Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have led to a paradigm shift in the treatment of hormone receptor-positive (HR+)/HER2- advanced breast cancer (ABC). Prior data has suggested a key role of tumor immunity in CDK4/6i success. We investigate immune-mediated resistance to CDK4/6i treatment.
63 samples from 55 patients with HR+HER2- ABC treated with CDK4/6i were recruited (34 primary, 21 metastatic (M1) and 8 paired biopsies). Gene expression (GE) was assessed using NanoString Breast Cancer 360™, including intrinsic subtype (IS). Patients were stratified in good/poor responders (GR/PR), considering hormone sensitivity and progression-free survival (PFS) data from pivotal studies (GR n=38, 66.5%). Multiple t-tests comparisons were used to identify GE differences and Kaplan Meier and Cox regression models for survival.
GE comparisons between primary and M1 biopsies showed significantly higher expression of immune-related features and oestrogen receptor (ER)-signalling in primary biopsies (T.test; p-value<0.05). GE profiles between response groups were compared to identify mechanisms of resistance to CDK4/6i. Most tumors were luminal A or B (n=23, 36.5% each). The IS were not significantly associated with response (Chi-square p>0.05). High GE of tumor-immunity related signatures such as macrophages, PD-L2, inflammatory-chemokines, IDO1, and T-regs were associated with reduced efficacy of CDK4/6i (mean log2FC 0.5; p<0.05). Survival analysis in first-line CDK4/6i confirmed longer PFS within patients with luminal tumours (p=0.02). Type of M1 (visceral or non-visceral) and type of response (PR vs GR) were also associated with significantly shorter PFS and overall survival (OS) (p<0.05), remaining as independent predictors after adjustment by the standard clinico-pathological variables. High expression of macrophages signature (HR: 3.14; p=0.03) and other genes related to immunity/inflammation (CD68, CD163, CCR1 or CDC25B) were also associated with worse OS (HR 1.8-6.1; p-value<0.05).
Immune function plays a key role in tumor evolution and CDK4/6i efficacy. Further investigation of immune-tumor crosstalk and the role of immunotherapy in this setting is needed to improve CDK4/6i efficacy.
Investigational grants: 1) ISCIII-FIS (CM20/00027 and MSII19/00012). Dates 2020- 2022; 2) ISCIII-FIS (PI17/00624 and PI21/00642). Dates: 2020-2023. Collaborations: 1) Pfizer grant (Pfizer, SA; Spain). Dates 2020-2023; 2) NanoString Translational Research Request. Dates: 13/01/2020-10/12/2022.
M.A. Bergamino: Financial Interests, Personal, Sponsor/Funding: ESAI, Novartis. E. Felip Falgas: Financial Interests, Personal, Sponsor/Funding: Novartis, Pfeizzer, Lilly, Roche. A. Ferrando Diez: Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Sponsor/Funding: MSD, Lilly, Roche, Merck. M. Romeo Marin: Financial Interests, Personal, Sponsor/Funding: GSK; Financial Interests, Personal, Research Grant: MSD, Clovis; Financial Interests, Personal, Speaker’s Bureau: AZ. A. Pous: Financial Interests, Personal, Sponsor/Funding: Lilly, Roche. M. Margeli Vila: Financial Interests, Personal, Sponsor/Funding: Novartis, Pfizer, Lilly, Gilead, PiereFabre; Financial Interests, Institutional, Research Grant: Pfizer. All other authors have declared no conflicts of interest.