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16P - Understanding the biologic determinants of ribociclib efficacy in breast cancer

Abstract

Background

Ribociclib improves survival in hormone receptor-positive (HR+)/HER2-negative (HER2-) advanced breast cancer (BC). Deeper understanding of the biology associated with ribociclib efficacy is needed, especially within the HER2-enriched (HER2-E) subtype given recent analysis of MONALEESA program. Here, we performed gene expression (GE) analysis with/without ribociclib monotherapy in BC patient-derived xenografts (PDX).

Methods

Eighteen PDXs representative of HR+/HER2- (n=11, 61%), HER2+ (n=6, 33%) and triple-negative (n=1, 6%) BC were treated with ribociclib monotherapy (75 mg/kg/day). The % change in tumor volume from baseline was calculated at day 35. RNA was obtained from flash-frozen tumors at baseline and day 12. PAM50 GE was analyzed by nCounter and associated with tumor response (as a continuous variable) using quantitative Statistical Analysis Microarrays (SAM). Differential GE during ribociclib treatment was identified using two-class paired SAM. All SAM used a false-discovery rate<5%.

Results

Baseline PAM50 subtype distribution was Luminal B (44%), HER2-E (33%) and Basal-like (B-L) (22%). HER2-E and Luminal B PDXs showed a statistically significant higher response to ribociclib (mean change in volume >40% and >140%), than B-L (>660%). Baseline GE analysis identified 6 genes highly expressed in responders (FOXA1, ERBB2, GRB7, MLPH, GPR160 and CXXC5), and 7 lower expressed genes (SFRP1, KRT17, MYC, CDH3, KRT5, MIA and KRT14). Paired GE analyses across PDXs identified 12 upregulated genes during treatment, including estrogen activation-related genes (ESR1, PGR, FOXA1, MAPT or BLVRA); and 12 downregulated genes, including proliferation-related genes (MKI67 or KIF2C) and HER2-E-related genes (ERBB2 or TMEM45B). Similar results were obtained with HR+/HER2- PDXs when analyzed separately.

Conclusions

In BC PDXs, B-L biology associates with lower response to ribociclib monotherapy than Luminal or HER2-E. Ribociclib induces a luminal phenotype with high GE of estrogen-regulated genes and low GE of proliferation genes, a biological switch that could explain the better efficacy of ribociclib in the endocrine therapy (ET)-resistant HER2-E subtype observed in clinical trials when combined with ET.

Legal entity responsible for the study

Institut d'Investigacions Biomèdiques August Pi i Sunyer.

Funding

Has not received any funding.

Disclosure

M. Oliveira: Honoraria (self): Roche, Novartis, Seattle Genetics; Advisory/Consultancy: Roche/Genentech, GlaxoSmithKline, Puma Biotechnology, AstraZeneca, Seattle Genetics; Research grant/Funding (institution): Philips Healthcare (Inst), Roche/Genentech (Inst), Novartis (Inst), AstraZeneca (Inst), Immunomedics (Inst), Seattle Genetics (Inst), Boehringer Ingelheim (Inst), GlaxoSmithKline (Inst), Cascadian Therapeutics (Inst), Sanofi (Inst), Celldex Therapeutics; Travel/Accommodation/Expenses: Roche, Novartis, Grünenthal Group, Pierre Fabre, GP Pharm, Eisai. N. Chic: Travel/Accommodation/Expenses: Novartis, Eisai, Pierre Fabre. R. Dienstmann: Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy: Boehringer Ingelheim; Speaker Bureau/Expert testimony: Ipsen; Speaker Bureau/Expert testimony: Amgen; Speaker Bureau/Expert testimony: Servier; Speaker Bureau/Expert testimony: Sanofi; Speaker Bureau/Expert testimony: Merck Sharp & Dohme; Research grant/Funding (self): Merck; Research grant/Funding (self): Pierre Fabre. C. Saura Manich: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca, Daiichi Sankyo, Merck, Sharp and Dohme España SA, Novartis, Pfizer, Puma, Synthon; Advisory/Consultancy, Travel/Accommodation/Expenses: Celgene, Clovis Oncology, Eisai, F. Hoffmann-La Roche Ltd., Genomic Health, Odonate Therapeutics, Philips Healthwork, Pierre Fabre, prIME Oncology, Sanofi Aventis, Zymeworks; Research grant/Funding (institution): Eli Lilly and Company, Genentech, Immunomedics, Macrogenics, Piqur Therapeutics, Roche, Synthon. A. Prat: Advisory/Consultancy, Research grant/Funding (self): Novartis Farma, SA; Advisory/Consultancy: Lilly Spain; Advisory/Consultancy: Pfizer, SLU; Advisory/Consultancy, Research grant/Funding (self): Roche Farma, SA; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Amgen, SA; Advisory/Consultancy: Daiichi; Advisory/Consultancy: Oncolytics Bioteck; Research grant/Funding (self): Sysmex Europe GmbH; Research grant/Funding (self): Medica Scientia Inno, Research, SL; Research grant/Funding (self): Celgene, SLU; Research grant/Funding (self): Astellas Pharma, SA; Research grant/Funding (self): NanoString Technologies; Officer/Board of Directors, Member executive Board: Breast International Group (BIG).; Officer/Board of Directors, Member executive Board and Foundation: SOLTI; Research grant/Funding (self): Puma; Research grant/Funding (self): Incyte. V. Serra: Research grant/Funding (self): Novartis, Genentech. All other authors have declared no conflicts of interest.

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