Zheng Chun-Hui, Liu Zhao-Yun, Yuan Chen-Xi, Dong Xiao-Yun, Li Hai-Mei, Wang Jin-Jin, Zhang Zhao-Peng, Liu Hong-Ying, Ding Xiao-Yan, Wu Wendy, Wang Rui-Ru, Wang Yong-Sheng
Breast Cancer Center, Shandong Cancer Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
Departments of Oncology Surgery, People's Hospital, Weifang, China.
Front Med (Lausanne). 2021 Mar 31;8:651904. doi: 10.3389/fmed.2021.651904. eCollection 2021.
The shrinkage mode of tumor extent after neoadjuvant chemotherapy (NAC) is an important index to evaluate the odds of breast-conserving surgery. However, there is no sufficient measurement to predict the shrinkage mode after NAC. In this study, we analyzed 24 patients' formalin-fixed, paraffin-embedded samples before and after treatment and analyzed 456 cancer-related genes panel by using target next-generation sequencing. Meanwhile, the pathological shrinkage mode was reconstructed in three dimensions after surgery, and the genetic heterogeneity level was estimated by mutant-allele tumor heterogeneity (MATH). We measured the genetic intra-tumor heterogeneity and explored its correlation with the shrinkage mode after NAC. A total of 17 matched pair samples of primary tumor tissue and residual tumor tissue were successfully accessed. It was found that the most common mutated genes were TP53 and PIK3CA in both samples before and after NAC, and no recurrent mutations were significantly associated with the shrinkage mode. Besides, the MATH value of formalin-fixed, paraffin-embedded samples before and after NAC was analyzed by the area under the curve of the receiver operating characteristic, and it is feasible to classify patients into concentric shrinkage mode and non-concentric shrinkage mode in NAC based on the MATH threshold of 58. Our findings indicate that the MATH value was associated with the shrinkage mode of breast cancer in a non-linear model. Patients with the MATH value below the threshold of 58 before and after NAC displayed a concentric shrinkage mode. The area under the curve was 0.89, with a sensitivity of 0.69 and specificity of 1. Our study might provide a promising application of intra-tumor heterogeneity that is measured by MATH to make a choice of surgery.
新辅助化疗（NAC）后肿瘤范围的缩小模式是评估保乳手术可能性的重要指标。然而，目前尚无足够的方法来预测NAC后的缩小模式。在本研究中，我们分析了24例患者治疗前后的福尔马林固定石蜡包埋样本，并通过靶向二代测序分析了456个癌症相关基因panel。同时，术后在三维空间重建病理缩小模式，并通过突变等位基因肿瘤异质性（MATH）评估基因异质性水平。我们测量了肿瘤内基因异质性，并探讨其与NAC后缩小模式的相关性。共成功获取了17对原发性肿瘤组织和残余肿瘤组织的匹配样本。结果发现，NAC前后两个样本中最常见的突变基因均为TP53和PIK3CA，且无复发性突变与缩小模式显著相关。此外，通过受试者工作特征曲线下面积分析NAC前后福尔马林固定石蜡包埋样本的MATH值，基于58的MATH阈值将NAC患者分为同心缩小模式和非同心缩小模式是可行的。我们的研究结果表明，MATH值与乳腺癌的缩小模式呈非线性模型相关。NAC前后MATH值低于58阈值的患者表现为同心缩小模式。曲线下面积为0.89，敏感性为0.69，特异性为1。我们的研究可能为通过MATH测量肿瘤内异质性在手术选择方面提供有前景的应用。
