乳腺癌肿瘤内异质性的驱动因素及临床研究进展

Progress of clinical research on the drivers of intratumoral heterogeneity in breast cancer

乳腺癌是第一种根据患者肿瘤的分子特征指导临床选择治疗策略的恶性肿瘤。然而,无论是基于免疫组织化学的分子分型还是基于基因组分析的固有分型,均存在一定的缺陷,二者不能完全解释乳腺癌预后和治疗的临床异质性。肿瘤内异质性(intratumoral heterogeneity,ITH)理论与乳腺癌的分型理论不同,异质性理论是指在同一肿瘤中存在多个不同亚型(空间异质性),并且肿瘤在不同时期不同表型间可相互转化(时间异质性)。这些异质性是由肿瘤细胞状态异质性和克隆进化驱动,同时受肿瘤微环境、代谢重编程的协同影响。对肿瘤内异质性ITH的研究可进一步解释乳腺癌转移和耐药机制,有望成为潜在的新型治疗靶点。本文将对乳腺癌ITH的驱动因素和临床意义的研究进展进行综述。

Breast cancer was the first human cancer wherein a personalized treatment strategy was driven by the molecular characterization of patient-specific tumors.However,determination of molecular and intrinsic subtypes based on immunohistochemistry and genome analysis,respectively,has a few limitations.Therefore,the clinical heterogeneity of breast cancer prognosis and treatment remains to be fully understood.The intratumoral heterogeneity(ITH)theory differs from the molecular subtyping of breast cancer.It acknowledges the existence of multiple subtypes within a single tumor(spatial heterogeneity)and the heterogeneous transformation between different phenotypes at different stages(temporal heterogeneity).ITH is driven by cell-state heterogeneity and clone evolution,and is affected by the surrounding microenvironment and metabolic reprogramming.Additionally,it can explain the mechanisms underlying breast cancer metastasis and drug resistance.Therefore,ITH can become a potential novel therapeutic target.This review summarizes the research progress on the factors that drive ITH as well as its clinical significance in breast cancer.