【原】中国乳腺癌术前靶向化疗效果预测因素

　　虽然现有HER2靶向治疗已经取得了巨大的成功，但是不同的HER2阳性乳腺癌患者对其疗效截然不同，其预测因素尚不明确。

　　2020年7月7日，施普林格自然旗下《乳腺癌研究与治疗》在线发表广东省人民医院、广东省医学科学院、华南理工大学、南方医科大学、广州燃石生物科技、美国德克萨斯大学MD安德森癌症中心的研究报告，对中国HER2阳性乳腺癌患者基因突变特征以及术前新辅助抗HER2治疗效果的基因预测因素进行了探讨。

　　该单中心队列研究采用了两个队列，第一队列来自2012～2018年在广东省人民医院进行治疗的181例HER2阳性乳腺癌患者，第二队列来自第一个队列的40例术前HER2靶向新辅助化疗患者。通过大规模并行测序对基因突变特征进行分析。病理完全缓解定义为术前新辅助治疗后乳房活检病理结果阴性或原位（ypT0/is）淋巴结活检病理结果阴性（ypN0）。

　　结果发现，HER2阳性乳腺癌患者突变比例最高的基因：

• TP53（74.6%）

• CDK12（64.6%）

• PIK3CA（46.4%）

　　术前HER2靶向新辅助化疗患者完全缓解与未完全缓解相比，以下因素显著不同：

• Ki67阳性<40%（P=0.028）

• TP53错义突变（P=0.019）

• TP53失功突变（P=0.005）

• PIK3CA突变（P=0.013）

• ROS1突变（P=0.049）

　　此外，TP53失功突变和Ki67阳性比例可预测病理完全缓解：

• TP53失功突变与否相比：病理完全缓解比例高7.086倍（95%置信区间：1.366～36.749，P=0.020）

• Ki67<40%与≥40%相比：病理完全缓解比例高6.007倍（95%置信区间：1.120～32.210，P=0.036）

　　因此，该研究结果表明，HER2阳性乳腺癌患者的TP53失功突变和Ki67阳性比例，可预测术前HER2靶向新辅助化疗的病理完全缓解。

Breast Cancer Res Treat. 2020 Jul 7. Online ahead of print.

Genetic mutation profile of Chinese HER2-positive breast cancers and genetic predictors of responses to Neoadjuvant anti-HER2 therapy.

Kai Li, Ning Liao, Bo Chen, Guochun Zhang, Yulei Wang, Liping Guo, Guangnan Wei, Minghan Jia, Lingzhu Wen, Chongyang Ren, Li Cao, Hsiaopei Mok, Cheukfai Li, Jiali Lin, Xiaoqing Chen, Zhou Zhang, Ting Hou, Min Li, Jing Liu, Charles M. Balch, Ning Liao.

Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China; School of Medicine, South China University of Technology, Guangzhou, China; The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China; Burning Rock Biotech, Guangzhou, China; University of Texas MD Anderson Cancer Center, Houston, TX, USA.

PURPOSE: Despite the therapeutic success of existing HER2-targeted therapies, tumors respond quite differently to them. This study aimed at figuring out genetic mutation profile of Chinese HER2-positive patients and investigating predictive factors of neoadjuvant anti-HER2 responses.

METHODS: We employed two cohorts. The first cohort was comprised of 181 HER2-positive patients treated at Guangdong Provincial People's Hospital from 2012 to 2018. The second cohort included 40 patients from the first cohort who underwent HER2-targeted neoadjuvant chemotherapy. Genetic mutations were characterized using next-generation sequencing. We employed the most commonly used definition of pathological complete response (pCR)-eradication of tumor from both breast and lymph nodes (ypT0/is ypN0).

RESULTS: In Chinese HER2-positive breast cancer patients, TP53 (74.6%), CDK12 (64.6%) and PIK3CA (46.4%) have the highest mutation frequencies. In cohort 2, significant differences were found between pCR and non-pCR groups in terms of the initial Ki67 status, TP53 missense mutations, TP53 LOF mutations, PIK3CA mutations and ROS1 mutations (p=0.028, 0.019, 0.005, 0.013, 0.049, respectively). Furthermore, TP53 LOF mutations and initial Ki67 status (OR 7.086, 95% CI 1.366-36.749, p=0.020 and OR 6.007, 95% CI 1.120-32.210, p=0.036, respectively) were found to be predictive of pCR status.

CONCLUSION: TP53 LOF mutations and initial Ki67 status in HER2-positive breast cancer are predictive of pCR status after HER2-targeted NACT.

DOI: 10.1007/s10549-020-05778-0