Frequency of actionable germline pathogenic variants identified through tumor next-generation sequencing in a...

Tumor next-generation sequencing can identify potential germline pathogenic variants associated with cancer susceptibility.

To describe the frequency of tumor sequencing results that met European Society of Medical Oncology (ESMO) recommendations for further germline genetic testing, and the frequency of germline variants among a cohort with gynecologic cancer.

Patients with gynecologic cancer who underwent tumor sequencing between September 2019 and February 2022 in a large healthcare system in New York City were retrospectively identified. Eligible patients with suspected germline pathogenic variants on tumor sequencing were identified based on ESMO guidelines. Logistic regression was used to explore variables associated with referral and completion of germline testing.

Of 358 patients with gynecologic cancers who underwent tumor sequencing, 81 (22.6%) had ≥1 suspected germline variant according to ESMO guidelines. Of the 81 patients with qualifying tumor sequencing results, 56 (69.1%) received germline testing: 41/46 (89.1%) eligible patients with ovarian cancer and 15/33 (45.5%) with endometrial cancer. In the endometrial cancer cohort, 11/33 (33.3%) eligible patients were not referred for germline testing and the majority of these patients had tumor variants in genes commonly known to cause hereditary cancer. Of the 56 patients who underwent germline testing, 40 (71.4%) had pathogenic germline variants. In multivariable analysis, race/ethnicity other than non-Hispanic white was associated with lower odds of germline testing referral and completion (OR=0.1, 95% CI 0.01 to 0.5 and OR=0.2, 95% CI 0.04 to 0.6, respectively).

Given the high rate of pathogenic germline variant detection and the importance of identifying such variants for both patients and their family, it is imperative that eligible patients undergo germline testing. Additional education for providers on multidisciplinary guidelines and development of clinical pathways to ensure germline testing of suspected pathogenic variants identified on tumor sequencing is warranted, especially in light of the racial/ethnic inequity observed.