BRCA1/2基因突变对乳腺癌保乳术后局部复发的影响及相关预后模型的构建
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中国人民解放军空军军医大学第一附属医院 甲乳血管外科,陕西 西安 710032

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张明坤,中国人民解放军空军军医大学第一附属医院主治医师,主要从事乳腺癌基础与临床方面的研究。

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国家自然科学基金青年科学基金资助项目(81902677);陕西省科技厅重点研发计划基金资助项目(2018ZDXM-SF-066)。


Impact of BRCA1/2 mutation on local recurrence of breast cancer patients following breast conserving surgery and construction of related prognostic model
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Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, China

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    摘要:

    背景与目的 保乳手术现已成为乳腺癌的标准手术方式之一,保乳手术能够保留患者的乳房外形,极大地改善患者术后的心理状态和生活质量。BRCA1/2基因是与乳腺癌密切相关的易感基因,BRCA1/2基因突变对保乳术后乳腺癌患者局部复发的影响目前尚有争议。因此,本研究分析BRCA1/2基因突变与乳腺癌保乳术后局部复发的关系,并构建相关预测模型,预测保乳术后乳腺癌患者的无局部复发生存(LRFS)率,为乳腺癌患者保乳手术适应证的选择提供可靠的依据。方法 回顾性分析2014年6月—2016年6月于中国人民解放军空军军医大学第一附属医院进行保乳手术的189例乳腺癌患者临床资料,并比较不同临床病理特征下患者BRCA1/2基因突变的差异,通过单因素及多因素Cox等比例回归模型分析BRCA1/2基因突变及其它临床病理因素对乳腺癌患者保乳术后局部复发的影响,并构建列线图来预测患者的LRFS率。通过一致性指数(C-index)、受试者工作特征(ROC)曲线及曲线下面积(AUC)对模型进行内部验证,通过校准曲线评估模型的准确性,并通过临床决策曲线分析(DCA)评价模型的临床获益和应用价值。结果 BRCA1/2基因突变组和未突变组的年龄和分子分型进行差异有统计学意义(均P<0.05)。单因素Cox等比例回归模型分析结果显示,BRCA1/2突变、肿瘤分级、肿瘤大小、N分期及分子分型是保乳术后乳腺癌患者LRFS率的影响因素(均P<0.1)。多因素Cox等比例回归模型分析结果显示,BRCA1/2基因突变、肿瘤大小、N分期及分子分型是保乳术后乳腺癌患者局部复发的独立影响因素(P<0.05)。将这些因素纳入并建立LRFS率的列线图预测模型。模型的C-index为0.86,内部验证C-index为0.81。ROC曲线分析结果显示,模型的3、5年LRFS率预测的AUC分别为0.89、0.85;校准曲线显示列线图预测的LRFS率与实际LRFS率接近;DCA分析显示模型的临床获益及应用价值较高。结论 BRCA1/2基因突变与保乳术后乳腺癌患者的局部复发相关,基于BRCA1/2基因突变列线图模型能够准确地预测保乳术后乳腺癌患者的LRFS率,并为乳腺癌患者手术方式的选择提供有效的科学依据。

    Abstract:

    Background and Aims Breast conserving surgery has become one of the standard surgical methods for breast cancer. Breast conserving surgery can preserve the mammary contour of patients and greatly improve the postoperative psychological state and quality of life. BRCA1/2 gene is a susceptibility gene closely related to breast cancer. The impact of BRCA1/2 gene mutation on local recurrence of breast cancer patients after breast conserving surgery is still controversial. This study was conducted to investigate the association of BRCA1/2 mutation with local recurrence of breast cancer patients undergoing breast conserving surgery, and construct a related prognostic model to predict the local recurrence free survival (LRFS) rate of breast cancer patients following breast conserving surgery, so as to provide guidance on indications for breast cancer patients to receive breast conserving surgery.Methods The clinical data of 189 breast cancer patients undergoing breast conserving surgery in Fourth Military Medical University Affiliated Xijing Hospital from June 2014 to June 2016 were retrospectively analyzed. The differences in BRCA1/2 mutation among patients with different clinicopathologic features were compared. The effects of BRCA1/2 mutation and other clinicopathologic factors on local recurrence were analyzed by univariate and multivariate Cox proportional regression models, and a nomogram was constructed to predict the LRFS rate. The model was internally verified by concordance index (C-index), receiver operating characteristic (ROC) curve, and area under curve (AUC). The accuracy of the model was assessed by calibration curves and the clinical benefits and application value of the model were evaluated by clinical decision curve analysis (DCA).Results There were significant differences in age and molecular subtype between the patients with and without BRCA1/2 gene mutation (both P<0.05). The results of univariate Cox equal proportional regression model showed that BRCA1/2 mutation, tumor grade, tumor size, N stage and molecular subtype were relevant risk factors for LRFS of breast patients receiving breast conserving surgery (all P<0.1). The results of multivariate Cox equal proportional regression model showed that BRCA1/2 mutation, tumor size, N stage and molecular subtype were independent risk factors for LRFS of breast patients after breast conserving surgery (all P<0.05). Based on the above variables, the nomogram models were constructed. The C-index of the model was 0.86, and the C-index for internal validation was 0.81. The ROC curve analysis results showed that the AUC of 3- and 5-year LRFS of the model were 0.89 and 0.85, respectively. The calibration curve analysis showed that predicted LRFS of the model had a good consistency with the actual observed values. The DCA showed that the model had high clinical benefit and application value.Conclusion BRCA1/2 mutation is associated with local recurrence in breast cancer patients undergoing breast conserving surgery. The nomogram model based on BRCA1/2 gene mutation can accurately predict the LRFS rate of breast cancer patients after breast conserving surgery, and provide an effective scientific basis for the selection of surgical methods for breast cancer patients.

    表 1 BRCA1/2突变和未突变患者的临床病理特征[n(%)]Table 1 Clinicopathologic features of BRCA1/2 mutant and non-mutant patients [n (%)]
    表 2 影响保乳术后乳腺癌患者LRFS率的单因素和多因素分析Table 2 Univariate and multivariate analysis of factors for LRFS in breast cancer patients undergoing breast conserving surgery
    图1 筛选因素对患者LRFS率影响的生存曲线分析Fig.1 Survival curve analysis of influences of the main variables on the LRFS of patients
    图2 LRFS率高危因素的森林图Fig.2 Forest map of high-risk factors of LRFS
    图3 LRFS率列线图预测模型Fig.3 Nomogram prediction model of LRFS
    图4 模型的3、5年LRFS率的ROC曲线分析Fig.4 ROC curve analysis of the model on 3- and 5-year LRFS
    图5 模型的3、5年LRFS率的校准曲线Fig.5 Calibration curves of the model on 3-year and 5-year LRFS
    图6 保乳术后乳腺癌患者的3年和5年LRFS率的DCA曲线Fig.6 DCA curve of 3- and 5-year LRFS in breast cancer patients undergoing breast conserving surgery
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张明坤,王哲,杨柳,侯兰,张聚良. BRCA1/2基因突变对乳腺癌保乳术后局部复发的影响及相关预后模型的构建[J].中国普通外科杂志,2022,31(11):1501-1509.
DOI:10.7659/j. issn.1005-6947.2022.11.012

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  • 收稿日期:2021-08-16
  • 最后修改日期:2022-06-13
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  • 在线发布日期: 2022-12-07