Groenendijk Floris H, Treece Tina, Yoder Erin, Baron Paul, Beitsch Peter, Audeh William, Dinjens Winand N M, Bernards Rene, Whitworth Pat
1Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Agendia, Irvine, CA USA.
NPJ Breast Cancer. 2019 Apr 18;5:15. doi: 10.1038/s41523-019-0109-7. eCollection 2019.
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) ( < 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 ( < 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 < 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.
免疫组化检测显示雌激素受体阳性、人表皮生长因子受体2阴性（ER+HER2-）的乳腺癌临床上归类为管腔型。我们之前表明，使用80基因特征（80-GS）进行分子亚型分类可将一部分ER+HER2-肿瘤重新分类为分子基底型。我们在此报告，分子重新分类与显性负性ER变体的表达相关，并在前瞻性新辅助NBRST研究（NCT01479101）中评估对新辅助治疗的反应及预后。80-GS将694例免疫组化检测为管腔型的肿瘤中的91例（13.1%）重新分类为分子基底型。重要的是，所有91例不一致的肿瘤均被归类为高危，而只有66.9%的ER+/管腔型肿瘤被归类为疾病复发高危（即管腔B型）（P<0.001）。对84例ER+/基底型肿瘤和48例ER+/管腔B型对照肿瘤进行的ER变体mRNA（ER∆3、ER∆7和ERα-36）分析显示，ER+/基底型肿瘤中的总ER mRNA显著更低。与ER+/管腔B型肿瘤相比，ER+/基底型肿瘤中ER∆7/总ER的相对表达显著更高（P<0.001）。ER+/基底型患者新辅助化疗后的病理完全缓解（pCR）率与ER- /基底型患者相似（分别为34.3%和37.6%），远高于ER+/管腔A型或B型患者（分别为2.3%和5.8%）。此外，ER+/基底型患者的3年无远处转移生存期（DMFI）为65.8%，显著低于ER+/管腔A型和B型患者的96.3%和88.9%（对数秩检验P<0.001）。总ER mRNA显著降低以及ER∆7显性负性变体表达增加，为ER+/基底型乳腺癌分子水平上雌激素受体阴性提供了理论依据。识别出这一相当大比例的患者群体具有临床相关性，因为其对新辅助化疗的pCR率更高且与临床预后相关。
