Luminal and basal subtyping of metastatic castration-resistant prostate cancer (mCRPC) and its clinical implications.
Bibliographic record
Abstract
197 Background: The PAM50 gene expression classifier (PAM50) identifies luminal and basal subtypes and predicts response to androgen deprivation therapy in localized prostate cancer. The clinical utility of using PAM50 to molecularly subtype mCRPC was evaluated. Methods: PAM50 was applied to RNA expression data from 86 metastatic tumor biopsies from the SU2C-AACR-PCF West Coast Prostate Cancer Dream Team (WCDT; NCT02432001). Overall survival (OS) differences between luminal A (LuA), luminal B (LuB), or basal patients (pts) were determined using Kaplan-Meier analyses. PAM50 was also applied to 15,136 prospectively collected radical prostatectomy (RP) samples from the Decipher GRiD database (NCT02609269). Drug response signatures (DRS) for 89 drugs were derived using publicly available data from the NCI60 cell line panel, and applied to gene expression data from the RP samples to predict patient-specific drug sensitivities. Differences in DRS as a function of PAM50 subtype were assessed using the Pearson’s chi-squared test. Results: The application of PAM50 to mCRPC transcriptional data segregated pts into LuA, LuB, and basal populations (43%, 14%, and 43%, respectively). The median OS for LuA, LuB, and basal pts was 20.6 months, 9.5 months, and 10.4 months, respectively (p=0.04), which was consistent with localized prostate cancer where LuB pts have the worst prognosis. DRS analyses revealed statistically significant differences in drug sensitivities, with LuA and LuB pts predicted to be markedly more sensitive to docetaxel than basal pts (p<0.00001), and basal pts predicted to be markedly more sensitive to platinums and etoposide than LuA and LuB pts (p<0.00001). Conclusions: PAM50 subtyping is prognostic in mCRPC, with LuA pts demonstrating the longest OS. Luminal and basal subtypes have distinct in silico drug response profiles that may be associated with response to mCRPC therapies. Prospective testing of DRS as a biomarker to guide treatment in mCRPC is warranted. Clinical trial information: NCT02432001, NCT02609269.
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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 | 0.001 | 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".