ME65CH07-Hayes
ARI
ANNUAL REVIEWS
19 December 2013
Further
Annu. Rev. Med. 2014.65:95-110. Downloaded from www.annualreviews.org by Lomonosov Moscow State University on 01/18/14. For personal use only.
Click here for quick links to Annual Reviews content online, including: • Other articles in this volume • Top cited articles • Top downloaded articles • Our comprehensive search
7:38
Molecular Testing in Breast Cancer Costanza Paoletti and Daniel F. Hayes Breast Oncology Program of the Comprehensive Cancer Center, and the Department of Internal Medicine, University of Michigan Health and Hospital System, Ann Arbor, Michigan 48109; email: [email protected]
Annu. Rev. Med. 2014. 65:95–110
Keywords
The Annual Review of Medicine is online at med.annualreviews.org
tumor biomarker tests, breast cancer
This article’s doi: 10.1146/annurev-med-070912-143853
Abstract
c 2014 by Annual Reviews. Copyright All rights reserved
Tumor biomarker tests are critical to implementation of personalized medicine for patients at risk for or affected by breast cancer. A tumor biomarker test must have high analytical validity and clinical utility to be used to guide clinical care in standard practice. Few tumor biomarkers meet these high standards. These include germline DNA single-nucleotide polymorphisms in the BRCA1 and -2 genes to determine high risk in unaffected women, selected tissue-based markers to determine prognosis and predict benefit from therapy, and circulating MUC1, CEA and perhaps tumor cells to monitor patients with metastatic disease. Efforts to discover biomarkers that predict therapeutic toxicity are promising but not yet successful. Further research is needed to enhance the number of tumor biomarker tests so that patients with breast cancer can get the correct treatment at the appropriate time.
95
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INTRODUCTION HER2: human epidermal receptor type 2 21-gene RS: 21-gene recurrence score
Annu. Rev. Med. 2014.65:95-110. Downloaded from www.annualreviews.org by Lomonosov Moscow State University on 01/18/14. For personal use only.
ER: estrogen receptor
“Personalized medicine” implies getting the right treatment to the right patient at the right time. Breast cancer causes substantial morbidity and mortality, and treatments for it have a very narrow benefit/toxicity ratio. Therefore, the development of highly validated tumor markers is crucial to guide diversified treatments. These considerations raise many questions. What is a tumor biomarker, and what are the tests to assay for it? What are the clinical uses for a tumor biomarker test? What are the necessary criteria to determine if and when a tumor biomarker test should be used to guide clinical decisions? And finally, what tumor biomarker tests have met these criteria for the specific uses one might identify?
WHAT IS A TUMOR BIOMARKER AND WHAT ARE THE TESTS TO ASSAY FOR IT? A tumor biomarker is defined as “a substance that is produced by cancer cells or by other cells of the body in response to cancer or certain benign (noncancerous) conditions” (1). This definition includes abnormalities in DNA (germline or somatic), RNA, proteins, metabolites, and abnormal cellular or tissue processes. The majority of tumor biomarker assays are performed on the cancer tissue itself. However, tumor biomarkers can also be monitored in blood, urine, stool, saliva, and in the case of breast cancer, breast ductal fluid. One must distinguish a putative tumor biomarker in concept from a specific test that measures the marker reliably. For example, the human epidermal receptor type 2 (HER2) is clearly an important tumor biomarker for breast cancer. However, HER2 abnormalities, as determined by a number of different assay platforms, include amplification, mutations, and/or overexpression at the message or protein levels (2, 52). Moreover, elevated circulating levels of the soluble extracellular domain of HER2 are frequently detected in patients with breast cancer (3, 4). Each of these distinct tests for each of these different types of 96
Paoletti
·
Hayes
abnormalities may have varying meanings and uses and cannot be considered interchangeable. Therefore, the clinician must be aware of these subtle but important technical nuances and understand that the test used to detect, quantify, or monitor a tumor biomarker is critical to its application in the clinic. Classically, a tumor biomarker test has been directed toward a single analyte (such as HER2 protein). However, with the advances in omicsbased technology during the past decade, several multi-parameter assays have emerged, in which multiple analytes, such as expression of several genes, are measured, and a weighted algorithm is developed to generate a single result, index, signature, or “score.” For example, a R , 21-gene recurrence score (RS) (OncotypeDx Genomic Health, Inc., Redwood City, CA) incorporates expression data from 16 informative and five control genes, including relative expression levels of estrogen receptor (ER), HER2, proliferation, and invasion and metastasis signaling pathways. This assay is now widely accepted for determination of prognosis and prediction of chemotherapy benefit in patients with newly diagnosed, ER-positive, node-negative breast cancer (3).
WHAT ARE THE CLINICAL USES FOR A TUMOR BIOMARKER TEST? It is important to understand the potential uses and contexts in which a tumor biomarker test might be applied. Each is different depending on the status of the patient. The spectrum of breast cancer patient status (Figure 1) ranges from unaffected individuals who are concerned about whether they should adopt preventive or screening strategies, to patients with early-stage disease for whom considerations of appropriate primary (surgery and radiation) and adjuvant systemic (chemo, endocrine, and anti-HER2) therapies are critical, to those who are free of disease but are concerned about recurrence, and finally to patients with established metastatic disease. In this regard, tumor biomarker tests might be useful for risk
ME65CH07-Hayes
ARI
19 December 2013
7:38
Clinical spectrum of breast cancer Normal
High risk Carcinoma
In situ
Invasive
Micro-metastatic Regional lymph nodes Bone marrow Blood
Detectable metastatic Distant organs
Risk categorization
Annu. Rev. Med. 2014.65:95-110. Downloaded from www.annualreviews.org by Lomonosov Moscow State University on 01/18/14. For personal use only.
Screening for new primary Differential diagnosis Prognosis and prediction Monitoring disease status Screening for occult metastases Determination of progression
Figure 1 Clinical spectrum of breast cancer and potential uses of tumor biomarkers.
categorization, screening, differential diagnosis, prognosis and/or prediction of benefit from therapy, or monitoring of disease status, in the adjuvant or metastatic settings (5) (Table 1).
WHAT ARE THE CRITERIA TO DETERMINE IF A TUMOR BIOMARKER TEST SHOULD BE USED IN A PATIENT’S CARE? Although there are thousands of papers in the literature that pertain to breast cancer tumor
biomarkers, very few have been adopted into the clinic. A Breast Cancer Tumor Marker Guidelines Panel convened by the American Society of Clinical Oncology (ASCO) has only recommended tests for five tissue-based biomarkers [ER, progesterone receptor (PgR), HER2, the 21-gene RS, and urinary plasminogen activator/plasminogen activator inhibitor 1 (UPA/PAI-1)] and for two circulating biomarkers [carcinoembryonic antigen (CEA) and the protein product of the mucin 1 (MUC1) gene] (3). Very similar recommendations have been
ASCO: American Society of Clinical Oncology PgR: progesterone receptor UPA: urinary plasminogen activator PAI-1: plasminogen activator inhibitor 1 CEA: carcinoembryonic antigen MUC1: mucin 1
Table 1 Potential uses of tumor biomarkers Risk categorization Screening for new primary cancers Differential diagnosis of abnormal finding on breast imaging Prognosis Prediction Monitoring disease course: patients who are free of disease to detect occult recurrence patients with established metastases
www.annualreviews.org • Molecular Testing in Breast Cancer
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issued by the National Comprehensive Cancer Network (NCCN) Breast Cancer Guidelines Panel (6). These guidelines are so conservative because the panels have tried to adhere to the principles of evidence-based medicine. In this regard, several initiatives have been proposed in the past 15 years to clarify the criteria to establish that a given tumor biomarker test should be used to guide an individual’s cancer management. In 2009, the Evaluation of Genomic Applications in Practice and Prevention working group articulated three important concepts to clarify the field: analytical validity, clinical validity, and clinical utility (7). Analytical validity implies that the test is accurate, reproducible, and reliable. Clinical validity implies that the test divides one population into two or more separate groups that have significantly different clinical outcomes. However, it does not imply that the test should be used to care for patients. A tumor biomarker test has clinical utility only if its use improves patient outcomes, as demonstrated with high levels of evidence (8). The criteria for clinical utility depend on the relative benefit and toxicities and costs of the therapeutic intervention, and on the perceptions of the patient, caregiver, and society regarding these benefits and costs. High levels of evidence must be generated with the same rigor used to demonstrate the clinical utility of new therapeutics. Investigators have proposed a hierarchy of studies that might result in the level of evidence required to demonstrate clinical utility, either within prospective clinical trials or “prospective retrospective” studies using archived specimens from earlier prospective trials (Table 2) (8–11). All of these concepts were recently summarized in a report released by the Institute of Medicine (IOM) regarding the generation of tumor biomarker omics-based tests (Figure 2) (12). Although the IOM Committee was charged with review of omics-based tests, these concepts are applicable to development of any tumor biomarker test. In summary, the decision whether to use a tumor biomarker test to direct the care of a pa-
Annu. Rev. Med. 2014.65:95-110. Downloaded from www.annualreviews.org by Lomonosov Moscow State University on 01/18/14. For personal use only.
NCCN: National Cancer Center Network
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tient with breast cancer is as important as selection of a drug and determination of the proper dose and schedule. The stakes are high: use of a tumor biomarker test with poor analytical validity or weak evidence that it has clinical utility will lead to mistreatment, with potentially catastrophic results.
WHICH TUMOR BIOMARKER TESTS ARE “READY FOR PRIME TIME”? Each of the contexts in which a tumor biomarker test might have clinical utility (Figure 1, Table 1) is different and deserves special discussion.
Risk Categorization Prevention and screening strategies for breast cancer successfully reduce the odds of having and/or dying of the disease (13, 14). However, each of these strategies is associated with adverse consequences and costs. Therefore, determination of risk, especially with a tumor biomarker test, would have enormous value. For example, the association between absence of a Y chromosome and incidence of breast cancer is one of the most powerful risk factors for any disease. The relative and attributable risks for breast cancer of being female are extraordinary. Women are 100-fold more likely to develop breast cancer than men, and 99% of breast cancers occur in women. Thus, preventive and screening strategies are almost exclusively confined to women, mostly aged 40–75. However, only ∼10% of all women will develop breast cancer in their lifetimes. Unfortunately, other than sex and age, few other risk factors have sufficient clinical utility to be used to focus screening and prevention strategies. Selected germline markers of susceptibility have analytical validity and clinical utility for risk assessment and therapeutic recommendations. Women with deleterious inherited single-nucleotide polymorphisms (SNPs) in the tumor suppressor genes, BRCA1 and BRCA2, have a five- to tenfold increased risk of developing a new breast cancer
ME65CH07-Hayes
ARI
19 December 2013
7:38
Table 2 Hierarchy of studies to establish levels of evidence for clinical utility of tumor biomarker tests (from Reference 8 with permission) Category of study type
Annu. Rev. Med. 2014.65:95-110. Downloaded from www.annualreviews.org by Lomonosov Moscow State University on 01/18/14. For personal use only.
Category Element
A Prospective
B Prospective using archived samples
C Prospective/observational
D Retrospective/observational
Clinical trial
PCT designed to address tumor marker
Prospective trial not designed to address tumor marker, but design accommodates tumor marker utility. Accommodation of predictive marker requires PRCT
Prospective observational registry, treatment and follow-up not dictated
No prospective aspect to study
Patients and patient data
Prospectively enrolled, treated, and followed in PCT
Prospectively enrolled, treated, and followed in clinical trial and, especially if a predictive utility is considered, a PRCT addressing the treatment of interest
Prospectively enrolled in registry, but treatment and follow-up standard of care
No prospective stipulation of treatment or follow-up; patient data collected by retrospective chart review
Specimen collection, processing, and archival
Specimens collected, processed and assayed for specific marker in real time
Specimens collected, processed, and archived prospectively using generic SOPs. Assayed after trial completion
Specimens collected, processed, and archived prospectively using generic SOPs. Assayed after trial completion
Specimens collected, processed and archived with no prospective SOPs
Statistical design and analysis
Study powered to address tumor marker question
Study powered to address therapeutic question; underpowered to address tumor marker question
Study not prospectively powered at all. Retrospective study design confounded by selection of specimens for study
Study not prospectively powered at all. Retrospective study design confounded by selection of specimens for study.
Focused analysis plan for marker question developed before doing assays
Focused analysis plan for marker question developed before doing assays
No focused analysis plan for marker question developed before doing assays
Result unlikely to be due to chance
Result more likely to be due to chance than A but less likely than C
Result very likely to be due to chance
Result very likely to be due to chance
Although preferred, validation not required
Requires one or more validation studies
Requires subsequent validation studies
Requires subsequent validation
Validation
Abbreviations: PCT, prospective controlled trial; PRCT, prospective randomized controlled trial; SOPs, standard operating practices.
compared to women with wildtype alleles (15). For women with abnormal BRCA1 or -2, the absolute risk by age 60 of developing breast cancer or ovarian cancer is 60–80% or 20–
30%, respectively. Furthermore, prophylactic mastectomy and ovariectomy have been shown to reduce the incidence and mortality of these two malignancies by 90% or more (16). www.annualreviews.org • Molecular Testing in Breast Cancer
99
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Discovery and test validation stage
Three potential pathways (IRB approval and FDA consultation)
Test validation phase Analytical and clinical/biological validation Product is a fully specified and locked-down omics-based clinical test
Bright line
Discovery phase Product is a fully specified candidate omics-based test with locked-down computational procedures
Evaluation for clinical utility and use stage
Prospective/ retrospective study with archived specimens
Prospective clinical trial; test does not direct patient management
Prospective clinical trial; test directs patient management
IDE needed? No
No
Yes
FDA approval/clearance or LDT process for clinical test
Annu. Rev. Med. 2014.65:95-110. Downloaded from www.annualreviews.org by Lomonosov Moscow State University on 01/18/14. For personal use only.
Additional high-quality evidence to evaluate clinical utility of the test Practice guidelines and reimbursement Clinical use
Figure 2 The omics-based biomarker test development process consists of two stages: discovery and test validation followed by evaluation for clinical utility. The latter includes three potential pathways: prospective/retrospective study with archived specimens, prospective clinical trial where the test does not direct patient management, and prospective clinical trial where the test directs patient management. Modified from Reference 12 with permission. Abbreviations: FDA, US Food and Drug Administration; IRB, institutional review board; IDE, investigational device exemption; LDT, laboratory-developed test.
IHC: immunohistochemistry
100
A highly validated assay for SNPs in these genes is commercially available (BRCAnalysis test, Myriad Genetics, Salt Lake City, UT). Testing is not appropriate for the general population; it is recommended only for women who are reasonably likely to test positive, and specific algorithms have been developed to identify such women. If an affected proband has wildtype genotypes for BRCA1 and -2, the decision to test the remaining members of the family depends on the relative cancer history of the proband (age of incidence, type of cancer) and the degree of suspicion based on the remaining family history. If s/he is positive, then other blood relatives, especially females, are strongly urged to seek genetic counseling and testing. Although the absolute risk for an individual harboring such germline abnormalities is quite high, the attributable risk of BRCA1/2 mutations in the general population is small, as
ARI
ANNUAL REVIEWS
19 December 2013
Further
Annu. Rev. Med. 2014.65:95-110. Downloaded from www.annualreviews.org by Lomonosov Moscow State University on 01/18/14. For personal use only.
Click here for quick links to Annual Reviews content online, including: • Other articles in this volume • Top cited articles • Top downloaded articles • Our comprehensive search
7:38
Molecular Testing in Breast Cancer Costanza Paoletti and Daniel F. Hayes Breast Oncology Program of the Comprehensive Cancer Center, and the Department of Internal Medicine, University of Michigan Health and Hospital System, Ann Arbor, Michigan 48109; email: [email protected]
Annu. Rev. Med. 2014. 65:95–110
Keywords
The Annual Review of Medicine is online at med.annualreviews.org
tumor biomarker tests, breast cancer
This article’s doi: 10.1146/annurev-med-070912-143853
Abstract
c 2014 by Annual Reviews. Copyright All rights reserved
Tumor biomarker tests are critical to implementation of personalized medicine for patients at risk for or affected by breast cancer. A tumor biomarker test must have high analytical validity and clinical utility to be used to guide clinical care in standard practice. Few tumor biomarkers meet these high standards. These include germline DNA single-nucleotide polymorphisms in the BRCA1 and -2 genes to determine high risk in unaffected women, selected tissue-based markers to determine prognosis and predict benefit from therapy, and circulating MUC1, CEA and perhaps tumor cells to monitor patients with metastatic disease. Efforts to discover biomarkers that predict therapeutic toxicity are promising but not yet successful. Further research is needed to enhance the number of tumor biomarker tests so that patients with breast cancer can get the correct treatment at the appropriate time.
95
ME65CH07-Hayes
ARI
19 December 2013
7:38
INTRODUCTION HER2: human epidermal receptor type 2 21-gene RS: 21-gene recurrence score
Annu. Rev. Med. 2014.65:95-110. Downloaded from www.annualreviews.org by Lomonosov Moscow State University on 01/18/14. For personal use only.
ER: estrogen receptor
“Personalized medicine” implies getting the right treatment to the right patient at the right time. Breast cancer causes substantial morbidity and mortality, and treatments for it have a very narrow benefit/toxicity ratio. Therefore, the development of highly validated tumor markers is crucial to guide diversified treatments. These considerations raise many questions. What is a tumor biomarker, and what are the tests to assay for it? What are the clinical uses for a tumor biomarker test? What are the necessary criteria to determine if and when a tumor biomarker test should be used to guide clinical decisions? And finally, what tumor biomarker tests have met these criteria for the specific uses one might identify?
WHAT IS A TUMOR BIOMARKER AND WHAT ARE THE TESTS TO ASSAY FOR IT? A tumor biomarker is defined as “a substance that is produced by cancer cells or by other cells of the body in response to cancer or certain benign (noncancerous) conditions” (1). This definition includes abnormalities in DNA (germline or somatic), RNA, proteins, metabolites, and abnormal cellular or tissue processes. The majority of tumor biomarker assays are performed on the cancer tissue itself. However, tumor biomarkers can also be monitored in blood, urine, stool, saliva, and in the case of breast cancer, breast ductal fluid. One must distinguish a putative tumor biomarker in concept from a specific test that measures the marker reliably. For example, the human epidermal receptor type 2 (HER2) is clearly an important tumor biomarker for breast cancer. However, HER2 abnormalities, as determined by a number of different assay platforms, include amplification, mutations, and/or overexpression at the message or protein levels (2, 52). Moreover, elevated circulating levels of the soluble extracellular domain of HER2 are frequently detected in patients with breast cancer (3, 4). Each of these distinct tests for each of these different types of 96
Paoletti
·
Hayes
abnormalities may have varying meanings and uses and cannot be considered interchangeable. Therefore, the clinician must be aware of these subtle but important technical nuances and understand that the test used to detect, quantify, or monitor a tumor biomarker is critical to its application in the clinic. Classically, a tumor biomarker test has been directed toward a single analyte (such as HER2 protein). However, with the advances in omicsbased technology during the past decade, several multi-parameter assays have emerged, in which multiple analytes, such as expression of several genes, are measured, and a weighted algorithm is developed to generate a single result, index, signature, or “score.” For example, a R , 21-gene recurrence score (RS) (OncotypeDx Genomic Health, Inc., Redwood City, CA) incorporates expression data from 16 informative and five control genes, including relative expression levels of estrogen receptor (ER), HER2, proliferation, and invasion and metastasis signaling pathways. This assay is now widely accepted for determination of prognosis and prediction of chemotherapy benefit in patients with newly diagnosed, ER-positive, node-negative breast cancer (3).
WHAT ARE THE CLINICAL USES FOR A TUMOR BIOMARKER TEST? It is important to understand the potential uses and contexts in which a tumor biomarker test might be applied. Each is different depending on the status of the patient. The spectrum of breast cancer patient status (Figure 1) ranges from unaffected individuals who are concerned about whether they should adopt preventive or screening strategies, to patients with early-stage disease for whom considerations of appropriate primary (surgery and radiation) and adjuvant systemic (chemo, endocrine, and anti-HER2) therapies are critical, to those who are free of disease but are concerned about recurrence, and finally to patients with established metastatic disease. In this regard, tumor biomarker tests might be useful for risk
ME65CH07-Hayes
ARI
19 December 2013
7:38
Clinical spectrum of breast cancer Normal
High risk Carcinoma
In situ
Invasive
Micro-metastatic Regional lymph nodes Bone marrow Blood
Detectable metastatic Distant organs
Risk categorization
Annu. Rev. Med. 2014.65:95-110. Downloaded from www.annualreviews.org by Lomonosov Moscow State University on 01/18/14. For personal use only.
Screening for new primary Differential diagnosis Prognosis and prediction Monitoring disease status Screening for occult metastases Determination of progression
Figure 1 Clinical spectrum of breast cancer and potential uses of tumor biomarkers.
categorization, screening, differential diagnosis, prognosis and/or prediction of benefit from therapy, or monitoring of disease status, in the adjuvant or metastatic settings (5) (Table 1).
WHAT ARE THE CRITERIA TO DETERMINE IF A TUMOR BIOMARKER TEST SHOULD BE USED IN A PATIENT’S CARE? Although there are thousands of papers in the literature that pertain to breast cancer tumor
biomarkers, very few have been adopted into the clinic. A Breast Cancer Tumor Marker Guidelines Panel convened by the American Society of Clinical Oncology (ASCO) has only recommended tests for five tissue-based biomarkers [ER, progesterone receptor (PgR), HER2, the 21-gene RS, and urinary plasminogen activator/plasminogen activator inhibitor 1 (UPA/PAI-1)] and for two circulating biomarkers [carcinoembryonic antigen (CEA) and the protein product of the mucin 1 (MUC1) gene] (3). Very similar recommendations have been
ASCO: American Society of Clinical Oncology PgR: progesterone receptor UPA: urinary plasminogen activator PAI-1: plasminogen activator inhibitor 1 CEA: carcinoembryonic antigen MUC1: mucin 1
Table 1 Potential uses of tumor biomarkers Risk categorization Screening for new primary cancers Differential diagnosis of abnormal finding on breast imaging Prognosis Prediction Monitoring disease course: patients who are free of disease to detect occult recurrence patients with established metastases
www.annualreviews.org • Molecular Testing in Breast Cancer
97
ME65CH07-Hayes
ARI
19 December 2013
7:38
issued by the National Comprehensive Cancer Network (NCCN) Breast Cancer Guidelines Panel (6). These guidelines are so conservative because the panels have tried to adhere to the principles of evidence-based medicine. In this regard, several initiatives have been proposed in the past 15 years to clarify the criteria to establish that a given tumor biomarker test should be used to guide an individual’s cancer management. In 2009, the Evaluation of Genomic Applications in Practice and Prevention working group articulated three important concepts to clarify the field: analytical validity, clinical validity, and clinical utility (7). Analytical validity implies that the test is accurate, reproducible, and reliable. Clinical validity implies that the test divides one population into two or more separate groups that have significantly different clinical outcomes. However, it does not imply that the test should be used to care for patients. A tumor biomarker test has clinical utility only if its use improves patient outcomes, as demonstrated with high levels of evidence (8). The criteria for clinical utility depend on the relative benefit and toxicities and costs of the therapeutic intervention, and on the perceptions of the patient, caregiver, and society regarding these benefits and costs. High levels of evidence must be generated with the same rigor used to demonstrate the clinical utility of new therapeutics. Investigators have proposed a hierarchy of studies that might result in the level of evidence required to demonstrate clinical utility, either within prospective clinical trials or “prospective retrospective” studies using archived specimens from earlier prospective trials (Table 2) (8–11). All of these concepts were recently summarized in a report released by the Institute of Medicine (IOM) regarding the generation of tumor biomarker omics-based tests (Figure 2) (12). Although the IOM Committee was charged with review of omics-based tests, these concepts are applicable to development of any tumor biomarker test. In summary, the decision whether to use a tumor biomarker test to direct the care of a pa-
Annu. Rev. Med. 2014.65:95-110. Downloaded from www.annualreviews.org by Lomonosov Moscow State University on 01/18/14. For personal use only.
NCCN: National Cancer Center Network
98
Paoletti
·
Hayes
tient with breast cancer is as important as selection of a drug and determination of the proper dose and schedule. The stakes are high: use of a tumor biomarker test with poor analytical validity or weak evidence that it has clinical utility will lead to mistreatment, with potentially catastrophic results.
WHICH TUMOR BIOMARKER TESTS ARE “READY FOR PRIME TIME”? Each of the contexts in which a tumor biomarker test might have clinical utility (Figure 1, Table 1) is different and deserves special discussion.
Risk Categorization Prevention and screening strategies for breast cancer successfully reduce the odds of having and/or dying of the disease (13, 14). However, each of these strategies is associated with adverse consequences and costs. Therefore, determination of risk, especially with a tumor biomarker test, would have enormous value. For example, the association between absence of a Y chromosome and incidence of breast cancer is one of the most powerful risk factors for any disease. The relative and attributable risks for breast cancer of being female are extraordinary. Women are 100-fold more likely to develop breast cancer than men, and 99% of breast cancers occur in women. Thus, preventive and screening strategies are almost exclusively confined to women, mostly aged 40–75. However, only ∼10% of all women will develop breast cancer in their lifetimes. Unfortunately, other than sex and age, few other risk factors have sufficient clinical utility to be used to focus screening and prevention strategies. Selected germline markers of susceptibility have analytical validity and clinical utility for risk assessment and therapeutic recommendations. Women with deleterious inherited single-nucleotide polymorphisms (SNPs) in the tumor suppressor genes, BRCA1 and BRCA2, have a five- to tenfold increased risk of developing a new breast cancer
ME65CH07-Hayes
ARI
19 December 2013
7:38
Table 2 Hierarchy of studies to establish levels of evidence for clinical utility of tumor biomarker tests (from Reference 8 with permission) Category of study type
Annu. Rev. Med. 2014.65:95-110. Downloaded from www.annualreviews.org by Lomonosov Moscow State University on 01/18/14. For personal use only.
Category Element
A Prospective
B Prospective using archived samples
C Prospective/observational
D Retrospective/observational
Clinical trial
PCT designed to address tumor marker
Prospective trial not designed to address tumor marker, but design accommodates tumor marker utility. Accommodation of predictive marker requires PRCT
Prospective observational registry, treatment and follow-up not dictated
No prospective aspect to study
Patients and patient data
Prospectively enrolled, treated, and followed in PCT
Prospectively enrolled, treated, and followed in clinical trial and, especially if a predictive utility is considered, a PRCT addressing the treatment of interest
Prospectively enrolled in registry, but treatment and follow-up standard of care
No prospective stipulation of treatment or follow-up; patient data collected by retrospective chart review
Specimen collection, processing, and archival
Specimens collected, processed and assayed for specific marker in real time
Specimens collected, processed, and archived prospectively using generic SOPs. Assayed after trial completion
Specimens collected, processed, and archived prospectively using generic SOPs. Assayed after trial completion
Specimens collected, processed and archived with no prospective SOPs
Statistical design and analysis
Study powered to address tumor marker question
Study powered to address therapeutic question; underpowered to address tumor marker question
Study not prospectively powered at all. Retrospective study design confounded by selection of specimens for study
Study not prospectively powered at all. Retrospective study design confounded by selection of specimens for study.
Focused analysis plan for marker question developed before doing assays
Focused analysis plan for marker question developed before doing assays
No focused analysis plan for marker question developed before doing assays
Result unlikely to be due to chance
Result more likely to be due to chance than A but less likely than C
Result very likely to be due to chance
Result very likely to be due to chance
Although preferred, validation not required
Requires one or more validation studies
Requires subsequent validation studies
Requires subsequent validation
Validation
Abbreviations: PCT, prospective controlled trial; PRCT, prospective randomized controlled trial; SOPs, standard operating practices.
compared to women with wildtype alleles (15). For women with abnormal BRCA1 or -2, the absolute risk by age 60 of developing breast cancer or ovarian cancer is 60–80% or 20–
30%, respectively. Furthermore, prophylactic mastectomy and ovariectomy have been shown to reduce the incidence and mortality of these two malignancies by 90% or more (16). www.annualreviews.org • Molecular Testing in Breast Cancer
99
ME65CH07-Hayes
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19 December 2013
7:38
Discovery and test validation stage
Three potential pathways (IRB approval and FDA consultation)
Test validation phase Analytical and clinical/biological validation Product is a fully specified and locked-down omics-based clinical test
Bright line
Discovery phase Product is a fully specified candidate omics-based test with locked-down computational procedures
Evaluation for clinical utility and use stage
Prospective/ retrospective study with archived specimens
Prospective clinical trial; test does not direct patient management
Prospective clinical trial; test directs patient management
IDE needed? No
No
Yes
FDA approval/clearance or LDT process for clinical test
Annu. Rev. Med. 2014.65:95-110. Downloaded from www.annualreviews.org by Lomonosov Moscow State University on 01/18/14. For personal use only.
Additional high-quality evidence to evaluate clinical utility of the test Practice guidelines and reimbursement Clinical use
Figure 2 The omics-based biomarker test development process consists of two stages: discovery and test validation followed by evaluation for clinical utility. The latter includes three potential pathways: prospective/retrospective study with archived specimens, prospective clinical trial where the test does not direct patient management, and prospective clinical trial where the test directs patient management. Modified from Reference 12 with permission. Abbreviations: FDA, US Food and Drug Administration; IRB, institutional review board; IDE, investigational device exemption; LDT, laboratory-developed test.
IHC: immunohistochemistry
100
A highly validated assay for SNPs in these genes is commercially available (BRCAnalysis test, Myriad Genetics, Salt Lake City, UT). Testing is not appropriate for the general population; it is recommended only for women who are reasonably likely to test positive, and specific algorithms have been developed to identify such women. If an affected proband has wildtype genotypes for BRCA1 and -2, the decision to test the remaining members of the family depends on the relative cancer history of the proband (age of incidence, type of cancer) and the degree of suspicion based on the remaining family history. If s/he is positive, then other blood relatives, especially females, are strongly urged to seek genetic counseling and testing. Although the absolute risk for an individual harboring such germline abnormalities is quite high, the attributable risk of BRCA1/2 mutations in the general population is small, as
