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JAMA Oncol. 2015 Oct;1(7):943-51. doi: 10.1001/jamaoncol.2015.2690.

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

Author information

1
Massachusetts General Hospital Cancer Center, Boston.
2
Stanford University School of Medicine, Stanford, California.
3
Invitae Corporation, San Francisco, California.
4
Beth Israel Deaconess Medical Center, Boston, Massachusetts5Harvard Medical School, Boston, Massachusetts.
5
Massachusetts General Hospital Cancer Center, Boston5Harvard Medical School, Boston, Massachusetts.

Abstract

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.

PMID:
26270727
DOI:
10.1001/jamaoncol.2015.2690
[Indexed for MEDLINE]

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