Department of Breast Surgery, Fudan University Shanghai Cancer Center; Cancer Institute, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, P.R. China.
Theranostics. 2018 Dec 8;8(22):6386-6399. doi: 10.7150/thno.29164. eCollection 2018.
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. 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). 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 (30.3% vs. 17.0%) and lower mutation rates (25.8% vs. 42.7%) and exhibited more (21.5% vs. 13.6%) and (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. 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.
雌激素受体阳性、孕激素受体阴性和人表皮生长因子受体 2（HER2）阴性（ER+PR-HER2-）乳腺癌构成了一种特殊类型的乳腺癌，约占所有乳腺癌患者的 10%。ER+PR-HER2-肿瘤从内分泌治疗中获益较少，而其基因组特征仍不清楚。在这项研究中，我们系统地评估了 ER+PR-HER2-乳腺癌的多组学特征和内分泌反应性。
该研究纳入了五个队列。第一和第二队列来自监测、流行病学和最终结果数据库（n=130856）和乳腺癌国际分子分类联盟（n=1055），用于分析生存结局和内分泌反应性。第三队列来自癌症基因组图谱（n=630），用于多组学分析和探索内分泌耐药亚组。第四队列来自 MD 安德森数据库（n=92），用于辅助基因选择。第五队列是来自复旦大学上海癌症中心的前瞻性观察队列（n=245），用于通过免疫组织化学（IHC）验证基因定义的亚组。
临床上，ER+PR-HER2-肿瘤的内分泌反应性低于 ER+PR+HER2-肿瘤。从基因组角度来看，PR 基因的拷贝数缺失或启动子甲基化发生在 75%的 ER+PR-HER2-肿瘤中，共同解释了 PR 缺失。与 ER+PR+HER2-肿瘤相比，ER+PR-HER2-肿瘤具有更高的（30.3%比 17.0%）和更低的（25.8%比 42.7%）突变率，并且具有更多的（21.5%比 13.6%）和（18.5%比 7.8%）扩增事件。在 ER+PR-HER2-肿瘤中，近 20%属于 PAM50 定义的非 luminal 样亚组，表现出较低的内分泌敏感性评分和丰富的生物合成、代谢和 DNA 复制途径。我们进一步使用三种免疫组化标志物 GATA3、CK5 和 EGFR 来识别非 luminal 样亚组。这些 IHC 定义的非 luminal 样（GATA3 阴性、CK5 阳性和/或 EGFR 阳性）肿瘤从辅助内分泌治疗中获益有限。
ER+PR-HER2-乳腺癌由临床和基因组上不同的亚群组成，可能需要不同的治疗策略。非 luminal 样亚组与内分泌治疗获益减少相关。
