BRCA1/2胚系突变对三阴性乳腺癌患者放疗后第二原发肿瘤的影响

doi:10.19401/j.cnki.1007-3639.2024.02.006

摘要/Abstract

摘要：

背景与目的：乳腺癌易感基因1/2（BRCA1/2）的编码产物在维持机体基因组稳定性方面发挥着重要的作用。BRCA1/2致病突变是否会导致机体对放射线的脆弱度增加，从而诱发第二原发肿瘤尚不清楚。本文旨在探讨BRCA1/2基因胚系突变的三阴性乳腺癌患者术后接受放射治疗是否是增加罹患第二原发肿瘤的危险因素。方法：基于复旦大学附属肿瘤医院2007年1月1日—2014年12月31日收集的回顾性三阴性乳腺癌队列（292例为BRCA1/2突变的女性三阴性乳腺癌患者），针对其开展分析，分别在非BRCA1/2胚系突变患者（n = 261）与BRCA1/2胚系突变患者（n = 31）中进行多元logistic回归分析，以评估影响第二原发肿瘤的风险因素，并对上述两人群中的分析结果进行交互作用分析，从而评估BRCA1/2胚系突变与放疗的交互作用。本研究除特殊说明外，均采用双侧检验且检验水准α = 0.05。本研究所有样本的获得与使用均得到了复旦大学附属肿瘤医院伦理委员会的批准（050432-4-2108），且每个患者均提供了书面知情同意。结果：在BRCA1/2胚系突变患者中进行多元logistic回归分析提示术后接受放疗相对于未接受放疗显著增加了第二原发肿瘤的风险[比值比（odds ratio，OR） = 2.479，95% CI：1.971 ~ 3.118，P<0.001）。而在非BRCA1/2胚系突变患者中，放疗对第二原发肿瘤的效应则不显著。BRCA1/2胚系突变与放疗对于第二原发肿瘤的发生无显著的交互作用（OR = 9.71，95% CI：0.32 ~ 295.25，P = 0.193）。结论：虽然统计学分析结果显示，与未接受放疗的患者相比，BRCA1/2胚系突变的患者术后放疗会增加罹患第二原发肿瘤的风险，但BRCA1/2胚系突变与放疗对第二原发肿瘤的发生并无相互交叉作用，因而BRCA1/2胚系突变患者术后接受放疗可能并不会增加罹患第二原发肿瘤的风险。

关键词: 乳腺癌, BRCA1, BRCA2, 放疗, 第二原发肿瘤

Abstract:

Background and purpose: BRCA1/2 plays an important role in maintaining the genome stability. Whether BRCA1/2 germline mutation could increase the tumor sensitivity to radiotherapy, thereby inducing secondary primary cancer after radiotherapy is unclear. This study aimed to investigate whether postoperative radiotherapy is a risk factor for the development of second primary cancer in triple-negative breast cancer (TNBC) patients with BRCA1/2 germline mutation. Methods: This research was based on a previously reported retrospective cohort, i.e., the Fudan University Shanghai Cancer Center TNBC cohort. Between January 1, 2007 and December 31, 2014, a total of 292 female TNBC patients with BRCA1/2 mutation were enrolled. We performed logistic regression analysis in patients without BRCA1/2 germline mutation (n=261) and BRCA1/2 germline mutation patients (n=31), respectively, to assess the risk factors affecting the incidence of second primary cancer. We then performed interactive analysis on the above two analyses to evaluate the interactive effect between BRCA1/2 germline mutation and postoperative radiotherapy. P<0.05 indicates a statistically significant difference. The research was approved by Fudan University Shanghai Cancer Center TNBC Ethics Committee (050432-4-2108), and each patient provided written informed consent. Results: Logistic regression analysis in patients with BRCA1/2 germline mutations showed that postoperative radiotherapy significantly increased the risk of secondary primary disease compared to non-radiotherapy [odds ratio (OR)=2.475, 95% confidence interval (CI): 1.933-3.167, P<0.001]. In patients without BRCA1/2 germline mutation, the effect of radiotherapy on the incidence of second primary tumor was not significant. There was a significant interaction between BRCA1/2 germline mutation and postoperative radiotherapy for the incidence of secondary primary cancer (OR=9.710, 95% CI: 0.320-295.250, P=0.193). Conclusion: Although statistical analysis results show that patients with BRCA1/2 germline mutations have an increased risk of developing a second primary tumor after postoperative radiotherapy compared to patients who have not received radiotherapy, there is no significant correlation between BRCA1/2 germline mutations and radiotherapy for the development of a second primary tumor. Therefore, patients with BRCA1/2 germline mutations who receive radiotherapy after surgery may not increase the risk of developing a second primary tumor.

Key words: Breast cancer, BRCA1, BRCA2, Radiotherapy, Second primary cancer

中图分类号:

R737.9

胡晓钰, 蔡毓文, 叶富贵, 邵志敏, 胡伟刚, 余科达. BRCA1/2胚系突变对三阴性乳腺癌患者放疗后第二原发肿瘤的影响[J]. 中国癌症杂志, 2024, 34(2): 185-190.

HU Xiaoyu, CAI Yuwen, YE Fugui, SHAO Zhimin, HU Weigang, YU Keda. Impact of BRCA1/2 germline mutation on the incidence of second primary cancer following postoperative radiotherapy in patients with triple-negative breast cancer[J]. China Oncology, 2024, 34(2): 185-190.

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参考文献 13

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Item	TNBC patients with BRCA1/2 mutation data (n = 292)		Item	TNBC patients with BRCA1/2 mutation data (n = 292)
Item	BRCA1/2 not mutated (n = 261)	BRCA1 or BRCA2 mutated (n = 31)	Item	BRCA1/2 not mutated (n = 261)	BRCA1 or BRCA2 mutated (n= 31)
Age at surgery/year	52 ± 11	45 ± 11	Chemotherapy
Menopause			No	4 (1.5%)	0
No	96 (36.8%)	17 (54.8%)	Yes	248 (95.0%)	31 (100.0%)
Yes	162 (62.1%)	14 (45.2%)	Surgery
Tumor grade			Breast conserved surgery	8 (3.1%)	1 (3.2%)
Ⅱ	51 (19.5%)	6 (19.4%)	Mastectomy	60 (23.0%)	9 (29.0%)
Ⅲ	192 (73.6%)	22 (71.0%)	Modified radical mastectomy	192 (73.6%)	21 (67.7%)
pT			mRNA subtype
T₁	96 (36.8%)	14 (45.2%)	Basal-like and immune-suppressed (BLIS)	85 (32.6%)	14 (45.2%)
T₂	159 (60.9%)	17 (54.8%)	Immunomodulatory (IM)	36 (13.8%)	5 (16.1%)
T₃	6 (2.3%)	0	Luminal androgen receptor (LAR)	43 (16.5%)	2 (6.5%)
pN			Mesenchymal-like (MES)	29 (11.1%)	1 (3.2%)
N₀	156 (59.8%)	23 (74.2%)	Radiation therapy
N₁	64 (24.5%)	4 (12.9%)	No	175 (67.0%)	22 (71.0%)
N_1mi	1 (0.4%)	0	Yes	85 (32.6%)	9 (29.0%)
N₂	25 (9.6%)	3 (9.7%)	Second primary cancer
N₃	15 (5.7%)	0	No	255 (97.7%)	30 (96.8%)
			Yes	6 (2.3%)	1 (3.2%)

	Odds ratio (95% confidence interval)	Pvalue		Odds ratio (95% confidence interval)	Pvalue
Age at surgery/year	1.000 (0.997-1.003)	0.896	Surgery		0.959
Menopause		0.567	Breast conserved surgery	-
No	-		Mastectomy	0.978 (0.829-1.152)
Yes	1.018 (0.958-1.082)		Modified radical mastectomy	0.982 (0.838-1.150)
Tumor grade		0.167	mRNA subtype		0.735
Ⅱ	-		Basal-like and immune-suppressed (BLIS)	-
Ⅲ	0.964 (0.916-1.015)		Immunomodulatory (IM)	0.990 (0.934-1.050)
Tumor size/cm	1.004 (0.983-1.026)	0.707	Luminal androgen receptor (LAR)	1.021 (0.964-1.081)
Number of positive lymph nodes	1.000 (0.995-1.006)	0.876	Mesenchymal-like (MES)	0.983 (0.924-1.046)
Chemotherapy		0.740	Radiation therapy		0.343
No	-		No	-
Yes	1.027 (0.878-1.202)		Yes	0.974 (0.922-1.028)

	Odds ratio (95% confidence interval）	Pvalue		Odds ratio (95% confidence interval）	Pvalue
Age at surgery/year	1.005 (0.996-1.014)	0.350	Modified radical mastectomy	-
Menopause		0.662	Mastectomy	0.919 (0.790-1.068)
No	-		mRNA subtype		<0.001
Yes	0.961 (0.810-1.140)		Basal-like and immune-suppressed (BLIS)	-
Tumor grade		0.843	Immunomodulatory (IM)	1.211 (1.023-1.433)
Ⅱ	-		Luminal androgen receptor (LAR)	0.390 (0.285-0.534)
Ⅲ	1.020 (0.847-1.227)		Mesenchymal-like (MES)	0.991 (0.772-1.271)
Tumor size/cm	0.976 (0.851-1.120)	0.723	Radiotherapy		<0.001
Number of positive lymph nodes	0.852 (0.784-0.926)	0.007	No	-
Surgery		0.307	Yes	2.479 (1.971-3.118)

Item	Odds ratio for multiplicative interaction (95% CI)	Pvalue
Within BRCA1/2 mutation	9.71 (0.32-295.25)	0.193
With BRCA1/2 mutation	9.71 (0.32-295.25)	0.193

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