Circulating tumor DNA mutational landscape and dynamics after progression on a CDK4/6 inhibitor in the PACE phase II trial for metastatic HR-positive/HER2-negative breast cancer
Bibliographic record
Abstract
BACKGROUND: Genomic determinants of response and resistance to endocrine therapy (ET) and cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) beyond progression in hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer are not well characterized. We analyzed serial circulating tumor DNA from the PACE trial in which patients who progressed on ET and CDK4/6i were randomized to fulvestrant, fulvestrant plus palbociclib, or fulvestrant, palbociclib, and avelumab. MATERIALS AND METHODS: Plasma samples from 200 of 220 PACE participants were collected for circulating tumor DNA analysis using the Guardant360 assay. Samples included baseline (n = 200), cycle 3, day 1 (C3D1; n = 124), and end of treatment (n = 137). The fulvestrant and fulvestrant + palbociclib arms were combined given similar clinical outcomes. The log-rank test was used to test associations between genomic alterations and progression-free survival (PFS). RESULTS: The most common baseline genomic alterations beyond progression on CDK4/6i plus ET, were mutations in ESR1 (54.0%), TP53 (35.5%), PIK3CA (34.0%), GATA3 (18.5%), and RB1 (10.0%). Among 150 patients treated with fulvestrant or fulvestrant + palbociclib, baseline mutations in TP53, PIK3CA, RB1, and the Y537S ESR1 mutation, were associated with shorter PFS. Mutations within the PI3K and cell cycle pathways were associated with significantly decreased PFS. We also observed increases in the allelic fractions of the ESR1, PIK3CA, and TP53 mutations at progression. CONCLUSIONS: Several mutations within genes and biological pathways are associated with CDK4/6i resistance beyond progression. Additional studies are needed to optimize treatment after resistance to CDK4/6i using genomic biomarkers.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| 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".