A comprehensive literature review and meta-analysis on prognostic value of BRCAm, HRRm and HRD+ across tumor types.
Authors: Shao Changxia , Marley Andrew , Tang Huilin , Wan Jun , Miller Chelsey , Brown Madeline , Song Yiqing , Han Jiali , Adeboyeje Gboyega 
Published: June 2021

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Background: Poly (ADP-ribose) polymerase inhibitor (PARPi) may have broad application in the treatment of cancer patients with mutations of BRCA (BRCAm) or other homologous recombination repair genes (HRRm) or HR deficiency positive (HRD+). A literature review and meta-analysis were conducted to evaluate the clinical prognostic outcomes by total BRCAm, HRRm, and HRD+ status across tumor types among patients treated with non-PARPi treatment. Methods: Comprehensive searches for eligible studies in Ovid MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cochrane reviews were performed in May 2020 to capture studies published in English within 10 years for manuscripts and 3 years for abstracts across geographic regions. A summary estimate with corresponding 95% CI was calculated using random-effects models due to varying effects sizes across studies. Results: A total of 135 eligible studies were included. Breast cancer (BC) patients with either BRCA1m or BRCA2m (BRCA1/2m) had a similar overall survival (OS) to those with wild-type BRCA1 and BRCA2 (BRCA1/2wt) across 18 studies reporting data on BRCA1m and BRCA2m. The pooled estimates of hazard ratio (HR) was 1.0 (95% CI: 0.8-1.3) overall and was 1.0 (0.7-1.5) for triple-negative BC (TNBC, 7 studies). Similarly, the HR was 1.1 (0.9-1.3) across all 10 studies reporting BRCA1m data and 1.1 (0.8-1.3) across all 7 studies reporting BRCA2m data. Ovarian cancer (OC) patients with BRCA1/2m had a significantly longer OS than those with BRCA1/2wt across 24 studies reporting BRCA1m and BRCA2m, with a HR of 0.7 (0.6-0.8). The HR was 0.6 (0.4, 0.8) across 4 studies on stage III-IV ovarian cancer. The HR was 0.8 (0.6-1.1) across 13 studies reporting BRCA1m and 0.5 (0.3-0.9) across 8 studies reporting BRCA2m. Less OS data were reported for other tumors, 6 studies for BRCA2m in prostate cancer with a HR of 1.9 (1.1-3.2) and 2 studies for BRCA1/2m in pancreatic cancer with a HR of 1.5 (0.8-3.1). Only 4 studies reported HRD+ by either BRCAm or genomic instability score (GIS) ≥ 42 and OS by HRD status; 3 on TNBC and 1 on high-grade serous ovarian cancer. The HR was 0.67 (0.43-1.02) for OS with HRD+ vs. HRD-. A total of 15 studies reported the association between HRRm and OS of cancers (5 on prostate, 4 on pancreas, 3 on ovary, 2 on breast and 1 on urothelial cancer), in which one or more HRR genes were examined. The HR was 1.0 (0.7-1.4) comparing patients with HRRm to those with HRRwt across tumor types. Due to the limited study number and inconsistent methodology/definitions of HRRm and HRD+, these results should be interpreted with caution. Conclusions: The effects of BRCA1/2m on OS in patients treated with chemotherapy varies by cancer type with no effect in BC and a positive association in OC. More study is required in other cancer types. There was no significant association found between HRD+ or HRRm with OS. These findings could help inform evidence-based treatment decisions.