PARP抑制剂在乳腺癌中的临床应用

doi:10.3760/cma.j.cn371439-20221023-00019

摘要/Abstract

摘要：

多腺苷二磷酸核糖聚合酶（PARP）抑制剂通过抑制DNA损伤修复，导致同源重组修复缺陷（HRD）的肿瘤合成致死。目前已有两种PARP抑制剂奥拉帕利和他拉唑帕利获批用于乳腺癌易感基因（BRCA）突变、人类表皮生长因子受体2（HER2）阴性晚期乳腺癌的挽救治疗和早期乳腺癌的辅助治疗。PAPR抑制剂单药表现出良好的抗肿瘤活性和可控的安全性。PAPR抑制剂联合化疗、放疗、抗血管治疗及免疫治疗等多项临床研究正在开展，PARP抑制剂的适应证也由BRCA突变延伸至HRD，从卵巢癌和乳腺癌扩展到其他实体瘤，将来有希望能惠及更多的肿瘤患者。

关键词: 乳腺肿瘤, PARP抑制剂, 生物标记, 肿瘤, 临床试验

Abstract:

Poly adenosine diphosphate ribose polymerase （PARP） inhibitors lead to synthetic lethality in homologous recombination repair-deficient （HRD） tumors by inhibiting DNA damage repair. Two PARP inhibitors，olaparib and talazoparib，have been approved for the salvage treatment of breast cancer susceptibility gene (BRCA) mutation，human epidermal growth factor receptor 2 （HER2） negative advanced breast cancer，and adjuvant treatment of early breast cancer. PAPR inhibitor single agent shows good antitumor activity and controllable safety. A number of clinical studies on PAPR inhibitors combined with chemotherapy，radiotherapy，antiangiogenic therapy and immunotherapy are being carried out. The indications of PARP inhibitors also extend from BRCA mutation to HRD，from ovarian cancer and breast cancer to other solid tumors，promising to benefit more patients in the future.

Key words: Breast neoplasms, PARP inhibitors, Biomarkers, tumor, Clinical trial

黎立喜, 张娣, 罗扬, 马飞. PARP抑制剂在乳腺癌中的临床应用[J]. 国际肿瘤学杂志, 2023, 50(2): 91-96.

Li Lixi, Zhang Di, Luo Yang, Ma Fei. Clinical application of PARP inhibitors in breast cancer[J]. Journal of International Oncology, 2023, 50(2): 91-96.

参考文献 32

[1]	Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249. DOI: 10.3322/caac.21660. doi: 10.3322/caac.21660
[2]	Daly MB, Pal T, Berry MP, et al. Genetic/Familial High-Risk As-sessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology[J]. J Natl Compr Canc Netw, 2021, 19(1): 77-102. DOI: 10.6004/jnccn.2021.0001. doi: 10.6004/jnccn.2021.0001
[3]	Valabrega G, Scotto G, Tuninetti V, et al. Differences in PARP in-hibitors for the treatment of ovarian cancer: mechanisms of action, pharmacology, safety, and efficacy[J]. Int J Mol Sci, 2021, 22(8):4203. DOI: 10.3390/ijms22084203. doi: 10.3390/ijms22084203
[4]	Murai J, Huang SY, Renaud A, et al. Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib[J]. Mol Cancer Ther, 2014, 13(2): 433-443. DOI: 10.1158/1535-7163.Mct-13-0803. doi: 10.1158/1535-7163.MCT-13-0803 pmid: 24356813
[5]	Banerjee S, Moore KN, Colombo N, et al. Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial[J]. Lancet Oncol, 2021, 22(12): 1721-1731. DOI: 10.1016/s1470-2045(21)00531-3. doi: 10.1016/s1470-2045(21)00531-3
[6]	Robson ME, Tung N, Conte P, et al. OlympiAD final overall survival and tolerability results: olaparib versus chemotherapy treatment of physician's choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer[J]. Ann Oncol, 2019, 30(4): 558-566. DOI: 10.1093/annonc/mdz012. doi: S0923-7534(19)31111-1 pmid: 31987272
[7]	Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation[J]. N Engl J Med, 2017, 377(6): 523-533. DOI: 10.1056/NEJMoa1706450. doi: 10.1056/NEJMoa1706450
[8]	Gelmon KA, Fasching PA, Couch FJ, et al. Clinical effectiveness of olaparib monotherapy in germline BRCA-mutated, HER2-negative metastatic breast cancer in a real-world setting: phase Ⅲb LUCY interim analysis[J]. Eur J Cancer, 2021, 152: 68-77. DOI: 10.1016/j.ejca.2021.03.029. doi: 10.1016/j.ejca.2021.03.029 pmid: 34087573
[9]	Litton JK, Rugo HS, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation[J]. N Engl J Med, 2018, 379(8): 753-763. DOI: 10.1056/NEJMoa1802905. doi: 10.1056/NEJMoa1802905
[10]	Tutt ANJ, Garber JE, Kaufman B, et al. Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer[J]. N Engl J Med, 2021, 384(25): 2394-2405. DOI: 10.1056/NEJMoa2105215. doi: 10.1056/NEJMoa2105215
[11]	Fasching PA, Link T, Hauke J, et al. Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency (GeparOLA study)[J]. Ann Oncol, 2021, 32(1): 49-57. DOI: 10.1016/j.annonc.2020.10.471. doi: 10.1016/j.annonc.2020.10.471 pmid: 33098995
[12]	Litton JK, Scoggins ME, Hess KR, et al. Neoadjuvant talazoparib for patients with operable breast cancer with a germline BRCA pathogenic variant[J]. J Clin Oncol, 2020, 38(5): 388-394. DOI: 10.1200/jco.19.01304. doi: 10.1200/jco.19.01304
[13]	Manzo J, Puhalla S, Pahuja S, et al. A phase 1 and pharmacodynamic study of chronically-dosed, single-agent veliparib (ABT-888) in patients with BRCA1- or BRCA2-mutated cancer or platinum-refractory ovarian or triple-negative breast cancer[J]. Cancer Chemother Pharmacol, 2022, 89(5): 721-735. DOI: 10.1007/s00280-022-04430-6. doi: 10.1007/s00280-022-04430-6
[14]	Turner NC, Balmaña J, Poncet C, et al. Niraparib for advanced breast cancer with germline BRCA1 and BRCA2 mutations: the EORTC 1307-BCG/BIG5-13/TESARO PR-30-50-10-C BRAVO study[J]. Clin Cancer Res, 2021, 27(20): 5482-5491. DOI: 10.1158/1078-0432.Ccr-21-0310. doi: 10.1158/1078-0432.Ccr-21-0310
[15]	Drew Y, Ledermann J, Hall G, et al. Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer[J]. Br J Cancer, 2016, 114(7): 723-730. DOI: 10.1038/bjc.2016.41. doi: 10.1038/bjc.2016.41
[16]	Diéras V, Han HS, Kaufman B, et al. Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): a randomised, double-blind, placebo-controlled, phase 3 trial[J]. Lancet Oncol, 2020, 21(10): 1269-1282. DOI: 10.1016/s1470-2045(20)30447-2. doi: 10.1016/s1470-2045(20)30447-2
[17]	Puhalla SL, Diéras V, Arun BK, et al. Relevance of platinum-free interval and BRCA reversion mutations for veliparib monotherapy after progression on carboplatin/paclitaxel for gBRCA advanced breast cancer (BROCADE3 crossover)[J]. Clin Cancer Res, 2021, 27(18): 4983-4993. DOI: 10.1158/1078-0432.Ccr-21-0748. doi: 10.1158/1078-0432.CCR-21-0748 pmid: 34131001
[18]	Loibl S, O'Shaughnessy J, Untch M, et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial[J]. Lancet Oncol, 2018, 19(4): 497-509. DOI: 10.1016/s1470-2045(18)30111-6. doi: 10.1016/s1470-2045(18)30111-6
[19]	Geyer CE, Sikov WM, Huober J, et al. Long-term efficacy and safety of addition of carboplatin with or without veliparib to standard neoadjuvant chemotherapy in triple-negative breast cancer: 4-year follow-up data from BrighTNess, a randomized phase Ⅲ trial[J]. Ann Oncol, 2022, 33(4): 384-394. DOI: 10.1016/j.annonc.2022.01.009. doi: 10.1016/j.annonc.2022.01.009
[20]	Severson TM, Wolf DM, Yau C, et al. The BRCA1ness signature is associated significantly with response to PARP inhibitor treatment versus control in the I-SPY 2 randomized neoadjuvant setting[J]. Breast Cancer Res, 2017, 19(1): 99. DOI: 10.1186/s13058-017-0861-2. doi: 10.1186/s13058-017-0861-2 pmid: 28851423
[21]	Llombart-Cussac A, Bermejo B, Villanueva C, et al. SOLTI NeoPARP: a phase Ⅱ randomized study of two schedules of iniparib plus paclitaxel versus paclitaxel alone as neoadjuvant therapy in patients with triple-negative breast cancer[J]. Breast Cancer Res Treat, 2015, 154(2): 351-357. DOI: 10.1007/s10549-015-3616-8. doi: 10.1007/s10549-015-3616-8
[22]	O'Shaughnessy J, Schwartzberg L, Danso MA, et al. Phase Ⅲ study of iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer[J]. J Clin Oncol, 2014, 32(34): 3840-3847. DOI: 10.1200/jco.2014.55.2984. doi: 10.1200/JCO.2014.55.2984 pmid: 25349301
[23]	Xu J, Keenan TE, Overmoyer B, et al. Phase Ⅱ trial of veliparib and temozolomide in metastatic breast cancer patients with and without BRCA1/2 mutations[J]. Breast Cancer Res Treat, 2021, 189(3): 641-651. DOI: 10.1007/s10549-021-06292-7. doi: 10.1007/s10549-021-06292-7
[24]	Kummar S, Wade JL, Oza AM, et al. Randomized phase Ⅱ trial of cyclophosphamide and the oral poly (ADP-ribose) polymerase inhibitor veliparib in patients with recurrent, advanced triple-negative breast cancer[J]. Invest New Drugs, 2016, 34(3): 355-363. DOI: 10.1007/s10637-016-0335-x. doi: 10.1007/s10637-016-0335-x
[25]	Loap P, Loirat D, Berger F, et al. Safety and tolerability of olaparib combined with breast radiotherapy in patients with triple-negative breast cancer: final results of the RADIOPARP phase 1 trial[J]. J Clin Oncol, 2022, 40(16_suppl): 534. DOI: 10.1200/JCO.2022.40.16_suppl.534. doi: 10.1200/JCO.2022.40.16_suppl.534
[26]	Wu S, Gao F, Zheng S, et al. EGFR amplification induces in-creased DNA damage response and renders selective sensitivity to talazoparib (PARP inhibitor) in glioblastoma[J]. Clin Cancer Res, 2020, 26(6): 1395-1407. DOI: 10.1158/1078-0432.CCR-19-2549. doi: 10.1158/1078-0432.CCR-19-2549
[27]	Stringer-Reasor EM, May JE, Olariu E, et al. An open-label, pilot study of veliparib and lapatinib in patients with metastatic, triple-negative breast cancer[J]. Breast Cancer Res, 2021, 23(1): 30. DOI: 10.1186/s13058-021-01408-9. doi: 10.1186/s13058-021-01408-9 pmid: 33663560
[28]	Domchek SM, Postel-Vinay S, Im SA, et al. Olaparib and durva-lumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study[J]. Lancet Oncol, 2020, 21(9): 1155-1164. DOI: 10.1016/s1470-2045(20)30324-7. doi: 10.1016/s1470-2045(20)30324-7
[29]	Pusztai L, Yau C, Wolf DM, et al. Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage Ⅱ/Ⅲ breast cancer: results from the adaptively randomized I-SPY2 trial[J]. Cancer Cell, 2021, 39(7): 989-998.e5. DOI: 10.1016/j.ccell.2021.05.009. doi: 10.1016/j.ccell.2021.05.009 pmid: 34143979
[30]	Han HS, Arun BK, Kaufman B, et al. Veliparib monotherapy following carboplatin/paclitaxel plus veliparib combination therapy in patients with germline BRCA-associated advanced breast cancer: results of exploratory analyses from the phase Ⅲ BROCADE3 trial[J]. Ann Oncol, 2022, 33(3): 299-309. DOI: 10.1016/j.annonc.2021.11.018. doi: 10.1016/j.annonc.2021.11.018
[31]	Floros TI, Papadopoulou E, Metaxa-Mariatou V, et al. Next generation sequencing (NGS) for the identification of PARP inhibitors' predictive biomarkers[J]. Ann Oncol, 2022, 33(suppl_7): S27-S54. DOI: 10.1016/annonc/annonc1037. doi: 10.1016/annonc/annonc1037
[32]	Eikesdal HP, Yndestad S, Elzawahry A, et al. Olaparib monothe-rapy as primary treatment in unselected triple negative breast cancer[J]. Ann Oncol, 2021, 32(2): 240-249. DOI: 10.1016/j.annonc.2020.11.009. doi: 10.1016/j.annonc.2020.11.009 pmid: 33242536