ABSTRACT

Introduction: TNBC is a subtype of breast cancer that accounts for 10-15% of instances and is distinguished by the lack of HER2 overexpression, progesterone receptors, and oestrogen receptors. Compared to other kinds of breast cancer, TNBC is more aggressive, has a worse prognosis and survival rate, and can only be treated with chemotherapy. In cancer cells with BRCA mutations, PARP inhibitors target the PARP enzyme in DNA repair, accumulating DNA damage and causing cell death. The objective of a systematic review was to assess the efficacy and safety of PARP inhibitors in the management of TNBC with BRCA mutations. Objective response rates and outcomes like overall survival and progression-free survival were evaluated.
Methods:The purpose of the systematic review is to evaluate how well PARP inhibitors, work to treat triple negative breast cancer. The Cochrane library and PubMed were searched for pertinent research, and the search period was from 2012 to 2022. Phase 2 and 3 randomised clinical trials examining the effectiveness of PARP inhibitors alone or in combination with other treatments and reporting progression-free survival, overall survival, and objective response rate met the inclusion criteria for the studies. Preclinical studies, single-arm studies, trials without information on BRCA status, case reports, and studies conducted in languages other than English were excluded. The JADAD score was used to evaluate the trials that were chosen. Patient characteristics, treatment modalities, and efficacy results were among the data retrieved from the research.
Results:When compared to the control group, patients using PARP inhibitors demonstrated statistically significant improvements in progression-free survival (PFS). However, there were no appreciable differences in overall survival (OS). The effectiveness of the PARP inhibitors varied among patient demographics and subgroups. Anemia, tiredness, and nausea were the most often reported side effects. In comparison to the control group, veliparib was linked to a greater incidence of anaemia and nausea. In both groups, a similar number of patients experienced serious adverse effects.
Discussion:The effectiveness of PARP inhibitors as monotherapy or in combination with carboplatin-paclitaxel has been shown in evaluated studies. Anemia, tiredness, and nausea were the most frequent adverse effects, and severe hematologic toxicities were of particular concern. However, future negative outcomes can be avoided by routine blood counts and the restriction of some PARP inhibitors to individuals who have recovered from hematologic toxicity. Patients with mutations in particular HR-related genes did not react to olaparib therapy, however some subsets of breast cancer and other cancers such as prostate cancer, may respond favourably to PARP inhibitors. The systematic review has shortcomings such research diversity and a dearth of trials with sufficient power, which can reduce the dependability of results.
Conclusion:PARP inhibitors have been proven in clinical trials to be beneficial in treating BRCA mutant TNBC, resulting in objective responses and complete/partial remissions. They have a good safety profile, with the majority of side effects being mild to moderate. Despite the increased risk of myelosuppression, PARP inhibitors are a viable treatment option for patients with BRCA mutant TNBC. More research is required to completely comprehend optimal use and long-term advantages.

KEYWORDS

PARP, Olaparib, Objective response rate, Progression Free Survival

REFERENCES

1) Anderson WF, Jatoi I, Tse J, Rosenberg PS. Male breast cancer: a population-based comparison with female breast cancer. Journal of Clinical Oncology. 2010;28(2):232.
2) DeSantis CE, Miller KD, Goding Sauer A, Jemal A, Siegel RL. Cancer statistics for african Americans, 2019. CA: a cancer journal for clinicians. 2019;69(3):211-33.
3) Gupta GK, Collier AL, Lee D, Hoefer RA, Zheleva V, Siewertsz van Reesema LL, et al. Perspectives on triple-negative breast cancer: current treatment strategies, unmet needs, and potential targets for future therapies. Cancers. 2020;12(9):2392.
4) Miller KD, Nogueira L, Mariotto AB, Rowland JH, Yabroff KR, Alfano CM, et al. Cancer treatment and survivorship statistics, 2019. CA: a cancer journal for clinicians. 2019;69(5):363-85.
5) Cortesi L, Rugo HS, Jackisch C. An overview of PARP inhibitors for the treatment of breast cancer. Targeted oncology. 2021;16(3):255-82.
6) Barchiesi G, Roberto M, Verrico M, Vici P, Tomao S, Tomao F. Emerging Role of PARP Inhibitors in Metastatic Triple Negative Breast Cancer. Current Scenario and Future Perspectives. Frontiers in Oncology. 2021;11.
7) Stevens KN, Vachon CM, Couch FJ. Genetic Susceptibility to Triple-Negative Breast Cancer Predisposition to Triple-Negative Breast Cancer. Cancer research. 2013;73(7):2025-30.
8) Liedtke C, Mazouni C, Hess KR, André F, Tordai A, Mejia JA, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. Journal of clinical oncology. 2008;26(8):1275-81.
9) Hahnen E, Hauke J, Engel C, Neidhardt G, Rhiem K, Schmutzler RK. Germline mutations in triple-negative breast cancer. Breast Care. 2017;12(1):15-9.
10) Wahba HA, El-Hadaad HA. Current approaches in treatment of triple-negative breast cancer. Cancer biology & medicine. 2015;12(2):106.
11) Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, et al. Oral poly (ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. The Lancet. 2010;376(9737):235-44.
12) Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Bmj. 2021;372:n71.
13) Arun BK, Han HS, Kaufman B, Wildiers H, Friedlander M, Ayoub J-P, et al. Efficacy and safety of first-line veliparib and carboplatin–paclitaxel in patients with HER2− advanced germline BRCA+ breast cancer: Subgroup analysis of a randomised clinical trial. European Journal of Cancer. 2021;154:35-45.
14) Tutt ANJ, Garber JE, Kaufman B, Viale G, Fumagalli D, Rastogi P, Gelber RD,de Azambuja E, Fielding A, Balmaña J, Domchek SM, Gelmon KA, Hollingsworth SJ,Korde LA, Linderholm B, Bandos H, Senkus E, Suga JM, Shao Z, Pippas AW, NoweckiZ, Huzarski T, Ganz PA, Lucas PC, Baker N, Loibl S, McConnell R, Piccart M,Schmutzler R, Steger GG, Costantino JP, Arahmani A, Wolmark N, McFadden E,Karantza V, Lakhani SR, Yothers G, Campbell C, Geyer CE Jr; OlympiA ClinicalTrial Steering Committee and Investigators. Adjuvant Olaparib for Patients withBRCA1– or BRCA2-Mutated Breast Cancer. N Engl J Med. 2021 Jun24;384(25):2394-2405. doi: 10.1056/NEJMoa2105215. Epub 2021 Jun 3. PMID:34081848; PMCID: PMC9126186.
15) Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, Delaloge S, Li W, TungN, Armstrong A, Wu W, Goessl C, Runswick S, Conte P. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med. 2017 Aug10;377(6):523-533. doi: 10.1056/NEJMoa1706450. Epub 2017 Jun 4. Erratum in: N
Engl J Med. 2017 Oct 26;377(17 ):1700. PMID: 28578601.
16) Tung NM, Robson ME, Ventz S, Santa-Maria CA, Nanda R, Marcom PK, Shah PD,Ballinger TJ, Yang ES, Vinayak S,Melisko M, Brufsky A, DeMeo M, Jenkins C,Domchek S, D’Andrea A, Lin NU, Hughes ME, Carey LA, Wagle N, Wulf GM, Krop IE,Wolff AC, Winer EP, Garber JE. TBCRC 048: Phase II Study of Olaparib forMetastatic Breast Cancer and Mutations in Homologous Recombination-RelatedGenes. J Clin Oncol. 2020 Dec 20;38(36):4274-4282. doi: 10.1200/JCO.20.02151.Epub 2020 Oct 29. PMID: 33119476.
17) Litton JK, Hurvitz SA, Mina LA, Rugo HS, Lee KH, Gonçalves A, Diab S,Woodward N, Goodwin A, Yerushalmi R, Roché H, Im YH, Eiermann W, Quek RGW, UsariT, Lanzalone S, Czibere A, Blum JL, Martin M, Ettl J. Talazoparib versuschemotherapy in patients with germline BRCA1/2-mutated HER2-negative advancedbreast cancer: final overallsurvival results from the EMBRACA trial. Ann Oncol.2020 Nov;31(11):1526-1535. doi: 10.1016/j.annonc.2020.08.2098. Epub 2020 Aug 20.
PMID: 32828825.
18) Arun BK, Han HS, Kaufman B, Wildiers H, Friedlander M, Ayoub JP, Puhalla SL,Bell-McGuinn KM, Bach BA, Kundu MG, Ratajczak CK, Maag D, Diéras V. Efficacy and safety of first-line veliparib and carboplatin-paclitaxel in patients with HER2-advanced germline BRCA+ breast cancer: Subgroup analysis of a randomised clinical trial. Eur J Cancer. 2021 Sep;154:35-45. doi:10.1016/j.ejca.2021.05.037. Epub 2021 Jul 6. PMID: 34243076.
19) Lee KH, Sohn J, Goodwin A, Usari T, Lanzalone S, Im SA, Kim SB. Talazoparib Versus Chemotherapy in Patients with HER2-negative Advanced Breast Cancer and a Germline BRCA1/2 Mutation Enrolled in Asian Countries: Exploratory Subgroup Analysis of the Phase III EMBRACA Trial. Cancer Res Treat. 2021Oct;53(4):1084-1095. doi: 10.4143/crt.2020.1381. Epub 2021 Mar 24. PMID:33781053; PMCID: PMC8524025.
20) Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. doi: 10.1136/bmj.n71
21) Cardoso F., Paluch-Shimon S., Senkus E. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5) Ann Oncol. 2020 Dec;31(12):1623–1649.
22) Breast Cancer Expert Committee of National Cancer Quality Control Center Breast cancer expert committee of China anti-cancer association; cancer drug clinical research committee of China anti-cancer association. [Guidelines for clinical diagnosis and treatment of advanced breast cancer in China (2020 edition)] Zhonghua Zhong Liu Za Zhi. 2020 Oct 23;42(10):781–797.
23) LaFargue CJ, Dal Molin GZ, Sood AK, Coleman RL. Exploring and comparing adverse events between PARP inhibitors. The Lancet Oncology. 2019 Jan 1;20(1):e15-28.24.
24) Liu Y, Meng J, Wang G. Risk of selected gastrointestinal toxicities associated with poly (ADP-ribose) polymerase (PARP) inhibitors in the treatment of ovarian cancer: a meta-analysis of published trials. Drug Design, Development and Therapy. 2018 Sep 17:3013-9.
25) Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009 Apr;361(2):123–134.
26) Zhou J.X., Feng L.J., Zhang X. Risk of severe hematologic toxicities in cancer patients treated with PARP inhibitors: a meta-analysis of randomized controlled trials. Drug Des Dev Ther. 2017 Oct 13;11:3009–3017.
27) Liu X, Wu K, Zheng D, Luo C, Fan Y, Zhong X, Zheng H. Efficacy and safety of PARP inhibitors in advanced or metastatic triple-negative breast cancer: A systematic review and meta-analysis. Frontiers in Oncology. 2021:4363.
28) https://www.nejm.org/servlet/linkout?suffix=r007&dbid=128&doi=10.1056%2FNEJ Moa17064 50&key=000354504100024 (Date accessed: 18th December 2022)
29) Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005;434:917-921
30) Pommier Y, O’Connor MJ, de Bono J. Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action. Sci Transl Med 2016;8:362ps17-362ps17
31) Pharmaceutical B. A study evaluating talazoparib (BMN 673), a PARP inhibitor, in advanced and/or metastatic breast cancer patients with BRCA mutation (EMBRACA Study).
32) Davies H, Glodzik D, Morganella S, et al: HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat Med 23:517-525, 2017).
33) Polak P, Kim J, Braunstein LZ, et al: A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer. Nat Genet 49:1476-1486, 2017