Hannah Bass

Introduction. BRCA1 and BRCA2 genes act as tumor suppressor genes by coding proteins that repair DNA or induce apoptosis¹. When mutated, these genes are unable to arrest cell proliferation, and benign or malignant tumors can form. BRCA mutations are classically associated with breast and ovarian cancer; however, recent studies have correlated BRCA mutations with an increased risk of prostate and pancreatic cancer. Germline BRCA mutations are found in ~10% of breast, ovarian and pancreatic cancers^2,3,13 with a lifetime risk of ~85%, ~40% and ~10% respectively⁴. Additionally, germline mutations in DNA repair pathways are found in ~27% of all prostate cancers¹⁵. Proper genetic testing is increasingly important as new treatment options are available pending key mutation findings; however, debate continues on how to best identify the right population and conduct testing (e.g., tumor normal sequencing)⁷. Synthetic lethality is a relatively new treatment that inhibits Poly(ADP-ribose) polymerases (PARPs) in order to induce cell death. When PARPs are inhibited, unrepaired single-strand breaks give rise to cytotoxic double-strand breaks. These are normally rescued by homologous recombination, but, in cells with suboptimal HR (e.g. BRCA mutation), PARP inhibition leads to genomic instability and cell death. Methods. For each BRCA mutation cancer, studies have been conducted to prove the efficacy of synthetic lethality. Using randomized trials, studies assign patient groups with BRCA mutation cancers to either the Olaparib or placebo group^10,11,12,14. The patients are then monitored for progression free survival and adverse effects. Discussion. Overall, each study across the four BRCA mutation cancers showed a positive response to Olaparib and increased survival rate compared to that of the placebo group. Additionally, use of PARP inhibitors did not decrease quality of life⁸ or cause serious side effects¹¹. While these studies show promising use of synthetic lethality in the future, researchers still note the challenge of identifying and validating potential synthetic lethal partner genes given the number of possible mutations and the associated cost⁵. Conclusion. Synthetic lethality studies are showing data of increased survival rate without decreasing quality of life across BRCA mutations ^6,10,11,12. This success of synthetic lethality in the treatment of these cancers highlights the increasing importance of accurate and comprehensive germline testing in cancer patients and those with a family history of the mutation given that treatment options change upon the identification of specific mutations. The positive results from PARP inhibitor use opens up exploration of using this technique in other areas of the DNA repair process and for other germline mutation cancers while also highlighting the need on how to overcome screening difficulties.

1. Varol U, Kucukzeybek K, Alacacioglu A, et al. BRCA genes: BRCA 1 and BRCA 2. JBUON. 2018; 23(4):862-866. PMID: 30358186.
2. Lee A, Moon B, Kim TH. BRCA1/BRCA2 Pathogenic Variant Breast Cancer: Treatment and Prevention Strategies. Ann Lab Med. 2020; 40:114-121. doi:10.3343/alm.2020.40.2.114
3. Rosen M, Goodwin R, Vickers M. BRCA mutated pancreatic cancer: A change is coming. World J Gastroenterol. 2021; 27(17):1943-1958. doi: 10.3748/wjg.v27.i17.1943
4. Pilarski R. The Role of BRCA Testing in Hereditary Pancreatic and Prostate Cancer Families. American Society of Clinical Oncology Educational Book. 2019; 39:79-86. doi: 10.1200/EDBK_238977
5. Topatana W,  Juengpanich S, Li S, et.al. Advances in synthetic lethality for cancer therapy: cellular mechanism and clinical translation. Journal of Hematology & Oncology. 2020; 13:118. doi: 10.1186/s13045-020-00956-5
6. Chandrasekaran A, Elias K. Synthetic Lethality in Ovarian Cancer. Mol Cancer Ther. 2021; 20:2117–28. doi: 10.1158/1535-7163.MCT-21-0500
7. Mandelker D, Zhang L, Keme Y, et al. Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. JAMA. 2017; 318(9):825-835. doi:10.1001/jama.2017.11137
8. Hammel P, Kindler H, Reni M, et.al. Health-related quality of life in patients with a germline BRCA mutation and metastatic pancreatic cancer receiving maintenance olaparib. Annals of Oncology. 2019; 30: 1959–1968. doi:10.1093/annonc/mdz406
9. O’Reilly E, Lee J, Zalupski M, et.al. Randomized, Multicenter, Phase II Trial of Gemcitabine and Cisplatin With or Without Veliparib in Patients With Pancreas Adenocarcinoma and a Germline BRCA/ PALB2 Mutation. Journal of Clinical Oncology. 2019; 38(13): 1378-1389. doi: 10.1200/JCO.19.02931
10. Golan T, Hammel P, Cutsem E, et.al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med. 2019; 381: 317-27. doi: 10.1056/NEJMoa1903387
11. Tutt A, Garber J, Kaufman B, et.al. Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer. N Engl J Med. 2021; 384: 2394-405. doi: 10.1056/NEJMoa2105215
12. Robson M, Im S, Senkus E, et. al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med. 2017; 377:523-33. doi: 10.1056/NEJMoa1706450
13. George A, Kaye S, Banerjee S. Delivering widespread BRCA testing and PARP inhibition to patients with ovarian cancer. NCR Clinical Onc. 2017; 14:284-296. doi:10.1038/nrclinonc
14. Anscher M, Chang E, Gao X, et.al. FDA Approval Summary: Rucaparib for the Treatment of Patients with Deleterious BRCA-Mutated Metastatic Castrate-Resistant Prostate Cancer. The Oncologist. 2021;26:139–146. doi; DOI: 10.1002/onco.13585
15. Risdon E, Chau C, Price D, et. Al. PARP Inhibitors and Prostate Cancer: To Infinity and Beyond BRCA. The Oncologist. 2021;26:e115–e129. doi: 10.1634/theoncologist.2020-0697