Clinical characteristics, response to poly (adenosine phosphate-ribose) polymerase inhibitors and platinum chemotherapy in patients with lung cancer harboring BRCA mutations.
Authors: Arnon Johnathan , Yakir Rottenberg , Zick Aviad , Tabi Michael , Asli Yusra , Pikarsky Eli , Avraham Eti , Popovtzer Aron , Yablonski-Peretz Tamar , Kadouri Luna , Nechushtan Hovav 
Published: June 2023

e21036

Background: BRCA1/2 are tumor suppressor genes involved in DNA double-strand break repair. Tumors harboring BRCA1/2 pathogenic mutations (BPM) are highly responsive to treatment with poly (adenosine phosphate-ribose) polymerase inhibitors (PARPi) and exhibit increased sensitivity to platinum-based chemotherapy (platinum). Somatic BPM are found in 1-2% of all cases of non-small cell lung cancer (NSCLC), the majority of which are not associated with germline variants. While platinum remains the backbone of first-line treatment of NSCLC, PARPi have not demonstrated efficacy in treatment of NSCLC and testing for BRCA mutations in NSCLC is not routine. We present the clinical characteristics and outcomes of patients with NSCLC harboring BPM treated with platinum and PARPi as part of clinical practice at our center. Methods: We retrospectively evaluated the onco-genetic and pathology data bases for patients with locally advanced or metastatic NSCLC who were treated at Hadassah Medical Center (HMC), underwent somatic molecular or genetic testing, and were found to have somatic BPM (according to ClinVar or Varsom). We compared the clinical outcomes to a matched cohort (age, gender, smoking, and performance status) of non-BPM NSCLC patients treated at HMC. Results: Since 2013 we evaluated 642 patients with locally advanced or metastatic NSCLC using comprehensive somatic or germline molecular panels. Twenty-two patients were found to have somatic BPM of which, 18 (81.8%) were found to be carriers of corresponding germline BRCA1/2 variants. This included 14 (63.6%) carriers of classical Ashkenazi-Jewish variants (10 - BRCA2 617delT, 2- BRCA1 185delAG and 2- BRCA1 5382incC) and representing less than 1% of all BRCA1/2 carriers at HMC. Median age of diagnosis was 67 yeas old (range 40–78). Eleven (50%) patients had a history of smoking, and 8 (36.3%) patients had a history of other malignancies, mainly breast cancer. Pathology for all patients revealed adenocarcinoma and 8 (36.6%) patients had additional actionable mutations ( EGFR, ALK, BRAF or ERBB2). Sixteen (72.7%) patients were treated with platinum, with an objective response rate (ORR) of 75% and a median progression free survival (mPFS) of 14 months (range 4-29), compared to ORR of 45% and mPFS of 8.5 months (range 3-18) in a matched cohort of non-BPM NSCLC patients treated with platinum. Six (27.7%) patients were treated with second or third line PARPi with ORR of 83.3%, mPFS of 21 months (range 6-34). Median overall survival (OS) for the entire cohort was 28 months (range 4-103) with 8 (36.4%) patients surviving for more than 3 years. Conclusions: In this cohort, patients with NSCLC harboring BPM show a durable response to platinum and PARPi with prolonged OS. The results support testing BRCA1/2 in NSCLC patients and treatment with platinum and PARPi for patients with BPM.