Universal Tumor DNA BRCA1/2 Testing of Ovarian Cancer

Prescreening PARPi Treatment and Genetic Predisposition

Janet R. Vos; Ingrid E. Fakkert; Joanne A. de Hullu; Anne M. van Altena; Aisha S. Sie; Hicham Ouchene; Riki W. Willems; Iris D. Nagtegaal; Marjolijn C. J. Jongmans; Arjen R. Mensenkamp; Gwendolyn H. Woldringh; Johan Bulten; Edward M. Leter; C. Marleen Kets; Michiel Simons; Marjolijn J. L. Ligtenberg; Nicoline Hoogerbrugge


J Natl Cancer Inst. 2020;112(2):161-169. 

In This Article

Abstract and Introduction


Background: Women with epithelial ovarian cancer (OC) have a higher chance to benefit from poly (ADP-ribose) polymerase inhibitor (PARPi) therapy if their tumor has a somatic or hereditary BRCA1/2 pathogenic variant. Current guidelines advise BRCA1/2 genetic predisposition testing for all OC patients, though this does not detect somatic variants. We assessed the feasibility of a workflow for universal tumor DNA BRCA1/2 testing of all newly diagnosed OC patients as a prescreen for PARPi treatment and cancer predisposition testing.

Methods: Formalin-fixed paraffin-embedded tissue was obtained from OC patients in seven hospitals immediately after diagnosis or primary surgery. DNA was extracted, and universal tumor BRCA1/2 testing was then performed in a single site. Diagnostic yield, uptake, referral rates for genetic predisposition testing, and experiences of patients and gynecologists were evaluated.

Results: Tumor BRCA1/2 testing was performed for 315 (77.6%) of the 406 eligible OC samples, of which 305 (96.8%) were successful. In 51 of these patients, pathogenic variants were detected (16.7%). Most patients (88.2%) went on to have a genetic predisposition test. BRCA1/2 pathogenic variants were shown to be hereditary in 56.8% and somatic in 43.2% of patients. Participating gynecologists and patients were overwhelmingly positive about the workflow.

Conclusions: Universal tumor BRCA1/2 testing in all newly diagnosed OC patients is feasible, effective, and appreciated by patients and gynecologists. Because many variants cannot be detected in DNA from blood, testing tumor DNA as the first step can double the identification rate of patients who stand to benefit most from PARP inhibitors.


Hereditary BRCA1/2 pathogenic variants are present in 10%–20% of women with (nonborderline) epithelial ovarian, fallopian tube, and primary peritoneal cancer tumors (denoted as ovarian cancer [OC]). Early identification of pathogenic BRCA1/2 variants can reduce morbidity and mortality from breast cancer and OC by preventive and curative strategies in both patients and families.[1,2] Generally, national guidelines therefore advise BRCA1/2 genetic predisposition testing for all OC patients.[3,4] OC patients with pathogenic BRCA1/2 variants in their tumor are likely to benefit from poly (ADP-ribose) polymerase inhibitor (PARPi) therapy.[5–8] PARPi therapy improves prognosis in patients with platinum-sensitive OC and is most effective in OC with defective homologous recombination mediated repair, especially BRCA1/2 defects.[9–14] An estimated 18%–24% of patients with OC carry a BRCA1/2 pathogenic variant in their tumor, often in the context of an inherited germline BRCA1/2 variant. It is estimated that of the patients with a tumor BRCA1/2 variant, 54%–74% represent hereditary defects and 27%–46% somatic defects that are present in the tumor only.[5–8]

Because a tumor BRCA1/2 test detects both hereditary and somatic BRCA1/2 variants, we developed a new workflow starting with universal tumor DNA BRCA1/2 testing in newly diagnosed OC patients. This workflow is based on our technical approach using single-molecule molecular inversion probe (smMIP) enrichment followed by next-generation sequencing (NGS) and allows rapid and reliable detection of both hereditary and somatic aberrations affecting BRCA1/2 in DNA derived from formalin-fixed paraffin-embedded (FFPE) tissue of OC.[15]

The new universal tumor BRCA1/2 workflow has three key features. First, it detects many more patients who are eligible for PARPi therapy than conventional genetic predisposition testing of DNA from blood. Individuals can subsequently decide whether to continue with testing for a heritable BRCA1/2 variant. Second, testing tumor DNA effectively serves as a prescreen to tailor genetic counseling to those with a high a priori risk of a hereditary pathogenic variant. Third, by focusing on treatment options, the strategy may improve uptake of BRCA1/2 genetic predisposition in patients with OC.

In this study, the novel workflow of universal tumor DNA BRCA1/2 testing was implemented in seven hospitals. Its feasibility, effectiveness, and appreciation were evaluated by uptake, diagnostic yield, and referral rates for subsequent genetic counseling. The experiences of patients and gynecologists were systematically assessed.