JAMA Network open access
Importance
The practice of genetic testing for hereditary breast and/or
ovarian cancer (HBOC) is rapidly evolving owing to the recent
introduction of multigene panels. While these tests may identify 40% to
50% more individuals with hereditary cancer gene mutations than does
testing for BRCA1/2 alone, whether finding such mutations will alter clinical management is unknown.
Objective To define the potential clinical effect of multigene panel testing for HBOC in a clinically representative cohort.
Design, Setting, and Participants Observational study of patients seen between 2001 and 2014 in 3 large academic medical centers. We prospectively enrolled 1046 individuals who were appropriate candidates for HBOC evaluation and who lacked BRCA1/2 mutations.
Interventions We carried out multigene panel testing on all participants, then determined the clinical actionability, if any, of finding non-BRCA1/2 mutations in these and additional comparable individuals.
Main Outcomes and Measures We evaluated the likelihood of (1) a posttest management change and (2) an indication for additional familial testing, considering gene-specific consensus management guidelines, gene-associated cancer risks, and personal and family history.
Results Among 1046 study participants, 40 BRCA1/2-negative patients (3.8%; 95% CI, 2.8%-5.2%) harbored deleterious mutations, most commonly in moderate-risk breast and ovarian cancer genes (CHEK2, ATM, and PALB2) and Lynch syndrome genes. Among these and an additional 23 mutation-positive individuals enrolled from our clinics, most of the mutations (92%) were consistent with the spectrum of cancer(s) observed in the patient or family, suggesting that these results are clinically significant. Among all 63 mutation-positive patients, additional disease-specific screening and/or prevention measures beyond those based on personal and family history alone would be considered for most (33 [52%] of 63; 95% CI, 40.3%-64.2%). Furthermore, additional familial testing would be considered for those with first-degree relatives (42 [72%] of 58; 95% CI, 59.8%-82.2%) based on potential management changes for mutation-positive relatives. This clinical effect was not restricted to a few of the tested genes because most identified genes could change clinical management for some patients.
Conclusions and Relevance In a clinically representative cohort, multigene panel testing for HBOC risk assessment yielded findings likely to change clinical management for substantially more patients than does BRCA1/2 testing alone. Multigene testing in this setting is likely to alter near-term cancer risk assessment and management recommendations for mutation-affected individuals across a broad spectrum of cancer predisposition genes.
Objective To define the potential clinical effect of multigene panel testing for HBOC in a clinically representative cohort.
Design, Setting, and Participants Observational study of patients seen between 2001 and 2014 in 3 large academic medical centers. We prospectively enrolled 1046 individuals who were appropriate candidates for HBOC evaluation and who lacked BRCA1/2 mutations.
Interventions We carried out multigene panel testing on all participants, then determined the clinical actionability, if any, of finding non-BRCA1/2 mutations in these and additional comparable individuals.
Main Outcomes and Measures We evaluated the likelihood of (1) a posttest management change and (2) an indication for additional familial testing, considering gene-specific consensus management guidelines, gene-associated cancer risks, and personal and family history.
Results Among 1046 study participants, 40 BRCA1/2-negative patients (3.8%; 95% CI, 2.8%-5.2%) harbored deleterious mutations, most commonly in moderate-risk breast and ovarian cancer genes (CHEK2, ATM, and PALB2) and Lynch syndrome genes. Among these and an additional 23 mutation-positive individuals enrolled from our clinics, most of the mutations (92%) were consistent with the spectrum of cancer(s) observed in the patient or family, suggesting that these results are clinically significant. Among all 63 mutation-positive patients, additional disease-specific screening and/or prevention measures beyond those based on personal and family history alone would be considered for most (33 [52%] of 63; 95% CI, 40.3%-64.2%). Furthermore, additional familial testing would be considered for those with first-degree relatives (42 [72%] of 58; 95% CI, 59.8%-82.2%) based on potential management changes for mutation-positive relatives. This clinical effect was not restricted to a few of the tested genes because most identified genes could change clinical management for some patients.
Conclusions and Relevance In a clinically representative cohort, multigene panel testing for HBOC risk assessment yielded findings likely to change clinical management for substantially more patients than does BRCA1/2 testing alone. Multigene testing in this setting is likely to alter near-term cancer risk assessment and management recommendations for mutation-affected individuals across a broad spectrum of cancer predisposition genes.
INTRODUCTION
ABSTRACT
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INTRODUCTION
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METHODS
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RESULTS
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DISCUSSION
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CONCLUSIONS
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ARTICLE INFORMATION
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REFERENCES
Genetic
testing for hereditary cancer predisposition genes represents an
important advance in cancer medicine. In particular, the identification
of individuals at elevated risk for hereditary breast and/or ovarian
cancers (HBOCs) has allowed the development of consensus recommendations
for cancer screening and prevention.1,2
Implementing mutation-based cancer screening and prevention guidelines,
such as prophylactic salpingo-oophorectomy for carriers of germline BRCA1 and BRCA2 (hereafter BRCA1/2) mutations, is associated with an increase in both cancer-specific and overall survival.3,4 While the clinical implementation of genetic testing for BRCA1/2
preceded the development of firm mutation-based management guidelines,
the wide availability of a validated platform for this testing
contributed to our understanding of genetic cancer risk and ultimately
to more effective management of these patients.5 ......
