雌激素受体阳性、孕激素受体阴性、人表皮生长因子受体2（HER2）阴性乳腺癌属于一种特殊类型的乳腺癌，约占所有乳腺癌患者的10%，对内分泌治疗的获益较少，而其基因组特征仍然难以捉摸。
2018年12月8日，常春藤旗下《治疗诊断学》正式发表复旦大学附属肿瘤医院刘西禹、马丁、徐晓恩、金希、余科达、江一舟、邵志敏的研究报告，系统评定了雌激素受体单阳性乳腺癌的多组学特征和内分泌疗效。
该研究共分析了五组数据：第一组13万0856例数据来自美国国家癌症研究所（NCI）监测流行病学最终结果（SEER）数据库，第二组1055例数据来自国际乳腺癌分子分类学联盟（METABRIC）数据库，用于分析生存结局和内分泌疗效；第三组630例数据来自美国国家人类基因组研究所（NHGRI）和国家癌症研究所（NCI）癌症基因组图谱（TCGA）数据库，用于多组学分析和内分泌耐药亚组探讨；第四组92例数据来自美国德克萨斯大学MD安德森癌症中心（UT-MDACC）数据库，用于辅助基因选择。第五组245例数据来自复旦大学附属肿瘤医院（FUSCC）2007年1月1日～2014年12月31日前瞻观察研究队列，用于通过免疫组化验证按基因定义的亚组。
结果发现：从临床角度而言，雌激素受体单阳性与雌孕激素受体双阳性的乳腺癌相比，内分泌疗效较差。
从基因角度而言，孕激素受体基因拷贝数丢失或启动子甲基化发生于75%的雌激素受体单阳性乳腺癌，共同解释了孕激素受体阴性。
雌激素受体单阳性与雌孕激素受体双阳性的乳腺癌相比：
TP53突变率较高（30.3%比17.0%）
PIK3CA突变率较低（25.8%比42.7%）
ZNF703扩增率较高（21.5%比13.6%）
RPS6KB1扩增率较高（18.5%比7.8%）
根据50基因（PAM50）评分，将近20%的雌激素受体单阳性乳腺癌属于非管腔型亚组，表现为内分泌敏感性评分较低，癌细胞的生物合成、代谢和DNA复制通路较活跃。
根据三种免疫组化标志（GATA3、CK5、EGFR）可以进一步确定非管腔型亚组（GATA3阴性、CK5阳性、EGFR阳性）乳腺癌对于内分泌辅助治疗获益有限。
因此，该研究结果表明，雌激素受体单阳性乳腺癌具有不同的临床和基因组特征，其中非管腔型亚组对于内分泌治疗的获益较少，可能需要不同的治疗策略，不能一刀切。
Theranostics. 2018 Dec 8;8(22):6386-6399.
Genomic Landscape and Endocrine-Resistant Subgroup in Estrogen Receptor-Positive, Progesterone Receptor-Negative, and HER2-Negative Breast Cancer.
Xi-Yu Liu, Ding Ma, Xiao-En Xu, Xi Jin, Ke-Da Yu, Yi-Zhou Jiang, Zhi-Ming Shao.
Fudan University Shanghai Cancer Center; Cancer Institute, Fudan University Shanghai Cancer Center; Shanghai Medical College, Fudan University, China.
Estrogen receptor-positive, progesterone receptor-negative, and human epidermal growth factor receptor 2 (HER2)-negative (ER+PR-HER2-) breast cancer comprise a special type of breast cancer that constitutes ~10% of all breast cancer patients. ER+PR-HER2- tumor benefits less from endocrine therapy, while its genomic features remain elusive. In this study, we systematically assessed the multiomic landscape and endocrine responsiveness of ER+PR-HER2- breast cancer.
METHODS: This study incorporated five cohorts. The first and second cohorts were from the Surveillance, Epidemiology, and End Results database (n=130,856) and Molecular Taxonomy of Breast Cancer International Consortium (n=1,055) for analyzing survival outcomes and endocrine responsiveness. The third cohort was from The Cancer Genome Atlas (n=630) for multiomic analysis and endocrine-resistant subgroup exploration. The fourth cohort, from the MD Anderson database (n=92), was employed to assist gene selection. The fifth cohort was a prospective observational cohort from Fudan University Shanghai Cancer Center (n=245) that was utilized to validate the gene-defined subgroup by immunohistochemistry (IHC).
RESULTS: Clinically, ER+PR-HER2- tumors showed lower endocrine responsiveness than did ER+PR+HER2- tumors. Genomically, copy number loss or promoter methylation of PR genes occurred in 75% of ER+PR-HER2- tumors, collectively explaining PR loss. ER+PR-HER2- tumors had higher TP53 (30.3% vs. 17.0%) and lower PIK3CA mutation rates (25.8% vs. 42.7%) and exhibited more ZNF703 (21.5% vs. 13.6%) and RPS6KB1 (18.5% vs. 7.8%) amplification events than ER+PR+HER2- tumors. Among ER+PR-HER2- tumors, nearly 20% were of the PAM50-defined non-luminal-like subgroup and manifested lower endocrine sensitivity scores and enriched biosynthesis, metabolism and DNA replication pathways. We further identified the non-luminal-like subgroup using three IHC markers, GATA3, CK5, and EGFR. These IHC-defined non-luminal-like (GATA3-negative, CK5-positive and/or EGFR-positive) tumors received limited benefit from adjuvant endocrine therapy.
CONCLUSION: ER+PR-HER2- breast cancer consists of clinically and genomically distinct groups that may require different treatment strategies. The non-luminal-like subgroup was associated with reduced benefit from endocrine therapy.
KEYWORDS: ER+PR-HER2-, endocrine resistance, multiomic, non-luminal-like, breast cancer
DOI: 10.7150/thno.29164
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