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

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-）乳腺癌是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，而其基因组特征仍然难以捉摸。在这项研究中，我们系统地评估了ER + PR-HER2-乳腺癌的多基因组情况和内分泌反应性。

方法：本研究纳入了五个队列。第一组和第二组来自“监测，流行病学和最终结果”数据库（n = 130,856）和乳腺癌国际联合会的分子分类学（n = 1,055），用于分析生存结果和内分泌反应性。第三组来自癌症基因组图谱（n = 630），用于多基因组分析和耐内分泌亚组研究。来自MD安德森数据库（n = 92）的第四个队列用于辅助基因选择。第五个队列是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。

结果：在临床上，ER + PR-HER2-肿瘤的内分泌反应性低于ER + PR + HER2-肿瘤。从基因组上讲，PR基因的拷贝数丢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丢失。ER + PR-HER2-肿瘤具有更高的TP53（30.3％对17.0％）和更低的PIK3CA突变率（25.8％对42.7％），并且具有更多的ZNF703（21.5％对13.6％）和RPS6KB1与ER + PR + HER2-肿瘤相比（18.5％比7.8％）扩增事件。在ER + PR-HER2-肿瘤中，近20％属于PAM50定义的非管腔样亚组，表现出较低的内分泌敏感性评分，并具有丰富的生物合成，代谢和DNA复制途径。我们进一步使用三种IHC标记物GATA3，CK5和EGFR鉴定了非管腔样亚组。这些IHC定义的非管腔样（GATA3阴性，CK5阳性和/或EGFR阳性）的肿瘤从辅助内分泌治疗中获得的收益有限。

结论： ER + PR-HER2-乳腺癌由临床和基因组不同的群体组成，可能需要不同的治疗策略。非管腔样亚组与内分泌治疗的获益减少有关。

关键词：ER + PR-HER2-，内分泌抵抗，多组学，非管腔样，乳腺癌