Abstract PD2-05: Biomarker analysis by baseline circulating tumor DNA alterations in the MONALEESA-3 study
Bibliographic record
Abstract
Abstract Background: In the Phase III MONALEESA-3 (NCT02422615) study, ribociclib (RIB; cyclin-dependent kinase 4/6 inhibitor) + fulvestrant (FUL) significantly prolonged progression-free survival (PFS) vs placebo (PBO) + FUL in postmenopausal women with hormone receptor-positive (HR+), HER2-negative (HER2–) advanced breast cancer (ABC). Here we present MONALEESA-3 efficacy data by molecular alterations detected in circulating tumor DNA (ctDNA) at baseline. Methods: Postmenopausal women (N=726) with HR+, HER2– ABC (treatment naïve or received ≤1 line of prior endocrine therapy for ABC) were randomized 2:1 to RIB or PBO (600 mg/day; 3-weeks-on/1-week-off) + FUL (500 mg per label). Biomarker analysis of baseline ctDNA was an exploratory endpoint. Baseline plasma samples were collected from 692 patients (pts), and plasma ctDNA was analyzed using next-generation sequencing with a targeted panel of ˜550 genes. The subgroup analysis was performed in 600 pts (RIB + FUL n=400; PBO + FUL n=200) with evaluable ctDNA data. Results were not adjusted for multiple testing. Results: Alterations (frequency) were observed in the following genes: PIK3CA (35%), ESR1 (14%), TP53 (18%), CDH1 (12%), FGFR1 (5%), FGFR1/ZNF703/WHSC1L1 (11%), cell cycle-related (CCC) genes (16%), and genes involved in receptor tyrosine kinase (RTK) signaling (20%), and the mitogen-activated protein kinase (MAPK) pathway (10%). PFS hazard ratios favored RIB vs PBO regardless of baseline ctDNA gene alteration status (Table). Events, n/NMedian PFS, months Gene(s)RIB + FULPBO + FULRIB + FULPBO + FULHazard ratio; 95% confidence intervalPIK3CAWT108/26570/12422.3416.490.67; 0.49–0.91Altered75/13549/7616.3611.100.75; 0.52–1.08ESR1WT141/33899/17622.3414.880.66; 0.51–0.85Altered42/6220/249.236.110.71; 0.41–1.23TP53WT132/32598/17022.3414.880.62; 0.47–0.80Altered51/7521/309.177.390.75; 0.44–1.27CDH1WT156/35697/17320.6316.490.70; 0.54–0.90Altered27/4422/2712.095.130.46; 0.24–0.86FGFR1WT165/378113/19221.3214.550.65; 0.51–0.83Altered18/226/88.346.110.64; 0.23–1.75FGFR1/ZNF703/WHSC1L1WT155/356105/18121.3214.650.67; 0.52–0.85Altered28/4414/1910.976.670.73; 0.37–1.43CCCWT138/331103/17422.0814.650.61; 0.47–0.79Altered45/6916/2612.659.130.92; 0.51–1.65RTKWT126/31595/16622.3414.820.61; 0.47–0.80Altered57/8524/349.175.780.82; 0.50–1.35MAPKWT158/357105/18320.0414.820.69; 0.54–0.89Altered25/4314/1714.723.610.47; 0.22–1.00 Numerically shorter PFS was observed in pts with altered vs wildtype (WT) genes, irrespective of treatment. A slight trend towards limited RIB benefit vs PBO was observed in pts with altered CCC and RTK genes. RIB benefit was more pronounced vs PBO in pts with altered CDH1 and MAPK genes. PIK3CA and ESR1 analyses for pts receiving treatment in the first- or second-line setting will be presented at the meeting. Conclusions: Generally consistent PFS benefit for RIB + FUL vs PBO + FUL was observed irrespective of baseline ctDNA alterations; altered status trended to correlate with a shorter PFS. Results are hypothesis generating and should be interpreted with caution for some subgroups due to small sample sizes. Citation Format: Neven P, Petrakova K, Val Bianchi G, De la Cruz-Merino L, Jerusalem G, Sonke GS, Nusch A, Beck JT, Chia S, Solovieff N, Rodriguez Lorenc K, Miller M, Su F, Lm S-A. Biomarker analysis by baseline circulating tumor DNA alterations in the MONALEESA-3 study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD2-05.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".