Breast cancers with high proliferation and low ER-related signalling have poor prognosis and unique molecular features with implications for therapy
Luca Licata, Marco Barreca, Barbara Galbardi, Matteo Dugo, Giulia Viale, Balázs Győrffy, Thomas Karn, Lajos Pusztai, Luca Gianni, Maurizio Callari, Giampaolo Bianchini
Abstract
Abstract Background Luminal breast cancers with high proliferation (MKS hi ) and low ER-related signalling (ERS lo ) have a poor prognosis. We investigated treatment responses and molecular features of MKS hi /ERS lo tumours to inform potential therapies. Methods 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. Results Compared to MKS hi /ERS hi tumours, MKS hi /ERS lo 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). MKS hi /ERS lo 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. MKS hi /ERS lo 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). Conclusions MKS hi /ERS lo 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.