Circulating Tumor DNA Genotyping of Intrinsic and Acquired Gene Alterations in Patients With Advanced Breast Cancer Receiving Palbociclib: Biomarker Results From POLARIS Study
Bibliographic record
Abstract
PURPOSE To identify gene alterations in circulating tumor DNA (ctDNA) from palbociclib-treated patients with advanced or metastatic breast cancer (ABC) in POLARIS to identify potential mutagenic drivers of resistance. METHODS POLARIS was a prospective, real-world study of palbociclib in patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2–) ABC in the United States and Canada. Patients who received ≥1 palbociclib dose and had ≥1 ctDNA measurement were included in the biomarker analysis. ctDNA samples were analyzed using the Guardant360 platform (73 genes) at baseline, cycle 2 day 1 (C2D1), and end of treatment (EOT). Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS A total of 344 patients were included in the biomarker analysis. Gene alterations were detected in 85% (286 of 336) of baseline samples, 72% (201 of 278) of C2D1 samples, and 85% (88 of 104) of EOT samples. The most frequently mutated genes were ESR1 , PIK3CA , and TP53 . CCND1 , FGFR1 , and EGFR were most frequently amplified. Real-world progression-free survival (rwPFS) was better in patients without baseline mutations in ESR1 (HR, 0.42) or PIK3CA (HR, 0.60) and amplifications in CCND1 (HR, 0.52) or FGFR1 (HR, 0.62) versus altered genes. Patients with undetectable versus detectable mutations at C2D1 also had better rwPFS (HR, 0.57). CONCLUSION Patients without altered ESR1 , PIK3CA , CCND1 , or FGFR1 at baseline had better rwPFS than patients with altered genes. Genotyping analysis of ctDNA over time highlights the emergence of mutations in estrogen receptor and cell cycle pathways under selective therapeutic pressure and could guide monitoring and therapeutic sequencing for patients with HR+/HER2– ABC.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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".