Expanded Gene Panel Use for Women With Breast Cancer: Identification and Intervention Beyond Breast Cancer Risk

Abstract

BackgroundClinicians ordering multi-gene next-generation sequencing panels for hereditary breast cancer risk have a variety of test panel options. Many panels include lesser known breast cancer genes or genes associated with other cancers. The authors hypothesized that using broader gene panels increases the identification of clinically significant findings, some relevant and others incidental to the testing indication. They examined clinician ordering patterns and compared the yield of pathogenic or likely pathogenic (P/LP) variants in non-BRCA genes of female breast cancer patients.MethodsThis study analyzed de-identified personal and family histories in 1085 breast cancer cases with P/LP multi-gene panel findings in non-BRCA cancer genes and sorted them into three groups by the panel used for testing: group A (breast cancer genes only), group B (commonly assessed cancers: breast, gynecologic, and gastrointestinal), and group C (a more expanded set of tumors). The frequency of P/LP variants in genes with established management guidelines was compared and evaluated for consistency with personal and family histories.ResultsThis study identified 1131 P/LP variants and compared variants in clinically actionable genes for breast and non-breast cancers. Overall, 91.5% of these variants were in genes with management guidelines. Nearly 12% were unrelated to personal or family history.ConclusionBroader panels were used for 85.6% of our cohort (groups B and C). Although pathogenic variants in non-BRCA genes are reportedly rare, the study found that most were in clinically actionable genes. Expanded panel testing improved the identification of hereditary cancer risk. Small, breast-limited panels may miss clinically relevant findings in genes associated with other heritable cancers.Electronic supplementary materialThe online version of this article (doi:10.1245/s10434-017-5963-7) contains supplementary material, which is available to authorized users.

Prevalence of nonfounder BRCA1/2 mutations in Ashkenazi Jewish patients presenting for genetic testing at a hereditary breast and ovarian cancer center

“…Among those patients with mutations, 78 patients (77.2%) had a BRCA1/2 AJ founder mutation, 3 patients (3.0%) had a nonfounder BRCA1/2 mutation, and 20 patients (19.8%) had a mutation in a gene other than BRCA1/2. 28,29 These findings have led many to conclude that comprehensive testing provides complete relevant genetic information for highrisk AJ patients. Of the 101 patients with pathogenic mutations, 23 patients (22.8%) would have had a missed opportunity for the diagnosis of a cancer-associated mutation using BRCA1/2 founder mutation testing alone.…”

“…Furthermore, the prevalence of non-BRCA1/2 mutations in AJ cohorts is not very different from rates reported in the general population. 28,29 These findings have led many to conclude that comprehensive testing provides complete relevant genetic information for highrisk AJ patients. 20 However, others have challenged the assertion that large multigene panels are appropriate for AJ patients.…”

SEOM clinical guidelines in hereditary breast and ovarian cancer (2019)

“…(b) Recent research supports BRCA testing in a broader range of individuals, if not in every breast cancer patient. This recommendation is based on the findings of studies that conclude that the traditional approach may miss up to 50% of mutation carriers [5,6].…”

Genetic testing for hereditary breast and ovarian cancer and the USPSTF recommendations

“…The identification of potentially actionable mutation in genes other than BRCA1 and BRCA2 has led to the suggestion that panel testing should replace BRCA testing alone for most women at increased risk for breast cancer, ovarian cancer, or both . Studies have shown the ability of expanded panel testing to not only improve identification of hereditary breast and ovarian cancer predisposition but also to impact the care of both patients with and without cancer . Furthermore, panel testing is more cost effective compared to BRCA‐only testing .…”

“…9 Studies have shown the ability of expanded panel testing to not only improve identification of hereditary breast and ovarian cancer predisposition but also to impact the care of both patients with and without cancer. 10,11 Furthermore, panel testing is more cost effective compared to BRCA-only testing. 12,13 Panel testing has now become the norm in cancer genetics programs, [14][15][16] although there are no specific guidelines regarding the optimal number of genes that should comprise a panel.…”