HER2低表达晚期乳腺癌预后新策略
学术
健康
2024-12-17 13:24
上海
HER2阴性乳腺癌大约占全部乳腺癌的70%至80%，其中40%至60%为HER2低表达，对曲妥珠单抗等传统HER2靶向治疗药物无效。近年来，德曲妥珠单抗等新药被发现对HER2低表达乳腺癌有效，提示HER2低表达乳腺癌与HER2零表达乳腺癌相比，临床病理学和分子特征可能有所不同。不过，由于HER2低表达乳腺癌异质性较大，并且缺乏标准化HER2检测平台，目前没有足够证据支持将HER2低表达乳腺癌归类为独立的生物学亚型。此外，值得注意的是，过去对HER2低表达乳腺癌分子特征的大多数研究主要依赖于早期乳腺癌原发病灶分析，由于晚期乳腺癌转移病灶采样的局限性，研究HER2低表达乳腺癌循环肿瘤DNA特征显然势在必行，这将使更广泛的乳腺癌患者获益于这些发现。 2024年12月9日，英国《自然》旗下《信号转导与靶向治疗》在线发表武汉大学中南医院易宗毕①和冯凯祥①、辽宁省肿瘤医院吕丹、北京吉因加医学检验所管彦芳、武汉大学泰康医学院邵尤城、中国医学科学院肿瘤医院马飞✉️和徐兵河✉️等学者的研究报告，首次对HER2低表达晚期乳腺癌循环肿瘤DNA进行了基因组分析。 作者首先对两项前瞻研究（二期单组非对照临床试验NCC201711008、三期两组随机对照临床试验CAMELLIA）和一项回顾研究共计1071例晚期乳腺癌患者（其中HER2零表达267例、HER2低表达488例、HER2阳性316例）及其循环肿瘤DNA进行回顾分析，比较HER2低表达状态对不同治疗方式的影响，探讨HER2低表达晚期乳腺癌患者的临床病理学和基因改变。- NCC201711008 (NCT03412383): A Phase II Study of Pyrotinib in Metastatic HER2 Non-amplified But HER2 Mutant Breast Cancer
- CAMELLIA (NCT01917279): A Randomized Phase III Study of Metronomic vs. Intermittent Capecitabine Maintenance Therapy Following First-line Capecitabine and Docetaxel Therapy in HER2-negative Metastatic Breast Cancer
结果发现，HER2低表达晚期乳腺癌最常见的突变基因为TP53、PIK3CA、ESR1，突变率分别为47.8%、37.1%、12.1%。HER2低表达与HER2零表达相比，所见突变与代谢信号传导通路改变显著相关。 此外，对于ERBB2突变并接受吡咯替尼治疗的患者，HER2低表达与HER2零表达相比，无进展生存显著较长（中位6.9个月比2.3个月, P=0.011）。 值得注意的是，HER2零表达和HER2低表达相比，乳腺癌患者对化疗、内分泌治疗或CDK4/6抑制剂治疗的反应未见统计学显著差异。有趣的是，对于代谢信号传导通路相关基因突变个体亚组，HER2低表达与HER2零表达相比，乳腺癌患者对化疗、内分泌治疗或CDK4/6抑制剂治疗的反应显著较好。动态分析表明，在最初两个治疗周期后，分子肿瘤负荷指数降低或者实现循环肿瘤DNA早期清除的HER2低表达晚期乳腺癌患者无进展生存或总生存显著较长。 根据以上结果，可将HER2低表达晚期乳腺癌分为三类，有助于为后续治疗提供参考，提高治疗的精准度。 因此，该研究为HER2低表达晚期乳腺癌生物学特征提供了有价值的新认识，并可能为个体化治疗策略提供参考，故有必要进一步开展前瞻研究进行验证。徐兵河：中国工程院院士，北京协和医学院长聘教授，博士研究生导师，主任医师，武汉大学弘毅客座讲席教授，武汉大学中南医院肿瘤医院名誉院长兼首席专家，国家癌症中心/中国医学科学院肿瘤医院国家新药（抗肿瘤）临床研究中心主任，国家肿瘤质控中心乳腺癌专家委员会主任委员，国家抗肿瘤药物临床监测专家委员会主任委员，中国抗癌协会肿瘤药物临床研究专业委员会主任委员，中国抗癌协会乳腺癌专业委员会名誉主任委员，中国医师协会内科医师分会副会长，北京乳腺病防治学会理事长Signal Transduct Target Ther. 2024 Dec 9;9:345. IF: 40.8Genomic landscape of circulating tumor DNA in HER2-low metastatic breast cancer.Yi Z, Feng K, Lv D, Guan Y, Shao Y, Ma F, Xu B.Zhongnan Hospital of Wuhan University, Wuhan, China; Cancer Hospital of China Medical University, Liaoning Cancer Hospital, Shenyang, China; Geneplus-Beijing, Beijing, China; TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, China; National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.The large population of HER2-low breast cancer patients necessitates further research to provide enhanced clinical guidance. In this study, we retrospectively analyzed 1071 metastatic breast cancer (MBC) patients and the circulating tumor DNA (ctDNA) to investigate clinicopathological and genetic alterations of HER2-low MBC patients. The effect of HER2-low status on different treatment modalities was explored in two prospective clinical trials (NCT03412383, NCT01917279) and a retrospective study. Our findings suggest TP53, PIK3CA, and ESR1 are frequently mutated genes in HER2-low MBC. Compared to the HER2-0 group, mutations observed in the HER2-low group are more closely associated with metabolic pathway alterations. Additionally, among patients with ERBB2 mutations and treated with pyrotinib, the HER2-low group may experience superior prognosis when compared to the HER2-0 group. Notably, we did not find any statistically significant disparity in the response to chemotherapy, endocrine therapy, or CDK4/6 inhibitor therapy between HER2-0 and HER2-low breast cancer patients. Interestingly, within the subgroup of individuals with metabolic pathway-related gene mutations, we found that HER2-low group exhibited a more favorable response to these treatments compared to HER2-0 group. Additionally, dynamic analysis showed the HER2-low MBC patients whose molecular tumor burden index decreased or achieved early clearance of ctDNA after the initial two treatment cycles, exhibited prolonged survival. Moreover, we classified HER2-low MBC into three clusters, providing a reference for subsequent treatment with enhanced precision. Our study offers valuable insights into the biology of HER2-low MBC and may provide reference for personalized treatment strategies.DOI: 10.1038/s41392-024-02047-0
