Breast cancers with high proliferation and low ER-related signalling have poor prognosis and unique molecular features with implications for therapy

BackgroundLuminal 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.MethodsGene 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.ResultsCompared 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).ConclusionsMKShi/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.

Automated summary

Luminal breast cancers with high proliferation and low ER signaling have poor prognosis. These tumors show high response to chemotherapy, but resistance to endocrine therapy and palbociclib. Immunotherapy may play a potential role in treating these tumors.