Clinical Utility of Identification and Return of Research Germline Mutation Results to Gynecologic Cancer Patients Enrolled in Total Cancer Care

Objectives: Approximately 18% of ovarian cancer and 5% of uterine cancer patients have underlying genetic predispositions. All women with ovarian cancer and young women with uterine cancer should receive germline genetic testing and counseling; however, fewer than 20% of ovarian cancer patients complete this process. Patients with germline alterations may respond differently to cancer therapies, and pharmacogene mutations may alter the efficacy and toxicity of cancer treatments. The objectives of our study were to identify associations between germline pharmacogene mutations in gynecologic cancers and to determine the clinical utility of returning research whole exome sequencing germline mutation results to gynecologic cancer patients enrolled in Total Cancer Care (TCC). Methods: At our institution, 229 patients enrolled in TCC underwent research germline whole exome sequencing and consented to return of these results. BAM files were processed in a Clinical Laboratory Improvement Amendments-compliant bioinformatics pipeline to identify clinically actionable and selected pharmacogene mutations. To date, our multidisciplinary Molecular Tumor Board has reviewed 112 sequencing reports; 25 of these patients have gynecologic malignancies. Patients with identified American College of Medical Genetics (ACMG)-reportable mutations are recommended to follow up with genetic counseling and confirmatory clinical testing. We compared mutation frequencies and genetic counseling practices with a cohort of 176 patients without malignancy who underwent similar sequencing. Results: We identified ACMG-reportable gene mutations, including BRCA2, MUTYH, and TP53, in 4/25 (16%) of gynecologic cancer patients. Two patients had previously completed genetic counseling and clinical testing. Two patients were recommended for follow-up genetic counseling and confirmatory clinical testing based on their research germline results; one followed up, and one did not. Clinical and research genetic testing were congruent in all cases. Patients with any cancer were more likely to carry any germline pharmacogene mutation (102/112, 91.1%) than patients without malignancy (115/176, 65.3%; p<0.001). In gynecologic cancer patients, mutations in UGT1A1, CYP4F2, TPMT, and CYP2C9 were seen with higher than expected population frequencies. Conclusions: Clinical genetic sequencing may only test for a small subset of pathogenic alterations; research whole exome sequencing may identify additional germline mutations that may carry clinical significance. Our experience reviewing and returning research sequencing results indicates this process can identify patients and families at risk and may identify additional treatment options. Further research on the risk of malignancy and treatment toxicities in patients with pharmacogenetic variants is warranted. Identifying women with germline mutations and follow-up genetic counseling is imperative for personalized cancer treatment. Approximately 18% of ovarian cancer and 5% of uterine cancer patients have underlying genetic predispositions. All women with ovarian cancer and young women with uterine cancer should receive germline genetic testing and counseling; however, fewer than 20% of ovarian cancer patients complete this process. Patients with germline alterations may respond differently to cancer therapies, and pharmacogene mutations may alter the efficacy and toxicity of cancer treatments. The objectives of our study were to identify associations between germline pharmacogene mutations in gynecologic cancers and to determine the clinical utility of returning research whole exome sequencing germline mutation results to gynecologic cancer patients enrolled in Total Cancer Care (TCC). At our institution, 229 patients enrolled in TCC underwent research germline whole exome sequencing and consented to return of these results. BAM files were processed in a Clinical Laboratory Improvement Amendments-compliant bioinformatics pipeline to identify clinically actionable and selected pharmacogene mutations. To date, our multidisciplinary Molecular Tumor Board has reviewed 112 sequencing reports; 25 of these patients have gynecologic malignancies. Patients with identified American College of Medical Genetics (ACMG)-reportable mutations are recommended to follow up with genetic counseling and confirmatory clinical testing. We compared mutation frequencies and genetic counseling practices with a cohort of 176 patients without malignancy who underwent similar sequencing. We identified ACMG-reportable gene mutations, including BRCA2, MUTYH, and TP53, in 4/25 (16%) of gynecologic cancer patients. Two patients had previously completed genetic counseling and clinical testing. Two patients were recommended for follow-up genetic counseling and confirmatory clinical testing based on their research germline results; one followed up, and one did not. Clinical and research genetic testing were congruent in all cases. Patients with any cancer were more likely to carry any germline pharmacogene mutation (102/112, 91.1%) than patients without malignancy (115/176, 65.3%; p<0.001). In gynecologic cancer patients, mutations in UGT1A1, CYP4F2, TPMT, and CYP2C9 were seen with higher than expected population frequencies. Clinical genetic sequencing may only test for a small subset of pathogenic alterations; research whole exome sequencing may identify additional germline mutations that may carry clinical significance. Our experience reviewing and returning research sequencing results indicates this process can identify patients and families at risk and may identify additional treatment options. Further research on the risk of malignancy and treatment toxicities in patients with pharmacogenetic variants is warranted. Identifying women with germline mutations and follow-up genetic counseling is imperative for personalized cancer treatment.