Tumor molecular profiling to differentiate extreme responses to first-line platinum-based chemotherapy in suboptimally debulked serous ovarian cancer patients.
Bibliographic record
Abstract
5561 Background: Patients with advanced high grade serous ovarian cancer (SOC) who undergo a suboptimal debulking primary surgery typically have adverse clinical outcomes. However, a spectrum of sensitivity to first line platinum-based chemotherapy is observed but poorly understood. In this study, we perform molecular characterization of two groups of responders (extreme versus poor) to first line carboplatin/taxol chemotherapy in suboptimally debulked SOC patients. Methods: Suboptimally debulked SOC patients with advanced disease (stage III-IV) were grouped by response to first-line chemotherapy and clinicopathologic data collected. Extreme platinum-sensitive (PS) responders had a PFI (progression-free interval) > 12 months (mo) and platinum-resistant (PR) responders had a PFI < 6mo. Tissue specimens were used to interrogate the molecular features of both PS and PR cohorts using whole exome and transcriptome sequencing. Sequence alignment and variant calling were performed using GATK and annotation was performed using Variant Effect Predictor for assessment of non-synonymous tumor mutation burden (TMB) and discovery of novel mutational signatures to predict platinum response. Results: There were 39 patient samples analyzed from primary surgery (PS group = 20; PR group = 19). Median PFI for PS and PR patient cohorts was 30 mo and 3 mo (p < 0.001), respectively. In all tumors, in addition to BRCA and TP53 mutations, additional oncogenic mutations were noted in genes associated with PI3K/AKT/mTOR signaling and in epigenetic regulation. The PS samples were characterized by mutations in BRCA1/2 and the PR samples by mutations in MGA. Compared to tumors in the PR cohort, PS tumors had a significantly higher non-synonymous mutation rate using TMP analysis (p < 0.05) with a trend towards increased immune response. Additional bioinformatics analysis is ongoing and will include copy number variation analysis, immune inference using ESTIMATE and Gene Set Enrichment Analysis. Conclusions: Contracting a mutational signature is feasible from patient tumors at primary surgery and helps to elucidate extreme responses to platinum-based chemotherapy.
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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 | 0.000 |
| 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) | 0.001 | 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".