Abstract P4-12-04: Clinical evaluation of multigene testing for hereditary breast and ovarian cancer
Authors: Ellisen Leif , Kurian Allison , Lincoln Stephen , Desmond Andrea , Mills Meredith , Shannon Kristen , Gabree Michelle , Anderson Michael , Kobayashi Yuya , Monzon Federico , Ford James 
Published: May 2015

Background: Advances in DNA sequencing technology have fueled the development of multigene panels for hereditary cancer testing. While such assays are potentially both practical and affordable for routine clinical genetic testing, there remains uncertainty regarding their proper application and interpretation. Among the unanswered questions are which patients are appropriate candidates for such expanded testing; what is the likelihood that finding deleterious variants will alter risk assessment and management, and what is the prevalence of variants of unknown significance (VUS) that may create uncertainty for providers and anxiety for patients.

Methods: 821 patients who met NCCN guidelines for BRCA1/2 testing for hereditary breast/ovarian cancer (HBOC) were prospectively recruited at two major academic medical centers. These patients received traditional BRCA1/2 tests as part of their clinical care and also were later tested for a panel of 29 known cancer risk genes. This panel also re-tested BRCA1/2. Both sequence changes and deletions/duplications were reported, and the panel-testing laboratory was blind to the earlier results. Panel testing results were validated by comparison with the earlier data or by independent testing using established technologies. Family history information was collected directly by genetic counselors.

Results: 13.8% of the patients carried BRCA1 or BRCA2 mutations, with &gt;99% concordance between the traditional and panel results for these two genes. 53 (7.6%) of the BRCA1/2-negative patients carried mutations in other cancer risk genes. Some of these findings confer a high risk for breast/ovarian cancer (e.g. TP53), while others (i.e. CHEK2, BRIP1, PALB2, RAD51C, CDKN2A, ATM, and NBN) confer a moderate increase in risk. 10 of these 55 patients were positive for genes involved in Lynch syndrome (MLH1, MSH2, MSH6, and PMS2), although breast and ovarian cancer are not uniformly accepted as part of this syndrome. 40% of these patients were heterozygous carriers of pathogenic variants in MUTYH, which have a less clear impact on breast/ovarian cancer, although this rate (3%) is higher than the expected carrier frequency in this population.

About 60% of patients had one or more VUS in the 29 genes. The rate of VUS was highly gene dependent, with ATM, APC, and PTCH1 providing the largest number. A small but significant subset of patients did not have personal or family histories consistent with the classical presentation of their identified mutation. Nevertheless, a majority of the non-BRCA1/2 findings would have prompted consideration of a management change for the tested patient even considering the personal and family cancer history.

Conclusions: Multigene panel testing for hereditary cancer risk assessment increased the yield of findings with potential clinical impact for almost 8% of patients. This is consistent with prior data from our laboratory and others. This study, carried out in a uniform clinical practice setting and with data collected directly by health care providers, provides a representative view of the benefit from such testing in an unselected patient population.

Citation Format: Leif Ellisen, Allison Kurian, Stephen Lincoln, Andrea Desmond, Meredith Mills, Kristen Shannon, Michelle Gabree, Michael Anderson, Yuya Kobayashi, Federico Monzon, James Ford. Clinical evaluation of multigene testing for hereditary breast and ovarian cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-12-04.