Clinical Actionability of Multigene Panel Testing for Hereditary Breast and Ovarian Cancer Risk Assessment

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.

INTRODUCTION

ABSTRACT | INTRODUCTION | METHODS | RESULTS | DISCUSSION | CONCLUSIONS | ARTICLE INFORMATION | 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 ......}