Neoadjuvant biomarker research study of palbociclib combined with endocrine therapy in estrogen receptor positive/HER2 negative breast cancer: The phase II NeoRHEA trial
Bibliographic record
Abstract
Background: 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. Trial design: 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: NCT03065621. Legal entity responsible for the study: Institut Jules Bordet. Funding: Pfizer. Disclosure: 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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".