July 2022 EMM Editor's Choice

The July 2022 EMM Editor’s Choice article is “A comprehensive literature review and meta-analysis of the prevalence of pan-cancer BRCA mutations, homologous recombination repair gene mutations, and homologous recombination deficiencies,” (https://onlinelibrary.wiley.com/doi/10.1002/em.22505) by Changxia Shao Jun Wan Fred C. Lam Huilin Tang Andrew R. Marley Yiqing Song Chelsey Miller Madeline Brown Jiali Hanand Gboyega Adeboyeje.

It is well known that cellular DNA damage detection and repair is critical in the maintenance of genomic stability during cellular division. One particularly vital pathway in DNA damage repair is the homologous recombination repair (HRR) pathway. BRCA1 and BRCA2 proteins are recruited to the damaged replication fork sites leading to a cascade of events resulting in the recruitment of further checkpoint signaling proteins and repair kinases. Mutations in the BRCA proteins are known to play a role in the development of cancers such as breast and ovarian. Fortunately, data from recent clinical trials have reported that BRCA1/2 are sensitive to enzyme poly-ADP ribose polymerase 1 (PARP1), leading to the FDA approval of six PARP inhibitors for the treatment of BRCA1/2 mutant cancers. Such a discovery has led to the development of biomarkers that can predict homologous recombination deficiency (HRD) in BRCA wild-type tumors in hopes of expanding clinical use of PARP inhibitors (PARPi). Therefore, the authors have performed a comprehensive review providing information on the prevalence of germline and somatic BRCA mutations, HRR mutations and HRD positivity in patients.

The authors identified studies of interest by first filtering for articles on patients possessing solid tumors containing germline BRCA1/2 mutations (gBRCA1/2m), somatic BRCA1/2 mutations (sBRCA1/2m), HRR gene mutations, or HRD positivity reported in the past 10 years. Search engines utilized were OVID, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cochrane Reviews. Once studies were collected, meta-analyses were conducted to evaluate the prevalence and confidence intervals of BRCA1/2 mutations and HRD positivity.

The authors search yielded 265 publications on BRCA1/2 mutation prevalence, 189 on HRR gene mutation prevalence, and 7 on HRD positivity prevalence. The prevalences of gBRCA1m and BRCA2m were 7.8% and 5.7% for breast cancer, 13.5% and 6.6% for ovarian cancer, 0.5% and 3.5% for prostate cancer, and1.1% and 4.1% for pancreatic cancer, respectively. The prevalences of sBRCA1m and BRCA2m were 3.4% and 2.7% for breast cancer, 4.7% and 2.9% for ovarian cancer, 5.7% and 3.2% for prostate cancer, and 1.2% and 2.9% for pancreatic cancer, respectively. The authors were able to identify 180 studies that evaluated mutations in one or more HRR genes other than BRCA1/2, and reported the prevalence of these mutations as such: ATM at 5.2%, CHEK2 at 1.6% and PALB2 showing the highest prevalence at 0.9%. The seven studies that evaluated HRD positivity in breast, ovarian, and prostate cancer patients documented the prevalence to be 56% overall (95% CI=48%–64%).

This comprehensive literature review and meta-analysis documents the prevalence of BRCA1/2and HRR pathway gene mutations and HRD positivity in multiple cancer types. As there is a need for improvement in precision medicine the authors believe their contribution can be useful, specifically in targeted therapy and chemotherapy selection. With evidence that PARPi provides positive outcomes, in conjunction with platinum agents, standardized biomarker assays could provide to be beneficial in discovering novel combination therapies to improve outcomes for cancer patients.

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