Immunohistochemically ER-positive HER2-negative (ER+HER2−) breast cancers are classified clinically as Luminal-type. We showed previously that molecular subtyping using the 80-gene signature (80-GS) reclassified a subset of ER+HER2− tumors to molecular Basal-type. We report here that molecular reclassification is associated with expression of dominant-negative ER variants and evaluate response to neoadjuvant therapy and outcome in the prospective neoadjuvant NBRST study (NCT01479101). The 80-GS reclassified 91 of 694 (13.1%) immunohistochemically Luminal-type tumors to molecular Basal-type. Importantly, all 91 discordant tumors were classified as high-risk, whereas only 66.9% of ER+/Luminal-type tumors were classified at high-risk for disease recurrence (i.e., Luminal B) (P < 0.001). ER variant mRNA (ER∆3, ER∆7, and ERα-36) analysis performed on 84 ER+/Basal tumors and 48 ER+/Luminal B control tumors revealed that total ER mRNA was significantly lower in ER+/Basal tumors. The relative expression of ER∆7/total ER was significantly higher in ER+/Basal tumors compared to ER+/Luminal B tumors (P < 0.001). ER+/Basal patients had similar pathological complete response (pCR) rates following neoadjuvant chemotherapy as ER−/Basal patients (34.3 vs. 37.6%), and much higher than ER+/Luminal A or B patients (2.3 and 5.8%, respectively). Furthermore, 3-year distant metastasis-free interval (DMFI) for ER+/Basal patients was 65.8%, significantly lower than 96.3 and 88.9% for ER+/Luminal A and B patients, respectively, (log-rank P < 0.001). Significantly lower total ER mRNA and increased relative ER∆7 dominant-negative variant expression provides a rationale why ER+/Basal breast cancers are molecularly ER-negative. Identification of this substantial subset of patients is clinically relevant because of the higher pCR rate to neoadjuvant chemotherapy and correlation with clinical outcome.

免疫组织化学ER阳性HER2阴性（ER + HER2-）乳腺癌在临床上被分类为Luminal型。先前我们证明了使用80基因签名（80-GS）进行的分子亚型化将ER + HER2-肿瘤的子集重新分类为分子基础型。我们在此报告分子重新分类与显性阴性ER变体的表达相关，并在前瞻性新辅助NBRST研究（NCT01479101）中评估对新辅助疗法的反应和结果。80-GS将694例中的91例（13.1％）通过免疫组化将Luminal型肿瘤重新分类为分子基础型。重要的是，所有91例不一致的肿瘤均被归为高危，而只有66.9％的ER + / Luminal型肿瘤因疾病复发而被归为高危（即Luminal B）（P <0.001）。对84例ER + /基础肿瘤和48例ER + / Luminal B对照肿瘤进行了ER变异mRNA（ER∆3，ER∆7和ERα-36）分析，发现ER + / Basal肿瘤中的总ER mRNA显着降低。与ER + / Luminal B肿瘤相比，ER + / Basal肿瘤中ER∆7 /总ER的相对表达显着更高（P  <0.001）。ER + / Basal患者在新辅助化疗后的病理完全缓解率（pCR）与ER- / Basal患者（34.3 vs. 37.6％）相似，并且远高于ER + / Luminal A或B患者（分别为2.3和5.8％）。此外，ER + /基础患者的3年远距离无转移间隔（DMFI）为65.8％，分别显着低于ER + / Luminal A和B患者的96.3和88.9％（log-rank P <0.001）。总ER mRNA的显着降低和相对ER∆7显性阴性的相对变体表达的增加，为ER + /基础乳腺癌在分子上为ER阴性提供了理论依据。由于新辅助化疗的较高pCR率以及与临床结果的相关性，因此，对这一大量患者的鉴定在临床上具有相关性。