Tandem duplicator phenotype: A novel targetable subgroup in pancreatic cancer?
Bibliographic record
Abstract
4161 Background: Validated biomarkers are urgently needed to provide a more precise approach in pancreatic cancer (PDAC). Homologous recombination deficiency (HRD) is a heterogenous cohort in PDAC and predicts platinum and PARP inhibitor sensitivity. The BRCA-1 genotype associates with distinct tandem duplications (TDs), however non-BRCA 1 TD phenotypes (TDP) have been observed across tumour types and may be associated with perturbations in CDK12, FBXW17, and CCNE1. Here, we characterize the prevalence and outcomes of TDP in a large series of prospectively sequenced PDAC. Methods: Whole-genome sequencing was performed in 191 early stage resected and 275 advanced PDAC cases in the PanCuRx initiative and the COMPASS trial at the Ontario Institute for Cancer Research and Princess Margaret Cancer Centre. Tumors underwent laser capture enrichment prior to sequencing. TD scores were calculated as previously described by Menghi et al, and HRDetect scores assigned. Samples were classified as classical or basal-like by Moffitt. Outcomes of patients with TDP tumors were evaluated. Tumors that are nonHRD and nonTDP are referred to as typicals. Results: Of 466 cases, 46 were identified as TDP (9.9%; 17 resected, 29 advanced). Subgroups of TDP by etiology included BRCA1 (n=8; 6 germline, 2 somatic), somatic CCNE1 (n=1), and unknown (n=37; no identified alterations in TDP-related genes). Pathogenic germline variants were not found in unique genes other than BRCA1. HRD TDP was associated with a significantly smaller TD size compared to nonHRD TDP (median 12 kb vs. 125 kb, p<0.0001) and median TD load of 114. NonHRD TDP genomes exhibited elevated TD load (median 70 vs. 13, p<0.0001) and HRDetect scores (p<0.0001) compared with typicals. NonHRD TDP was not prognostic in resected PDAC disease (p=0.6361) compared with typicals. We observed a trend towards improved response to 1st-line platinum therapy in nonHRD TDP vs. typicals (p=0.066) for patients with advanced disease. When stratified for only ‘classical’ RNA subtype cases as per Moffitt classification (HRD TDP:2 basal-like, 8 classical, 1 unknown; nonHRD TDP: 9 basal-like, 25 classical, 1 unknown), platinum therapy was correlated with better response in non-HRD TDP vs. typicals (n= 10, 70% ORR, p=0.0108) highlighting the chemoresistance of the basal-like subgroup. Superior survival was not observed in this small cohort. Conclusions: In PDAC, the etiology of nonHRD TDP is unclear but may represent a potential marker for platinum and DNA damage response agents. Further investigation is warranted with a larger sample size.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 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".