Efficacy analysis of neoadjuvant chemotherapy regimens for patients with breast cancer carrying germline mutations in DNA damage repair genes
-
摘要:
目的 分析携带DNA损伤修复(DNA damage repair,DDR)相关基因突变的乳腺癌患者对基础蒽环类新辅助化疗方案(anthracycline,A)、蒽环联合紫杉类新辅助化疗方案(anthracycline-taxane,A-T)、蒽环联合紫杉和铂类新辅助化疗方案(anthracycline-taxane/carboplatin,A-TP)的疗效反应。 方法 2003年10月至2015年5月,105例携带DDR基因胚系突变(非BRCA)的原发性乳腺癌患者在北京大学肿瘤医院分别接受A(n=69)、A-T(n=19)、A-TP(n=17)3种新辅助化疗方案。通过χ2检验或Fisher精确检验比较3组患者的病理完全缓解(pathological complete remission,pCR)率;采用Kaplan-Meier生存分析和Cox回归模型分析患者的乳腺癌特异生存(breast cancer-specific survival,BCSS)及无复发生存(recurrence-free survival,RFS)。 结果 93.3%(98/105)的患者接受了4~8个周期的新辅助化疗。接受A、A-T、A-TP新辅助方案的3组患者的pCR率分别为11.6%、21.1%和35.3%。A-TP组pCR率显著高于A组(P=0.028),A-TP组pCR率也高于A-T组,但未达到统计学差异。经过65.6个月的中位随访, A-TP组的BCSS(HR=0.50,95%CI:0.09~2.73,P=0.41)和RFS(HR=0.51,95%CI:0.15~1.74,P=0.27)略优于A-T组,但无统计学差异。 结论 DDR基因胚系突变患者应用A-TP新辅助化疗方案可显著提高pCR率,加入铂类药物或可提高患者的药物反应性及预后 。 Abstract:Objective To explore the efficacy of anthracycline(A), anthracycline-taxane (A-T), and anthracycline-taxane/carboplatin (A-TP) neoadjuvant chemotherapy regimens in patients with breast cancer harboring germline mutations in DNA damage repair (DDR) genes. Methods A total of 105 patients with operable primary breast cancer, carrying germline mutations in any of the 15 DDR genes, were given neoadjuvant treatment in Peking University Cancer Hospital & Institute from October 2003 to May 2015. Among them, 69, 19, and 17 patients received the neoadjuvant regimens A, A-T, and A-TP, respectively. The pathological complete remission (pCR) rates of the three groups to the neoadjuvant chemotherapy were compared by χ2 or Fisher’s exact test. The Kaplan-Meier survival analysis and Cox proportional hazards model were used to determine the breast cancer-specific survival (BCSS) and recurrence-free survival (RFS) rates in patients with breast cancer. Results 93.3% of patients received four to eight cycles of neoadjuvant chemotherapy. The respective pCR rates of the A, A-T, and A-TP groups were 11.6%, 21.1%, and 35.3%. The pCR rate of the A-TP group was significantly higher than that of the A group (P=0.028). The A-TP group also displayed a better pCR rate relative to that of the A-T group, but the difference was not statistically significant. After a median follow-up of 65.6 months, DDR gene mutation carriers treated with the A-TP regimen exhibited better BCSS (hazard ratio [HR]=0.50, 95% confidence interval [CI]: 0.09–2.73, P=0.41) and RFS (HR=0.51, 95%CI: 0.15–1.74, P=0.27) than patients treated with the A-T regimen; however, the variation did not reach the significance threshold. Conclusions Results of this study suggested that patients with germline mutations in DDR genes can achieve higher pCR rates when carboplatin is added to the standard A-T-based neoadjuvant chemotherapy. The A-TP regimen also showed a trend towards better prognosis compared with the A regimen. -
表 1 DDR基因及其构成比
DNA损伤修复基因 例数 % PALB2# 25 23.36 ATM# 17 15.89 TP53 14 13.08 CHEK2 13 12.15 RAD51D# 11 10.28 RAD50 8 7.48 BLM 5 4.67 NBN 3 2.80 MSH2 3 2.80 RAD51C 2 1.87 PMS2 2 1.87 FANCC 1 0.93 MER11A 1 0.93 MLH1 1 0.93 MSH6 1 0.93 总计 107 100 #:1例患者同时携带RAD51D和ATM胚系突变,另1例患者同时携带PALB2和RAD51D胚系突变 表 2 三组治疗组患者的临床病理信息比较
例(%) 肿瘤特征 例数 A A-T A-TP P1 P2 P3 总例数 105 69(65.7) 19(18.1) 17(16.2) 年龄(岁) 0.290 0.060 0.460 ≤45 48 27(39.1) 10(52.6) 11(64.7) >45 57 42(60.9) 9(47.4) 6(35.3) 肿瘤大小(cm) 0.770 0.550 0.860 ≤2 26 18(26.1) 4(21.1) 4(23.5) >2 79 51(73.9) 15(78.9) 13(76.5) 月经状况# 0.240 0.650 0.710 已绝经 33 24(35.3) 4(21.1) 5(29.4) 未绝经 71 44(64.7) 15(78.9) 12(70.6) 组织学分级 0.570 0.220 0.850 Ⅰ 4 3(4.8) 1(5.6) 0 Ⅱ 75 51(82.3) 13(72.2) 11(68.8) Ⅲ 17 8(12.9) 4(22.2) 5(31.3) 未知 9 7 1 1 淋巴结状态 0.910 0.820 0.780 阴性 42 28(40.6) 8(42.1) 6(37.5) 阳性 62 41(59.4) 11(57.9) 10(62.5) 未知 1 0 0 1 乳腺癌家族史 0.100 0.620 0.660 否 94 64(92.8) 15(78.9) 15(88.2) 是 11 5(7.2) 4(21.1) 2(11.8) ER表达状态 0.010 0.001 0.550 阴性 31 12(17.6) 9(47.4) 10(58.8) 阳性 73 56(82.4) 10(52.6) 7(41.2) 未知 1 1 0 0 PR表达状态 0.050 0.007 0.530 阴性 36 17(24.6) 9(47.4) 10(58.8) 阳性 69 52(75.4) 10(52.6) 7(41.2) HER2表达状态 0.002 1.000 0.037 阴性 75 54(78.3) 8(42.1) 13(76.5) 阳性 30 15(21.7) 11(57.9) 4(23.5) Ki-67 1.000 0.310 0.140 阴性 9 5(8.9) 1(7.1) 3(25.0) 阳性 73 51(91.1) 13(92.9) 9(75.0) 未知 23 13 5 5 分子分型 0.001 0.100 0.090 HR+ & HER2- 58 46(67.6) 4(21.1) 8(47.1) HER2+ 30 15(22.1) 11(57.9) 4(23.5) TNBC 16 7(10.3) 4(21.1) 5(29.4) 未知 1 1 0 0 #:女性患者共104例,男性患者1例;A:蒽环类新辅助化疗方案;A-T:蒽环联合紫杉类新辅助化疗方案;A-TP:蒽环联合紫杉和铂类新辅助化疗方案; P1: A vs. A-T;P2: A vs. A-TP;P3: A-T vs. A-TP 表 3 携带DDR基因突变的患者(n=105)化疗方案与pCR率的关系
例(%) 新辅助化疗方案 例数 non-pCR pCR P1 P2 P3 蒽环 69 61(88.4) 8(11.6) 0.28 0.028 0.46 蒽环联合紫杉 19 15(78.9) 4(21.1) 蒽环联合紫杉和铂类 17 11(64.7) 6(35.3) P1: A vs. A-T;P2: A vs. A-TP;P3: A-T vs. A-TP -
[1] Loibl S. Neoadjuvant treatment of breast cancer: maximizing pathologic complete response rates to improve prognosis[J]. Curr Opin Obstet Gynecol, 2015, 27(1):85-91. doi: 10.1097/GCO.0000000000000147 [2] Luangdilok S, Samarnthai N, Korphaisarn K. Association between pathological complete response and outcome following neoadjuvant chemotherapy in locally advanced breast cancer patients[J]. J Breast Cancer, 2014, 17(4):376-385. doi: 10.4048/jbc.2014.17.4.376 [3] Chen S, Liu Y, Ouyang QW, et al. Clinical and pathological response to neoadjuvant chemotherapy based on primary tumor reduction is correlated to survival in hormone receptor-positive but not hormone receptor-negative locally advanced breast cancer[J]. Ann Surg Oncol, 2015, 22(1):32-39. doi: 10.1245/s10434-014-3894-0 [4] Bear HD, Anderson S, Smith RE, et al. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: national Surgical Adjuvant Breast and Bowel Project Protocol B-27[J]. J Clin Oncol, 2006, 24(13):2019-2027. doi: 10.1200/JCO.2005.04.1665 [5] van der Hage JA, van de Velde CJ, Julien JP, et al. Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902[J]. J Clin Oncol, 2001, 19(22):4224-4237. doi: 10.1200/JCO.2001.19.22.4224 [6] von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes[J]. J Clin Oncol, 2012, 30(15):1796-1804. doi: 10.1200/JCO.2011.38.8595 [7] Ali R, Rakha EA, Madhusudan S, et al. DNA damage repair in breast cancer and its therapeutic implications[J]. Pathology, 2017, 49(2):156-165. [8] Maryam M, Yousefi B. DNA repair and damage pathways in breast cancer development and therapy[J]. DNA Repair (Amst), 2017, 54:22-29. doi: 10.1016/j.dnarep.2017.03.009 [9] Kwei KA, Kung Y, Salari K, et al. Genomic instability in breast cancer: pathogenesis and clinical implications[J]. Mol Oncol, 2010, 4(3):255-266. doi: 10.1016/j.molonc.2010.04.001 [10] Bhattacharyya A, Ear US, Koller BH, et al. The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross-linking agent cisplatin[J]. J Biol Chem, 2000, 275(31):23899-23903. doi: 10.1074/jbc.C000276200 [11] Lin ZP, Lee YS, Lin F, et al. Reduced level of ribonucleotide reductase R2 subunits increases dependence on homologous recombination repair of cisplatin-induced DNA damage[J]. Mol Pharmacol, 2011, 80(6):1000-1012. doi: 10.1124/mol.111.074708 [12] Wang ZG, Xu ZF, Zhu GY. A platinum(Ⅳ) anticancer prodrug targeting nucleotide excision repair to overcome cisplatin resistance[J]. Angew Chem Int Ed Engl, 2016, 55(50):15564-15568. [13] Takatsuka R, Ito S, Iwai S, et al. An assay to detect DNA-damaging agents that induce nucleotide excision-repairable DNA lesions in living human cells[J]. Mutat Res Genet Toxicol Environ Mutagen, 2017, 820:1-7. doi: 10.1016/j.mrgentox.2017.05.009 [14] Tutt A, Tovey H, Cheang MCU, et al. Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial[J]. Nat Med, 2018, 24(5):628-637. doi: 10.1038/s41591-018-0009-7 [15] Jacot W, Lusque A, Vicier C, et al. Outcomes of patients with HER2-negative metastatic breast cancer after platinum- and non-platinum-based first-line chemotherapy among patients with and without pathogenic germline BRCA1/2 mutations[J]. Br J Cancer, 2022, 127(11):1963-1973. [16] Zhang J, Yao L, Liu YQ, et al. Impact of the addition of carboplatin to anthracycline-taxane-based neoadjuvant chemotherapy on survival in BRCA1/2-mutated triple-negative breast cancer[J]. Int J Cancer, 2021, 148(4):941-949. doi: 10.1002/ijc.33234 [17] Fan ZH, Hu L, Ouyang T, et al. Germline mutation in DNA-repair genes is associated with poor survival in BRCA1/2-negative breast cancer patients[J]. Cancer Sci, 2019, 110(10):3368-3374. doi: 10.1111/cas.14175 [18] Jeggo PA, Pearl LH, Carr AM. DNA repair, genome stability and cancer: a historical perspective[J]. Nat Rev Cancer, 2016, 16(1):35-42. doi: 10.1038/nrc.2015.4 [19] Sun J, Meng H, Yao L, et al. Germline mutations in cancer susceptibility genes in a large series of unselected breast cancer patients[J]. Clin Cancer Res, 2017, 23(20):6113-6119. [20] Curtin NJ. DNA repair dysregulation from cancer driver to therapeutic target[J]. Nat Rev Cancer, 2012, 12(12):801-817. doi: 10.1038/nrc3399 [21] Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5):405-424. doi: 10.1038/gim.2015.30 [22] Byrski T, Huzarski T, Dent R, et al. Pathologic complete response to neoadjuvant cisplatin in BRCA1-positive breast cancer patients[J]. Breast Cancer Res Treat, 2014, 147(2):401-405. doi: 10.1007/s10549-014-3100-x [23] von Minckwitz G, Schneeweiss A, Loibl S, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial[J]. Lancet Oncol, 2014, 15(7):747-756. doi: 10.1016/S1470-2045(14)70160-3 [24] Wang C, Zhang J, Wang Y, et al. Prevalence of BRCA1 mutations and responses to neoadjuvant chemotherapy among BRCA1 carriers and non-carriers with triple-negative breast cancer[J]. Ann Oncol, 2015, 26(3):523-528. doi: 10.1093/annonc/mdu559 [25] Arun, Bayraktar S, Liu DD, et al. Response to neoadjuvant systemic therapy for breast cancer in BRCA mutation carriers and noncarriers: a single-institution experience[J]. J Clin Oncol, 2011, 29(28):3739-3746. [26] Hahnen E, Lederer B, Hauke J, et al. Germline mutation status, pathological complete response, and disease-free survival in triple-negative breast cancer: secondary analysis of the GeparSixto randomized clinical trial[J]. JAMA Oncol, 2017, 3(10):1378-1385. doi: 10.1001/jamaoncol.2017.1007 [27] Telli ML, Timms KM, Reid J, et al. Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer[J]. Clin Cancer Res, 2016, 22(15):3764-3773. doi: 10.1158/1078-0432.CCR-15-2477 [28] Telli ML, Jensen KC, Vinayak S, et al. Phase Ⅱ study of gemcitabine, carboplatin, and iniparib As neoadjuvant therapy for triple-negative and BRCA1/2 mutation-associated breast cancer with assessment of a tumor-based measure of genomic instability: PrECOG 0105[J]. J Clin Oncol, 2015, 33(17):1895-1901. doi: 10.1200/JCO.2014.57.0085 [29] Denkert C, Untch M, Benz S, et al. Reconstructing tumor history in breast cancer: signatures of mutational processes and response to neoadjuvant chemotherapy[J]. Ann Oncol, 2021, 32(4):500-511. doi: 10.1016/j.annonc.2020.12.016 [30] Teo MY, Bambury RM, Zabor EC, et al. DNA damage response and repair gene alterations are associated with improved survival in patients with platinum-treated advanced urothelial carcinoma[J]. Clin Cancer Res, 2017, 23(14):3610-3618. doi: 10.1158/1078-0432.CCR-16-2520 [31] Tung N, Battelli C, Allen B, et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel[J]. Cancer, 2015, 121(1):25-33. doi: 10.1002/cncr.29010 [32] Graffeo R, Livraghi L, Pagani O, et al. Time to incorporate germline multigene panel testing into breast and ovarian cancer patient care[J]. Breast Cancer Res Treat, 2016, 160(3):393-410. doi: 10.1007/s10549-016-4003-9 [33] Thompson ER, Rowley SM, Li N, et al. Panel testing for familial breast cancer: calibrating the tension between research and clinical care[J]. J Clin Oncol, 2016, 34(13):1455-1459. doi: 10.1200/JCO.2015.63.7454 [34] 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. [35] Loibl S, Weber KE, Timms KM, et al. Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response-final results from GeparSixto[J]. Ann Oncol, 2018, 29(12):2341-2347. doi: 10.1093/annonc/mdy460 [36] Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage Ⅱ to Ⅲ triple-negative breast cancer: CALGB 40603 (Alliance)[J]. J Clin Oncol, 2015, 33(1):13-21. doi: 10.1200/JCO.2014.57.0572 [37] Ando M, Yamauchi H, Aogi K, et al. Randomized phase II study of weekly paclitaxel with and without carboplatin followed by cyclophosphamide/epirubicin/5-fluorouracil as neoadjuvant chemotherapy for stage Ⅱ/ⅢA breast cancer without HER2 overexpression[J]. Breast Cancer Res Treat, 2014, 145(2):401-409.