Palbociclib (P) is a CDK4/6 inhibitor used in combination with endocrine therapy (ET) in metastatic estrogen receptor (ER)+/HER2- breast cancer (BC). The role of P in early BC treatment is currently being tested in phase III trials. Biomarkers that help us predict primary resistance to P may lead to better patient selection and thus avoid toxicity and reduce costs. In vitro studies suggest that CDK4 T172 phosphorylation is associated with sensitivity to P and an 11-gene expression signature has been developed that can predict the CDK4 modification profile in breast tumors. In order to identify biomarkers of resistance to P/ET and validate the 11-gene signature, we have launched the NeoRHEA study.
Single arm, phase II trial, enrolling patients with ER+/HER2- breast tumors ≥ 15mm, N0-N1. Subjects will receive 4 months of neoadjuvant P/ET (tamoxifen± goserelin or letrozole). Subjects’ response to therapy will be evaluated before and after treatment by ultrasound, using WHO criteria. Biopsy samples will be collected at baseline and surgery. Primary objective is to identify biomarkers of resistance to P/ET (defined as stable or progressive disease by ultrasound) using RNA-sequencing of baseline samples. A key secondary objective is to validate the 11-gene signature as a biomarker of resistance to P/ET. Other secondary objectives include: to evaluate the safety of P/ET; to identify biomarkers of resistance to P/ET, defined as residual cancer burden of 3 or high tumor proliferation by the Genomic Grade Index; to understand mechanisms of resistance to P/ET by comparing tumors transcriptome at baseline and at surgery; to assess the role of plasma ctDNA in monitoring response to P/ET. Assuming a resistance rate of 20%-25% and a 10% dropout, 100 subjects are needed to develop a binary predictor. Any biomarker identified will be further validated in other studies e.g. NeoPAL (preliminary agreement in place). Accrual started in July 2017 and 38 patients have been enrolled thus far. The study is expected to be completed in 2019. Trial number is NCT03065621. Study sponsor is Institut Jules Bordet with a research grant from Pfizer.
Clinical trial identification
Legal entity responsible for the study
Institut Jules Bordet.
M. Ignatiadis: Consulting or advisory role: Celgene, Roche, Pfizer, Seattle Genetics; Research funding: Roche; Patents: Université Libre de Bruxelles. S. Drisis: Travel, accomodation: Philips. M. Piccart: Honoraria: Pfizer. P. Vuylsteke: Honoraria: Roche, AstraZeneca, Pfizer; Travel, accommodation: Roche, Téva. C. Sotiriou: Consulting or advisory role: Pfizer; Research funding: Pfizer. All other authors have declared no conflicts of interest.