment and had significantly decreased situational anxiety immediately after learning the results of the Oncotype DX test. 12-months after the assay most women continued to feel satisfied that they had used the RS assay, but those patients who were not satisfied (n = 5) noted a negative impact on quality of life, treatment side-effects including aches, hot flashes, pain, mood alteration, and negative impact on self-image.{6}

The literature contains little information about the impact of using prognostic tests on different social areas. Some points were made in the literature about the impact of Oncotype DX on anxiety and quality of life, which are summarised above.

The domain methodology was used for this question (analysis of selected studies extracted from the basic literature search).

There are no studies that address these questions.

The domain methodology was used for this question (analysis of selected studies extracted from the basic literature search).

Evidence from literature review is all related to Oncotype DX. It showed a psychological impact and emotional reaction to the test results, such that the following types of support should be made available as the test is put to use for women with invasive breast cancer.

Emotional and psychological support

Since these tests may have a psychological impact on patients, emotional and psychological support should be provided.

Richman (2011) reported that most women experienced test-related distress. Stronger feelings of distress were also related to receiving chemotherapy, not receiving radiation, and having more frequent worries about breast cancer recurrence. {10}According to Tzeng et al. (2010), as women with intermediate and high genomic-based recurrence risks are more likely to worry about recurrence and be distressed about their test result, they deserve special attention. {11} Retèl et al. reported that the psychological impact on patients seems especially related to discordance between a low risk based on clinicopathological factors and a high genomic risk signatureand to its successive communication. {9}

Psychological impact was measured by Retèl et al. (2009) both through a questionnaire to 77 women, that was used to assess the respondents’ emotional reactions to the test results, also called “negative affects”, and by the Cancer Worries Scale which assessed how worried the women were after receiving the 70-gene prognosis signature. The scores for “thought about chances of getting cancer again influencing the mood” on the Cancer Worries scale  differed significantly (p = 0.01; n = 77) according to risk group: 43% of patients with a clinically low risk but a poor genomic signature and 29% with a clinically high risk and no signature (due to failure in the testing process) often worried about recurrence, compared with 0% of the patients with a clinically high risk and a good signature, 20% of those with a clinically low risk and no signature, 13% with a clinically high risk and a poor signature and 3% with a clinically low risk and a good signature. {9}

Educational support (verbal and printed information)

A number of studies showed that knowledge about some aspects of the prognostic tests was low and having higher health literacy and numeracy increases patients’ ability to recall information about recurrence risk testing. {9},{10},{5} Healthcare organisations should provide patients with counselling and educational materials to inform them about the potential benefits and harms associated with testing and should discuss whether the test results are likely to change the patient’s decision about therapy. {1} According to Richman et al. (2011), knowledge was higher among women who recalled receiving both verbal and printed information about the test and among women who recalled that their doctors described the results of the test using numbers. These findings offer preliminary information on communication approaches that may be most effective. For example, when communicating recurrence risk test information with patients, health professionals and educators should pay attention to patient health literacy and numeracy, and perhaps adjust the delivery of and time spent on communicating with patients. {10}

The domain methodology was used for this question (analysis of selected studies extracted from the basic literature search).

A number of studies reported how patients react and act upon the prognostic or genetic tests for breast cancer. Evidence from literature review is all related to Oncotype DX and MammaPrint; nothing was found about the uPA/PAI-1 test.

Oncotype DX

According to data presented at the 2007 and 2008 San Antonio Breast Cancer Symposia, following the use of the Oncotype DX assay patients usually experience reduced anxiety over their treatment decision, greater satisfaction, and increased confidence in their choice of therapy. The investigators reported that 95% of patients were glad that they had taken the Oncotype DX assay, and 83% of patients stated that the assay influenced their treatment decision. Patients reported significantly lower conflict about the decision for adjuvant treatment after obtaining the results of the RS assay. Decisional conflict was not repeated at 12 months, but it would have been interesting to see whether decisional conflict continued to be lower longer term. {6}

Good satisfaction about the Oncotype DX test is also reported by Richman et al. (2011). Women in this study had few concerns and were satisfied with the test, saying that they would recommend it to others and would still have the test if faced with the decision again today. In general, they perceived more benefits than concerns about the test. Approximately 26% (17 of 65) of women agreed or strongly agreed that getting the test result made them worried and anxious and test-related distress was associated with higher recurrence risk based on the test. {10}

MammaPrint

The satisfaction reported by Retèl et al. about receiving the 70-gene signature (MammaPrint) per risk-group was 76%. Of seventy patients 6 (8.6%) were very dissatisfied, of whom 4 had a discordant clinically low risk with a high risk signature, 2 (not discordant) were dissatisfied about the way the result of the 70-gene signature was communicated. Eleven patients had a neutral opinion. The overall satisfaction regarding the total trajectory, from diagnosis to the time of interviewing, around 2 months after surgery, was 82% (n = 77). Significant differences (P = 0.001) were found between the different risk groups for emotional reactions after receiving the 70-gene signature. Women with discordant clinically low risks with high genomic risk signatures and clinically high risks with no signature (due to failure in the testing process) had the highest negative affect-scores (n = 77). {9}

Data on satisfaction and existential experiences come from observational studies and surveys, so the reliability of results is not very high.

The domain methodology was used for this question (analysis of selected studies extracted from the basic literature search).

The introduction and diffusion of new prognostic or genetic tests raise the question of the extent to which patients are prepared to participate in informed decision making about their care. It is important to give information to patients, and others who may be affected that is at a low threshold, understandable and evidence based. (National Health and Medical Research Council, 2004)

Oncotype DX

Different studies using patient interviews and questionnaires showed that, given the level of knowledge on genetic tests for cancer, there is room for improvement in the patient information {9}. Healthcare organisations should provide patients with counselling and educational materials to inform them about the potential benefits and harms associated with testing and should discuss whether the test results are likely to change the patient’s decision about therapy. {1}

Knowledge about genomic recurrence-risk testing was also assessed by Richman et al. (2011) and Tzeng et al. (2010) through a questionnaire with a 13-item scale mailed to 78 women, treated for early stage, oestrogen receptor-positive breast cancer with 0–3 positive lymph nodes, whose medical records indicated they received Oncotype DX testing earlier. They found low knowledge about many aspects of genomic recurrence risk testing. Most women understood the relationship between the test and chemotherapy (e.g. test aids decisions about chemotherapy) and general test procedures (e.g. it is done after surgery that removes the breast tumour). However, few understood that the test result indicates the likelihood of metastasis assuming additional treatment and that the test does not provide information about familial risk for breast cancer. The authors present the need to continue developing optimal ways to communicate and ensure both perceived and actual comprehension of genomic-based information. Further research is needed on the testing information provided to patients and best practices for patient education. {10, 11}

According to Lillie SE et al. (2008) health literacy may affect women’s capacity to learn about the new genomic tests (Oncotype DX). Women with lower health literacy recalled less of the information provided about the recurrence risk test than women with higher health literacy. Health literacy was not related to the amount of additional information women desired. {5}

MammaPrint

Questionnaires and interviews about knowledge and psychological impact of MammaPrint were conducted by Retèl et al. (2009). The results of the knowledge test show that important issues are the predictive accuracy of the test (87% wrong answers) and the consequences of the test (66% wrong answers). The authors stated that the number of patient questionnaires was too small to conduct extensive statistical analysis. {9}

Data on knowledge about genetic tests come from observational studies and surveys, so the reliability of results is not high. The limitations of some studies are reported below.

• Findings of Richman et al. (2011) and Tzeng et al. (2010) on Oncotype DX are based on self-report and the sample of women enrolled in the study was small.
• In the observational study by Retèl et al. (2009) the selection of participating hospitals was not at random, but all were probably early adoptors and willing to put effort into the implementation process of MammaPrint. Furthermore, because more questionnaires were returned by concordant low-risk patients, these patients might be more inclined towards responding or the present results might too positive and not representative.

The domain methodology was used for this question (analysis of selected studies extracted from the basic literature search).

Oncotype DX

A clinical roundtable monograph funded by Genomic Health, manufacturers of Oncotype DX, about incorporating the Oncotype DX breast cancer assay into routine clinical practice, reported that the discussion generally begins in the surgeon’s office, where the Oncotype DX assay is first introduced as an evaluation tool. At this time, the patient is provided with basic information, so that they are familiar with Oncotype DX when they first meet with their medical oncologist. Therefore, the Oncotype DX assay is sometimes ordered by the surgeon before the patient ever meets with a medical oncologist. In most cases, the patient would then discuss the assay result with their medical oncologist. Pathologists generally have no communication with the patient about the Oncotype DX assay, because their main role is to select the most representative tumour block to send out after receiving a request. {2}

Palmer et al. stated that, given the anxiety that patients experience following surgery and prior to making an adjuvant treatment decision, there could be value in surgeons ordering the Oncotype DX assay as this is expected to reduce the time required for patients to receive results. Moreover, having RS results at the time of the first consultation with the medical oncologist can lead to a smoother and more meaningful conversation with the patient. {8}

Tzeng JP studied how women receive and incorporate the results of Oncotype DX into decisions about adjuvant treatment for early-stage breast cancer. Most of the women surveyed (77 women with early-stage, oestrogen receptor-positive breast cancer with 0 to 3 positive lymph nodes who received Oncotype DX between 2004 and 2009) preferred having an active (38%) or shared (49%) role in medical decisions. {11}

Although genomic tests can help inform treatment decisions, a challenge is how best to communicate and incorporate test results when making complex decisions about adjuvant treatment for cancer. Informed decision making about adjuvant treatments often involves discussions about patients’ chances of recurrence. To date, there is little consensus about the most effective method of communicating risk information. Moreover, cognitive constraints such as low health literacy or low numeracy may result in reduced understanding of medical and probabilistic information. {5, 11}

A recent US study assessed retention of information about genomic tests among a proxy population of breast cancer patients who had not received Oncotype DX, but who were provided with an oral and written description of the test immediately before completing the survey. According to Lillie et al. (2008) health literacy may affect women’s capacity to learn about the new genomic tests as well as their desire for informed participation in their medical care. The retention of information about the risk of recurrence of breast cancer is sensitive to the individual’s capacity for processing information; patient-oriented educational materials about the recurrence risk test must help to reduce this effect. These data suggest that clinicians and health educators should be concerned about patients’ health literacy levels when discussing genomic recurrence risk tests. {5}

The literature contains little information on how information about the use of prognostic tests for breast cancer is processed and exchanged. There are no studies that address these questions for the MammaPrint and uPA/PAI-1 tests.

The domain methodology was used for this question (analysis of selected studies extracted from the basic literature search).

Oncotype DX

Genomic tests can help to inform treatment decisions, but a challenge is how best to communicate and incorporate test results when patients make complex decisions about adjuvant treatment for cancer. As shown in various studies most of the women preferred having an active or shared role in medical decisions. {5}, {11}

Lillie et al. (2008) investigated the effect of health literacy on desire for active participation in two decisions: the decision to have the recurrence risk test and the decision to use the test results to inform decisions about which adjuvants should be used after surgery. Interviews of 167 patients (recruited only post-surgery and post-treatment who either did not receive neoadjuvant or adjuvant chemotherapy or had completed it) showed that the women’s desires to be actively involved in both the decision to have the recurrence risk test done and in treatment decisions based on test results differed according to their health literacy levels. Women with higher health literacy indicated a preference for more active participation in the decision to have the recurrence risk test than did women with lower health literacy. This finding was statistically significant (P = 0.03). Similarly, women with higher health literacy more often indicated that they preferred active participation in the decision to use the results of the recurrence risk test to make treatment decisions than did women with lower health literacy (P<0.001). Women with lower health literacy reported an interest in passive decision making (34%) that those with higher health literacy did not have (6%). They showed there is a larger effect of health literacy on decision-making preferences for use of the recurrence risk test results to inform care than for being tested in the first place. Experiences with Oncotype DX and beliefs about the test are also potentially important because they can reduce breast cancer patients’ willingness to let the results guide treatment decisions. {5}

The results of the multicentre trial by Lo et al. confirm that the RS assay impacts patient treatment choice. The trial consecutively enrolled 89 women with lymph node-negative, oestrogen-positive breast cancer who were medically fit to receive adjuvant chemotherapy. Several authors declared financial ties to Genomic Health and the trial received direct funding from Genomic Health. Patients’ treatment decisions before and after Oncotype-DX testing were recorded and the results showed a change for 24 women (27%). Patients usually experience reduced anxiety over their treatment decision, greater satisfaction, and increased confidence in their choice of therapy. They reported significantly lower conflict about the decision for adjuvant treatment  after the RS assay and had significantly decreased situational anxiety immediately after learning the results of the RS assay, which remained stable at 12 months. The perceived risk of recurrence was an important factor in women’s choice of treatment. On a scale of 0 to 100, with 100 indicating definite recurrence, patients ‘mean estimated risk before the RS assay was 22.4 and after the assay was 16.0 (P = 0.001). Patients’ estimated risk of recurrence post-RS was significantly correlated with their RS assay result (r = 0.42; P = 0.001) and significantly lower immediately after the RS assay, but lost significance at 12 months. {6}

The literature contains little information on the consequences of using prognostic tests in decision making. There are no studies that address this question for the MammaPrint and uPA/PAI-1tests.