DNA损伤修复基因胚系突变乳腺癌新辅助化疗疗效分析

刘婧思; 陈久安; 孙洁; 姚璐; 张娟; 解云涛; 徐晔

doi:10.12354/j.issn.1000-8179.2023.20230054

DNA损伤修复基因胚系突变乳腺癌新辅助化疗疗效分析

doi: 10.12354/j.issn.1000-8179.2023.20230054

北京大学肿瘤医院家族遗传性肿瘤中心，恶性肿瘤发病机制及转化研究教育部重点实验室（北京市100142）

基金项目: 本文课题受国家自然科学基金项目（编号：82072898，81772824）和北京市属医院科研培育计划（编号：PX2021042）资助

详细信息

作者简介:
刘婧思：专业方向为家族遗传性乳腺癌临床与基础研究

通讯作者:
徐晔　xuye@bjmu.edu.cn

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出版历程
- 收稿日期: 2023-01-19
- 录用日期: 2023-04-13
- 修回日期: 2023-04-04

Efficacy analysis of neoadjuvant chemotherapy regimens for patients with breast cancer carrying germline mutations in DNA damage repair genes

Familial & Hereditary Cancer Center, Peking University Cancer Hospital & Institute, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Beijing 100142, China

Funds: This work was supported by the National Natural Science Foundation of China (No.82072898, No. 81772824）and Beijing Municipal Administration of Hospitals Incubating Program (No. PX2021042)

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Corresponding author: Ye Xu; E-mail:xuye@bjmu.edu.cn

摘要

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。
- 乳腺癌 /
- DNA损伤修复基因 /
- 新辅助化疗 /
- 病理完全缓解
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.
- breast cancer /
- DNA damage repair (DDR) genes /
- neoadjuvant chemotherapy /
- pathological complete remission (pCR)

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图 1 接受3种新辅助化疗方案的DDR基因胚系突变乳腺癌患者的特异性生存曲线

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

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图 2 接受3种新辅助化疗方案的DDR基因胚系突变乳腺癌患者的无复发生存曲线

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

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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

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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

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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

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