具有高增殖（MKShi）和低 ER 相关信号（ERSlo）的管腔乳腺癌预后较差。我们研究了 MKShi/ERSlo 肿瘤的治疗反应和分子特征，为潜在的治疗提供信息。接受新辅助化疗 (NAC) 且不使用 (MDACC，N = 199) 或使用派姆单抗 (I-SPY2，N = 40) 的患者的基因表达数据，分析不使用（POETIC，N = 172）或使用哌柏西利（NeoPalAna，N = 32）的内分泌治疗（NET），以评估 MKS/ERS 亚组的治疗反应。 TCGA 用于评估 MKS/ERS 亚组与 Palbociclib 耐药性（Cyclin-E、RBsig、IRPR）和免疫治疗反应（TMB、TIL、T 细胞炎症）相关的突变情况和生物标志物。与 MKShi/ERShi 相比MKShi/ERSlo 肿瘤对 NAC 的病理缓解率较高（22% vs 8%，p = 0.06），但复发风险较高（4 年无转移生存率 70% vs 94%，p = 0.01）。 MKShi/ERSlo 肿瘤经常携带 TP53 (34%) 和 PIK3CA (33%) 突变，并显示 Cyclin-E、RBsig 和 IRPR 高表达、高 TMB 以及升高的 TIL 和 T 细胞炎症元基因表达。 MKShi/ERSlo 肿瘤在使用或不使用 Palbociclib 的 NET 治疗后仍保持高增殖性，但在 NAC 中添加派姆单抗时具有更高的病理完全缓解率（42% vs 21%，p = 0.07）。MKShi/ERSlo 肿瘤的预后较差，且在化疗中丰富-敏感但对 ET 和 Palbociclib 耐药的肿瘤。生物标志物分析和临床数据表明免疫疗法在该群体中具有潜在作用。© 2023。作者。

Luminal breast cancers with high proliferation (MKShi) and low ER-related signalling (ERSlo) have a poor prognosis. We investigated treatment responses and molecular features of MKShi/ERSlo tumours to inform potential therapies.Gene expression data from patients who received neoadjuvant chemotherapy (NAC) without (MDACC, N = 199) or with pembrolizumab (I-SPY2, N = 40), or endocrine therapy (NET) without (POETIC, N = 172) or with palbociclib (NeoPalAna, N = 32) were analyzed to assess treatment response by MKS/ERS-subgroups. TCGA was used to assess the mutational landscape and biomarkers associated with palbociclib-resistance (Cyclin-E, RBsig, IRPR) and immunotherapy-response (TMB, TILs, T-cell inflamed) by MKS/ERS-subgroups.Compared to MKShi/ERShi tumours, MKShi/ERSlo tumours had higher pathological response rates to NAC (22% vs 8%, p = 0.06) but a higher recurrence risk (4-year metastasis-free survival 70% vs 94%, p = 0.01). MKShi/ERSlo tumours frequently harboured TP53 (34%) and PIK3CA (33%) mutations, and showed high expression of Cyclin-E, RBsig and IRPR, high TMB and elevated TIL and T-cell inflamed metagene expression. MKShi/ERSlo tumours retained high proliferation after NET with or without palbociclib but had higher pathological complete response rates when pembrolizumab was added to NAC (42% vs 21%, p = 0.07).MKShi/ERSlo tumours have dismal outcomes and are enriched in chemotherapy-sensitive but ET- and palbociclib-resistant tumours. Biomarker analysis and clinical data suggest a potential role for immunotherapy in this group.© 2023. The Author(s).