Molecular characterization of long-term and short-term survivors of advanced pancreatic ductal adenocarcinoma.
Bibliographic record
Abstract
4024 Background: Median overall survival (mOS) for advanced pancreatic ductal adenocarcinoma (PDAC) is ≤1 year. However, there are patients (pts) who live for >2 years on chemotherapy and those who rapidly progress prior to a first scan, underscoring biological heterogeneity in PDAC subgroups. Understanding these differences is important in clinical trial design and provides prognostic information for pts. Methods: Clinical and molecular data (WGS and RNAseq) from pts with a diagnosis of locally advanced or metastatic PDAC enrolled in the COMPASS (NCT02750657) and POG/PanGen (NCT02155621, NCT02869802) studies were available for analysis as part of the TFRI’s EPPIC program and Marathon of Hope Cancer Centres Network, a multi-institutional collaborative network aiming to implement precision medicine in Canada. Clinical data were collected prospectively from both cohorts. Pts had an ECOG PS 0-1 and chemotherapy regimen was based on clinician’s preference. Profiling was performed on fresh biopsies and homologous recombination deficiency was identified with the HRDetect assay. We compared pts with very short OS (STS; ≤3 months, mo) vs long OS (LTS; ≥24 mo). Results: 341 pts were included in the analysis of which 47 were STS (mOS 1.6 mo) and 42 LTS (mOS 29.7 mo). There was no difference in median age, BMI or sex (p>0.1) between cohorts. STS were more likely to have an ECOG PS 1 vs 0 (p=0.03), higher tumor burden (RECIST) (p<0.001) and higher CA19.9 (p=0.04) at diagnosis. In STS, 71% had non evaluable responses as a result of clinical decline or death before first scan, and 28% PD as best response; in LTS, ORR to chemotherapy was 69%. Sixty-four % and 33% of LTS and 32% and 36% of STS had received mFFX and GA, respectively. There was no difference in the prevalence of KRAS mutations (90% vs 98%, ns) or specific mutant alleles, however amplification of mutant KRAS was more common in STS (35% vs 65%, p=0.01). The prevalence of inactivating driver mutations in TP53, CDKN2A, and SMAD4 (90% vs 98%, ns), and in genes involved in chromatin modification ( ARID1A, SMARCA4, PBRM1, KDM6A) (17% vs 30%, ns) was similar in both groups. However, STS had a higher prevalence of mutations resulting in activation of the PI3K/AKT/mTOR pathway ( PIK3CA, PTEN loss, STK11) (10% vs 26%, p=0.049). Genotypes consistent with HRD were present (17% vs 11%); however, in LTS 6/7 were a result of germline pathogenic variants, compared with only 1/5 in STS. Median structural variant loads, ploidy, TMB and substitution base signatures were similar in both cohorts. More basal-like PDAC were present in STS vs LTS (3% vs 30%, p=0.006). Conclusions: Pts who survive ≤3 mo with advanced PDAC are characterized by a higher tumor burden and molecular profiles consistent with enhanced RAS signaling, a deregulation of the PI3K/AKT/mTOR pathway, and a basal-like transcriptomic subtype. HRD genotypes are heterogeneous with germline carriers accounting for some of the LTS.
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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) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| 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".