Abstract 12P
Background
In the CORALLEEN trial, R+L achieved similar response rates to multi-agent CT. We present a comprehensive gene expression analysis done before, during, and after therapy to fully characterize the biology behind the primary results of the trial.
Methods
CORALLEEN was a randomized study in postmenopausal women with stage I-IIIA hormone receptor positive (HR+)/HER2-negative Luminal B breast cancer by PAM50. Patients (pts) received either 6 cycles of R+L or 4 cycles of AC followed by 12 doses of paclitaxel. Primary endpoint was rate of PAM50 Risk of Relapse (ROR) low disease at surgery. Baseline, week 2, and surgical specimens were collected. Expression of 770 genes and 31 signatures were determined using the Breast360TM nCounter-based codeset. Response was defined as ROR-low disease at surgery, relative/absolute changes in ROR between baseline/week 2 and surgery, RCB-0/I or levels of Ki67 at surgery. To identify genes associated with response, a significance of microarrays (SAM) analysis with a false discovery rate (FDR) <5% was performed.
Results
A total 297/318 (93.4%) samples were available. No genes or signatures at baseline, or week 2, were found to be associated with response at surgery in each arm. At week 2, 146 (14.6%) genes or signatures were found significantly up-regulated (n=47) and down-regulated (n=99) in the R+L arm compared to CT. R+L induced higher expression of genes related to DNA damage repair and immune activation (e.g. TP53, RAD52, GZMM and CD19) and lower expression of cell-cycle and hormone-related genes (e.g. PGR, CDK1 and MKI67). At surgery, 102 (10.2%) genes or signatures were found significantly up-regulated (n=4) and down-regulated (n=98) in the R+L arm compared to CT. R+L induced higher downregulation of estrogen- and proliferation-related genes and signatures (e.g. PGR, ER signaling, and MKI67).
Conclusions
No genes were able to predict response. Compared to CT, R+L induced higher downregulation of proliferation-related genes and signatures at week 2 and surgery. These results support the strategy to use the neoadjuvant setting to select patients who achieve a large molecular downstaging following CDK4/6 inhibition.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
SOLTI Breast Cancer Research Group.
Funding
Novartis, Nanostring, Breast Cancer Research Foundation-AACR Career Development Award (to AP), PhD4MD grant (to NC), Fundación Científica Asociación Española Contra el Cáncer - Ayuda Postdoctoral AECC 2017 (to FB-M), This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under Grant agreement No. 847912.
Disclosure
N. Chic: Travel/Accommodation/Expenses: Novartis. C. Saura: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Puma biotechnology; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Celgene; Advisory/Consultancy, Travel/Accommodation/Expenses: Daiichi-Sankyo; Advisory/Consultancy, Travel/Accommodation/Expenses: Eisai; Advisory/Consultancy, Travel/Accommodation/Expenses: Genomyc Health; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: Pierre Fabre; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Synthon biopharmaceuticals; Research grant/Funding (institution): Roche-Genentech; Research grant/Funding (institution): Macrogenics; Research grant/Funding (institution): Piqur; Research grant/Funding (institution): BMS. M. Muñoz: Speaker Bureau/Expert testimony, Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Breast Cancer Research Foundation-AACR; Research grant/Funding (institution): Breast Cancer Now Career Catalyst; Travel/Accommodation/Expenses: Roche; Speaker Bureau/Expert testimony: Pfizer; Speaker Bureau/Expert testimony: Lilly. X. González-Farré: Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Eisai. M. Oliveira: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: GlaxoSmithKline; Advisory/Consultancy: Puma Biotechnology; Research grant/Funding (institution): Philips Healthcare; Travel/Accommodation/Expenses: Grünenthal Group; Travel/Accommodation/Expenses: Novartis; Travel/Accommodation/Expenses: Pierre Fabre; Travel/Accommodation/Expenses: GP Pharm. M. Gil-Gil: Honoraria (self): Genentech; Honoraria (self): Novartis; Honoraria (self), Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Travel/Accommodation/Expenses: Daiichi; Honoraria (self): Eisai; Travel/Accommodation/Expenses: Roche. E.M. Ciruelos: Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: Lilly; Advisory/Consultancy: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer. P. Villagrasa: Speaker Bureau/Expert testimony: NanoString. J. Gavila Gregori: Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Roche. A. Prat: Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy: Lilly; Advisory/Consultancy: NanoString; Advisory/Consultancy, Research grant/Funding (institution): Amgen; Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy: Oncolytics; Advisory/Consultancy: Daiichi; Advisory/Consultancy: Puma; Advisory/Consultancy: BMS. All other authors have declared no conflicts of interest.