Hypoxia-Associated Gene Signatures Are Not Prognostic in High-Risk Localized Prostate Cancers Undergoing Androgen Deprivation Therapy With Radiation Therapy
Bibliographic record
Abstract
Purpose Men with high-risk prostate cancer (PCa) are treated with androgen deprivation therapy (ADT) and radiation therapy, but the disease reoccurs in 30% of patients. Biochemical recurrence of PCa after treatment is influenced by tumor hypoxia. Tumors with high levels of hypoxia are aggressive, resistant to treatment, and have increased metastatic capacity. Gene expression signatures derived from diagnostic biopsies can predict tumor hypoxia and radiosensitivity, but none are in routine clinical use, due to concerns about the applicability of these biomarkers to new patient cohorts. There has been no or limited testing in cohorts of high-risk PCa. Methods and Materials We generated transcriptomic data for cohorts of patients with high-risk PCa. Patients were treated with ADT followed by external beam radiation therapy with or without a brachytherapy boost. Biomarkers curated from the literature were calculated from pretreatment biopsy gene expression data. The primary endpoint for survival analyses was biochemical recurrence-free survival and the secondary endpoints were distant metastasis-free survival and overall survival. Results The performance of the selected biomarkers was poor, with none achieving prognostic significance for biochemical recurrence-free survival or distant metastasis-free survival in any cohort. The brachytherapy boost cohort received shorter durations of ADT than the conventionally fractionated or hypofractionated cohorts (Wilcoxon rank sum test, P = 2.1 × 10 −18 and 2.3 × 10 −10 , respectively) and had increased risk of distant metastasis (log-rank test, P = 8 × 10 −4 ). There were no consistent relationships between biomarker score and outcome for any of the endpoints. Conclusions Hypoxia and radiosensitivity biomarkers were not prognostic in patients with high-risk PCa treated with ADT plus radiation therapy. We speculate that the lack of prognostic capability could be caused by the variable hypoxia-modifying effects of the ADT that these high-risk patients received before and during definitive treatment with radiation therapy. A deeper understanding of biomarker construction, performance, and inter-cohort transferability in relation to patient characteristics, sample handling, and treatment modalities is required before hypoxia biomarkers can be recommended for routine clinical use in the pretreatment setting.
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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 | 0.000 | 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".