716 A randomized phase II window of opportunity clinical trial of PD-1 +/- IL-4 inhibition in early-stage ER+ HER2- breast cancer
Bibliographic record
Abstract
<h3>Background</h3> Immune checkpoint inhibition has been shown to enhance response to neoadjuvant therapy and survival in triple negative breast cancer (BC). However, the majority of BCs are estrogen receptor positive (ER+), which is traditionally considered to be immunologically cold, with low expression of PD-L1, decreased tumour mutational burden, and reduced neoantigen presentation. Window of Opportunity (WOO) trial designs support rapid evaluation of therapeutic combinations and predict effectiveness in larger neoadjuvant trials. We conducted a WOO trial in ER+ BC patients to determine whether the response to immune checkpoint inhibitors (cemiplimab, a PD-1 inhibitor) within the tumor could be enhanced by the addition of IL-4R antagonist (dupilumab). <h3>Methods</h3> Female preoperative patients with newly diagnosed primary invasive T1/T2 ER+Her2- BC were randomized 1:1 to a single dose of cemiplimab (350mg IV) or in combination +/- dupilumab (600mg sc). Pre-(baseline biopsy) and post- treatment (surgical resection one week later) tissue were profiled through targeted multi-omic profiling and sequencing (DNA and RNA) spatial proteomics (NanoString’s GeoMx) and TCR sequencing. <h3>Results</h3> 20 patients were successfully recruited on the trial, 10 in each arm. Mean patient age was 61.5 years and average tumor size was 2.5cm. Most adverse events were grade 1, most commonly fatigue which was equally present in both arms. In 40 pre-treatment biopsies profiled with OCAPlus, the most frequently mutated genes included PIK3CA (25%), TP53 (23%), CDH1 (25%) and KMT2C (20%). Frequent copy number changes were identified in CCND1 (20%), FGF19 (20%), and FGF4 (20%). In the combination arm, differential gene expression and subsequent pathway analysis of enriched genes demonstrated enhanced interferon signaling, antigen presentation and processing pathways; while proteomic profiling showed only minimal changes in immune cell composition. <h3>Conclusions</h3> This WOO trial has demonstrated immunogenic effects of combining immune checkpoint inhibitors with IL-4 antagonists in ER+ BC. These findings support further exploration of this therapeutic strategy in larger neoadjuvant clinical trials aimed at improving immunotherapy responses in immunologically cold tumors. <h3>Trial Registration</h3> NCT05967884. <h3>Ethics Approval</h3> The study was approved by Clinical Trials Ontario Streamlined Research Ethics Review System, approval number 4510.
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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 | 0.003 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| 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) | 0.000 | 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".