Lessons learned: single cancer rollout experience of reflex BRCA1/2 gene mutation tumor tissue testing for patients with high-grade serous carcinoma

Abstract

<h3>Objectives:</h3> Recommendation for referral of patients with upper Müllerian tract High Grade Serous Carcinoma (HGSC) for genetic counseling and germline <i>BRCA1/2</i> mutation testing has existed for over a decade. In Nov 2018, tumor (somatic) <i>BRCA1/2</i> mutation testing became provincially funded in Ontario, Canada, based on the approval of Poly (ADP-ribose) polymerase inhibitor (PARPi) therapy (Olaparib) as maintenance therapy in newly diagnosed and recurrent platinum sensitive HGSC patients with <i>BRCA1/2</i> germline and somatic mutations. This is a summary of a single cancer center's institutional experience with the clinical rollout of this process. <h3>Methods:</h3> 252 patients undergoing surgery for HGSC at our centre between Nov 2018 - Oct 2020 underwent tumor tissue, germline or combined <i>BRCA1/2</i> mutation testing at external provincially accredited molecular laboratories in the greater Toronto area. We performed comprehensive chart reviews with emphasis on 1) utilization of tumor and/or germline test ordering 2) tumor tissue test report structure and recommendations 3) laboratory handling of failed tumor tissue tests. <h3>Results:</h3> The results are summarized in Figure 1. Tumor tissue testing only was performed at Labs A and B, germline and tumor tissue testing at Lab C, and germline testing only at Lab D. 234 (93 %) cases underwent tumor tissue <i>BRCA1/2</i> mutation testing, either in conjunction with germline testing (140, 56 %), or alone (94, 37%). 18 (7%) HGSC patients were assessed only for <i>BRCA1/2</i> germline mutations. Tumor tissue testing was ordered by gynecologic oncologists from Nov 2018 to April 2020 and by pathologists from May 2020 to October 2020. From Nov 2018 – Aug 2019 services of Labs B and C were used for tumor tissue testing. Workflow readjustments occurred in Sept 2019, and services of Lab A were henceforth predominantly engaged. Germline variants were reported according to the ACMG guidelines 2015/2017. For reporting of somatic variants, Lab A used the AMP/ASCO/CAP guidelines, whereas Labs B and C used ACMG 2015/2017 guidelines. Statements about eligibility for PARPi were reported by Labs A and B, and not by Lab C or Lab D. Overall, testing fail rate was approximately 6 % (14 out of 252 samples) with insufficient material in 4 samples and poor DNA quality in 10 samples. Tumor tissue testing on alternative tumor samples was suggested by Labs A and C, and no recommendations were made by Lab B. <h3>Conclusions:</h3> There was a high order rate (over 90 %) of the newly available <i>BRCA1/2</i> mutation tumor testing at our institution in the initial rollout period. However, among the three external laboratories that carried out the testing, there was non-uniformity of utilization for reporting guidelines of somatic mutations, recommendations for PARPi administration and suggestions for management of failed tests. Our institutional experience underscores the need for establishing provincial and national guidelines with respect to tumor tissue <i>BRCA1/2</i> mutation testing in accredited laboratories.