Germline and Somatic Testing in Ovarian Cancer: Shifting Sands of Recommendations

Abstract

Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy. In 2020, an estimated 13,940 American women will die of this disease [ [2] American Cancer Society Cancer Facts and Figures 2020. 2020 Google Scholar ]. However, as of 2016, 133,381 women were living with ovarian cancer in the United States [ [3] U.S. Cancer Statistics Working Group U.S. Cancer Statistics Data Visualiztions Tool, based on November 2018 submission data (1999-2016). Publisher Name: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institutewww.cdc.gv/cancer/dataviz Google Scholar ]. Multiple advances play a role in the increasing number of ovarian cancer survivors, including better supportive care, dissemination of best practices, and development of active agents that incrementally improved progression-free and overall survival. Another critical factor is the increased recognition of EOC as at least five different diseases, inclusive of high-grade serous (HGS), low-grade serous, endometrioid, clear cell and mucinous histologic subtypes, each driven by distinct genetic aberrations and warranting different therapeutic strategies [ [4] Vaughan S. Coward J.I. Bast Jr., R.C. et al. Rethinking ovarian cancer: recommendations for improving outcomes. Nat. Rev. Cancer. 2011; 11: 719-725 Crossref PubMed Scopus (815) Google Scholar ]. Both germline and somatic genetic aberrations are associated with the development and treatment of EOC, emphasizing that genetic assessment is integral to modern management. For women with EOC, offering indicated testing is a mandatory component of the standard of care; however, uncertainty remains as to whom to test, what specimen to test, what test to order, and how to operationalize results. In this issue of Gynecologic Oncology, Jorge et al. present compelling data on simultaneous germline and somatic testing among a cohort of women with EOC [ [5] Jorge S.M.A. Doll K.M. Pennington K.P. Norquist B.M. Bennett R.L. Pritchard C.C. Swisher E.M. Simultaneous germlilne and somatic sequencing inovarian carcinoma: mutation rate and impact on clincal decision making. Gynecol. Oncol. 2020; 156: 517-522 Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar ]. They completed combined germline and somatic testing of EOC patients starting in 2017 using the BROCA assay, which reports all germline mutations and those somatic mutations that are considered actionable (defined as an FDA-approved therapy exists or a relevant clinical trial is available). Out of a series of 43 patients, 14% had germline mutations, 35% had somatic mutations, and 2% had both, for an overall rate of 51%. Confirming previous data, only 21% had a family history of breast or ovarian cancer; along with BRCA1 and BRCA2, other genes were mutated; and histologic subtypes other than HGS were noted to carry mutations. Their results should be taken in the context of the January 2020 release of the first American Society of Clinical Oncology (ASCO) guideline for germline and somatic testing in EOC [ [6] Konstantinopoulos P.A. Norquist B. Lacchetti C. et al. Germline and Somatic Tumor Testing in Epithelial Ovarian Cancer: ASCO Guideline. J. Clin. Oncol. 2020; JCO1902960 Crossref PubMed Scopus (46) Google Scholar ]. While this editorial is not an attempt to review that article, we think it is useful to summarize what experts consider the current standard of care for testing. 1.All women with EOC should be offered germline testing for ovarian cancer susceptibility genes through a multigene panel inclusive of BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, MLH1, MSH2, MSH6, PMS2 and PALB2. Somatic tumor testing for BRCA1 and BRCA2 pathogenic and likely pathogenic variants should be performed in women who do not have a germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants. This testing ideally should occur at the time of diagnosis, as the results have implications for management of frontline maintenance therapy decisions, but for women with recurrent disease who have not had testing, catch-up testing is indicated. 2.Women diagnosed with clear cell, endometrioid or mucinous EOC should be offered somatic tumor testing for mismatch repair deficiency (dMMR), as specific FDA-approved therapies exist based on the results. Testing may be extended to other histologic subtypes. 3.Genetic evaluations should be carried out by or in conjunction with health care providers who have expertise in interpretation and dissemination of results. First- and second-degree relatives of patients with a germline pathogenic or likely pathogenic variant should be offered individualized genetic risk evaluations. 4.Routine use of commercially available homologous recombination deficiency (HRD) assays is not recommended at this time. 5.Clinical decisions should NOT be made based on variants of uncertain significance (VUS); follow-up of VUS status for reclassification is warranted, with repeat counseling if indicated [ [6] Konstantinopoulos P.A. Norquist B. Lacchetti C. et al. Germline and Somatic Tumor Testing in Epithelial Ovarian Cancer: ASCO Guideline. J. Clin. Oncol. 2020; JCO1902960 Crossref PubMed Scopus (46) Google Scholar ].