Abstract P5-02-22: Circulating Tumor DNA Genotyping of Intrinsic and Acquired Gene Alterations in Patients With Advanced Breast Cancer Receiving the Cyclin-Dependent Kinase 4/6 Inhibitor Palbociclib: Biomarker Results from POLARIS
Bibliographic record
Abstract
Abstract Background: POLARIS is a prospective, real-world study of palbociclib in patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC) in the United States and Canada. We present results from analyses of serial circulating tumor gene alteration profiles from patients treated with palbociclib in the first and second or later lines of ABC treatment to illustrate the potential mutagenic drivers of resistance (intrinsic/acquired) and carrier-mutations (intrinsic/maintained). Methods: The clinical database cutoff date was March 30, 2022. Patients in the biomarker analysis group provided consent for serial blood sample collection, received ≥1 dose of initial palbociclib combination treatment, and had ≥1 circulating tumor DNA (ctDNA) measurement available. The Guardant360 platform with somatic single-nucleotide variants in complete or critical exons of 73 genes was used. Tumor gene alteration profiles (at baseline, on-treatment at Cycle 2 Day 1 [C2D1], and at end of treatment [EOT]) were evaluated. Cox proportional hazard models were used to estimate hazard ratios and 95% CIs. Results: Patient samples (n=345) were analyzed and gene alterations were detected in 85% of baseline samples (n=337), 72% of on-treatment samples (n=280), and 85% of EOT samples (n=104). Most frequently altered genes were PIK3CA (38%), TP53 (28%), and ESR1 (15%) at baseline; TP53 (28%), PIK3CA (24%), and NF1 (10%) at C2D1; and TP53 (40%), PIK3CA (40%), and ESR1 (33%) at EOT. Most frequent gene amplifications (amp) were detected in CCND1 (8.3%), FGFR1 (7.7%), and EGFR (5.9%) at baseline; FGFR1 (5.0%), CCND1 (4.3%), and EGFR (3.2%) at C2D1; and CCND1 (13.5%), FGFR1 (9.6%), and EGFR (9.6%) at EOT. Baseline mutations of ESR1 and PIK3CA led to shorter real-world progression-free survival (rwPFS) than wild-type (hazard ratio [95% CI], 1.99 [1.38, 2.86] and 1.67 [1.24, 2.25], respectively). Baseline amp of CCND1 and FGFR1 also led to shorter rwPFS than wild-type (2.13 [1.36, 3.34] and 1.93 [1.20, 3.10]). Acquired mutations in ESR1, ATM, and RB1 were observed at EOT. Most frequently acquired ESR1 mutations at EOT were D538G, Y537N, and Y537S. Patients with all mutations cleared at C2D1, had longer rwPFS than those without (hazard ratio [95% CI], 0.58 [0.41, 0.83]). Conclusion: Patients with mutated ESR1 and PIK3CA or CCND1 and FGFR1 amp at baseline had shorter rwPFS than patients with wild-type genes. Genotyping analysis of progression ctDNA 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– MBC. ClinicalTrials.gov: NCT03280303 Citation Format: Debu Tripathy, Joanne L. Blum, Shibing Deng, Steven L. McCune, Kamal Patel, Yao Wang, Shailendra Lakhanpal, Meghan S. Karuturi, Zhe Zhang, Chetan Deshpande, Monica Z. Montelongo, Eric Gauthier, Yuan Liu, Gabrielle B. Rocque, Aditya Bardia. Circulating Tumor DNA Genotyping of Intrinsic and Acquired Gene Alterations in Patients With Advanced Breast Cancer Receiving the Cyclin-Dependent Kinase 4/6 Inhibitor Palbociclib: Biomarker Results from POLARIS [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-22.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".