Reversion mutations in BRCA1 or BRCA2 genes: Resistant mechanism(s) in patients treated with platinum-based agents or poly (ADP-ribose) polymerase(PARP) inhibitors.
Authors: Darabi Sourat , Braxton David R. , Xiu Joanne , Carneiro Benedito A. , Swensen Jeffrey , Antonarakis Emmanuel S. , Liu Stephen V. , McKay Rana R. , Spetzler David , El-Deiry Wafik S. , Demeure Michael J. 
Published: June 2022

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Background: Reversion mutations (RM) in homologous recombination pathway genes including BRCA1/2 have been identified in patients with ovarian, breast, and prostate cancers whose tumors have become refractory to platinum chemotherapy or PARP inhibition. Utilizing a multi-institutional molecular database, we report the prevalence of BRCA1/2 RM in a large cohort across various tumor types. Methods: Primary and/or metastatic tumor samples underwent DNA (underwent NextSeq, 592 genes; NovaSeq, whole-exome) and RNA (NovaSeq, whole transcriptome) sequencing (Caris Life Sciences, Phoenix, AZ). RM were identified by a board-certified molecular geneticist and called only if the patient had been treated with a PARPi or a platinum agent. Baseline clinical and outcomes data were obtained through linked insurance claims data. Results: Among 118,000 solid tumors profiled, RM were observed in 54 tumors samples. RMs were seen most commonly in ovarian cancer (OC), 1.5% (23/1500) of tumors with BRCA1/2 pathogenic mutations (mut), followed by breast cancer (BC) (2.4%, 17/700), endometrial cancer (1.0%, 4/400), pancreatic cancer (1.0%, 2/210), cholangiocarcinoma (2.5%, 2/80), prostate cancer (1.3%, 3/230), cervical cancer (1.4%, 1/70), cancer of unknown primary (1.0%, 1/100), and a neuroendocrine tumor of prostate (1 RM of 9 BRCA mut). Among all RM, we detected 17 in BRCA1 and 6 in BRCA2 in OC. In BC, we identified 7 RM in BRCA1 and 10 in BRCA2. Frameshift mut that restored the reading frame in BRCA1/2 were the most common type of RM. Molecular profiles of 14 high-grade serous ovarian cancers (HGSOC) with RM were compared to 87 control HGSOC with pathogenic BRCA1/2 mut without RM. Tumors with RM had lower ER expression (25% vs. 64%, p = 0.024) and higher KDM6A mut rate (15% vs. 0, p = 0.016). Additionally, TP53 mut rates were similar in RM and control (100% vs. 95%), seen in HGSOC. In patients with RM, 7 of the 14 (50%) TP53 mut were gain-of-function (GOF) while only 19 of 84 (23%) TP53 mut in the control group were GOF (p = 0.048). More detailed clinical data were available for 29 patients with RM (17 BRCA1 & 12 BRCA2). Among these patients, 7 had received prior platinum-based chemotherapy (carboplatin or cisplatin), 7 patients were treated with PARP inhibitors (olaparib or rucaparib), or both (n = 7). Notably, 5 patients had been treated with carboplatin (n = 2, ovarian), olaparib (n = 1, breast), or both agents (n = 2, ovarian and prostate) after the detection of RM. Conclusions: This dataset is one of the largest reporting on the prevalence of BRCA1/2 RM across various tumor types. We demonstrate that the rate of RM was low among BRCA1/2 mutated tumors; this may be because some patients may not have repeat profiling post-treatment. Repeating tumor profiling at times of treatment resistance can help inform therapy selection in the refractory disease setting.