Molecular profiling of PDAC and response to chemotherapy: An update from the COMPASS trial
Bibliographic record
Abstract
Background: Predictive mutational and transcriptional features in advanced PDAC are urgently needed for improved patient stratification and treatment selection. Methods: As part of the COMPASS trial patients (pts) with advanced PDAC are prospectively recruited prior to first-line combination chemotherapy for whole genome sequencing (WGS) and RNA sequencing (RNASeq). Fresh tumor tissue is acquired by percutaneous core needle biopsy. Laser capture microdissection ensures high-resolution genomic analyses with results available within 8 wks. Tumor responses and clinical outcomes in this update were correlated with molecular characteristics. Results: 121 pts underwent a biopsy between December 2015 and April 2018; WGS and RNASeq were successful in 120 (99%) and 119 (98%) respectively, meeting all QC endpoints. 113 genomes have been reported in pts planned to receive chemotherapy; the median time from biopsy to report was 35.5 days. The median age was 63 years (29-81), 53% were male, and 17 (15%) had locally advanced disease. 20 pts (18%) were non evaluable for response. 64 (57%) received modified FFX as first line treatment. 24 (21%) tumors displayed the Moffitt basal-like RNA expression signature which associated with chemotherapy resistance, with tumor shrinkage mainly observed in the classical RNA subtype (p = 0.002). GATA6 expression (log10 scale) clearly separated Moffitt subgroups with classical tumors exhibiting high expression (p < 0.0001). EGFR overexpression was associated with the basal subtype (p = 0.002). The tumor of 1 pt at progression, switched from a basal to a classical phenotype. Of 89 pts with ≥ 6 months follow-up, median overall survival in the classical group was 10 mths vs. 5.1 months in the basal group (HR 0.32 95% CI 0.16–0.68, p = 0.0025). Signatures of homologous recombination deficiency were found in 4 pts (4%) including 2 with germline BRCA2 mutations, 1 of which was newly detected. 2 of 3 pts with a novel duplicator phenotype responded to folfirinox. 30% of pts had potentially actionable genetic alterations. Conclusions: Prospective comprehensive profiling of advanced PDAC indicates that chemotherapy response differs according to genomic/transcriptomic subtypes, providing strong rationale for improved first line trial design. Clinical trial identification: NCT02750657. Legal entity responsible for the study: University Health Network. Funding: Ontario Institute for Cancer Research (PanCuRx Translational Research Initiative) through funding provided by the Government of Ontario. Wallace McCain Centre for Pancreatic Cancer Pancreatic Cancer Canada Foundation Princess Margaret Cancer Foundation Wallace McCain Centre for Pancreatic Cancer Pancreatic Cancer Canada Foundation Ontario Institute for Cancer Research (PanCuRx Translational Research Initiative) through funding provided by the Government of Ontario Princess Margaret Cancer Foundation. Disclosure: All authors have declared no conflicts of interest.
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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 | 0.004 | 0.004 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 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".