Alex K. Bryant

Background: Overtreatment of low‐risk prostate cancer (PC) undermines screening efforts. Active surveillance is preferred for low‐risk PC, but declining treatment may reflect diagnostic or treatment‐selection changes. We assessed diagnostic risk‐group trends among localized PC and low‐risk trends among radiation‐treated patients since 2010. Methods: We analyzed localized PC in Surveillance, Epidemiology, and End Results Program (SEER; 2010–2023); Veterans Affairs (VA; 2010–2024); and Michigan Radiation Oncology Quality Consortium (MROQC; 2021–2025). Low‐risk PC was defined as grade group 1, prostate‐specific antigen <10 ng/mL, and clinical stage ≤T2a. Diagnosis‐based analyses described risk‐group trends among all localized PC diagnoses in SEER and VA and treatment among low‐risk patients. The primary outcome was the proportion of radiation‐treated patients classified as low‐risk, evaluated using logistic regression. Results: Among localized PC, low‐risk disease at diagnosis declined from 28.8% to 24.0% in SEER and from 32.3% to 21.9% in VA. Among diagnosed low‐risk patients, receipt of neither radiation nor prostatectomy increased from 33.6% to 83.4% in SEER and from 51.6% to 96.3% in VA. Among 207,196 patients treated with radiation for localized PC (170,213 SEER; 34,635 VA; and 2348 MROQC), the proportion with low‐risk disease declined from 33.7% to 6.5% in SEER, from 22.9% to 2.0% in VA, and remained ≤4.2% in MROQC. Declines persisted after adjustment. Conclusion: Since 2010, low‐risk PC has become less common at diagnosis, whereas diagnosed low‐risk patients increasingly avoid treatment. Radiation for low‐risk PC has markedly declined, paralleling surgical trends and reflecting a nationwide shift toward active surveillance.

Supplementary Data S1 from Polygenic Risk Scores for Prediction of Immune Checkpoint Inhibitor Thyroid Toxicity in Diverse Populations

Supplementary Methods, Tables, and Figures.

Background: Immune-related adverse events (irAEs) have been associated with improved overall survival (OS) in patients with cancer treated with immune checkpoint inhibitors (ICIs), as irAEs are thought to signify a potentially robust antitumor immune response. The interplay between irAE subtypes, irAE severity, and oncological outcomes remains understudied. Methods: We conducted a retrospective study of patients with cancer in the US Veteran Health Administration who received first-line or second-line ICI therapy (programmed cell death protein 1, programmed death-ligand 1, cytotoxic T-lymphocyte-associated protein 4, or lymphocyte activation gene 3 inhibitors)±chemotherapy from 2010 to 2023. Manual chart review was performed on a random sample to ascertain irAEs. The primary outcome was OS, analyzed by irAE status (no irAE vs irAE), severity (steroid-requiring vs non-steroid-requiring), and subtype (thyroid/cutaneous vs other). To account for immortal time bias, OS was analyzed with multivariable time-dependent Cox regression and 180-day landmark analysis. Results: Among 1707 patients, 465 (27.2%) experienced at least one irAE (median onset: 108 days; unadjusted 2-year rate: 38.2% (35%–41%)). The occurrence of any-grade irAE was not associated with improved OS (adjusted HR (aHR) 0.87; 95% CI 0.75 to 1.01). Analysis stratified by steroid requirement (n=222/465 events, 47.7%) showed improved survival with non-steroid-requiring irAE (aHR 0.69, 95% CI 0.57 to 0.84), whereas steroid-requiring irAEs were associated with a trend toward worse survival (aHR 1.13, 95% CI 0.92 to 1.38). The non-steroid-requiring irAE subset was enriched for thyroid (45% vs 8%) and cutaneous (27% vs 16%) toxicities compared with the steroid-requiring group. Exploration of the impact of irAE subtype on OS showed significant survival benefit in patients with thyroid/cutaneous irAEs (aHR 0.57, 95% CI 0.46 to 0.71) but not other irAE subtypes. Conclusions: irAEs are not uniformly associated with improved survival. Favorable outcomes are driven by thyroid-related and skin-related, non-steroid-requiring irAEs, suggesting shared biological mechanisms underlying organ-specific autoimmunity and antitumor immune response.

Purpose: Immune checkpoint inhibitor (ICI)–induced thyroiditis is a common immune-related adverse event (irAE) linked to improved survival. Polygenic risk scores (PRS) for autoimmune hypothyroidism predict thyroid irAEs in European-ancestry patients; performance in non-European populations is unclear. Experimental Design: In the Veterans Affairs Million Veteran Program (MVP; 2011–2023), we identified ICI-treated patients with germline genotyping and a chemotherapy-treated control cohort, excluding those with thyroid disease or prior thyroid-directed treatments. Harmonized ancestry and race/ethnicity (HARE) defined non-Hispanic White (NHW) and non-Hispanic Black (NHB) groups. Thyroid irAEs within 1 year were defined using laboratory criteria capturing both hyperthyroid and hypothyroid phases. We compared two PRSs: a published European-derived PRS and an updated PRS selected across multiple genome-wide association study (GWAS) sources and methods (including the MVP multiancestry GWAS) to maximize discrimination in African-ancestry individuals in a held-out test set. HARE-stratified multivariable Cox models estimated time to thyroiditis; a 6-month landmark analysis assessed overall survival. Results: The ICI cohort included 4,289 patients (3,473 NHW; 816 NHB). The baseline PRS was associated with thyroiditis in NHW [adjusted hazard ratio (aHR) per standard deviation, 1.33; 95% confidence interval (CI), 1.19–1.50) but not NHB patients or controls. The updated PRS improved risk stratification in NHW (aHR, 1.45; 95% CI, 1.28–1.63) and predicted thyroiditis in NHB patients (aHR, 1.48; 95% CI, 1.11–1.98) but not in controls. Thyroiditis within 6 months was associated with improved survival, but neither PRS was. Conclusions: Germline polygenic liability to hypothyroidism predicts ICI-induced thyroiditis in NHW and NHB patients when PRSs are selected via ancestry-stratified validation. Careful exploration of the dataset-method space is critical for equitable PRS development.

PURPOSE: Pemetrexed remains part of guideline-recommended maintenance pemetrexed/pembrolizumab in advanced/metastatic non–oncogene-driven nonsquamous non–small cell lung cancer (NSCLC). Whether pemetrexed contributes to the combination's survival benefit is unknown. In this propensity-weighted analysis of US Veterans Affairs data, we compared real-world effectiveness and safety of maintenance pemetrexed/pembrolizumab versus maintenance pembrolizumab alone and estimated US government payer spending on maintenance pemetrexed. METHODS: We identified Veterans who received four cycles of carboplatin/cisplatin, pemetrexed, and pembrolizumab followed by at least one dose of maintenance pemetrexed/pembrolizumab or pembrolizumab. A propensity-weighted Cox model was used to adjust for baseline between-group differences using inverse probability of treatment weights. The primary effectiveness outcome was overall survival (OS; time from first maintenance dose to death). The primary financial outcome was the estimated spending on maintenance pemetrexed across VA, Medicare Part B, and Medicaid (2017-2022). RESULTS: The real-world outcomes cohort included 622 patients (473 pemetrexed/pembrolizumab; 149 pembrolizumab alone). After propensity weighting, pemetrexed was not associated with improved OS (adjusted hazard ratio [aHR] pemetrexed/pembrolizumab v pembrolizumab, 1.06 [95% CI, 0.83 to 1.36, P = .62]) but was associated with higher toxicity risk (grade ≥3 acute kidney injury [aHR 3.35, 95% CI, 1.08 to 10.41, P = .04]; neutropenia [aHR 2.86, 95% CI, 1.44 to 3.05; P = .004]; anemia [aHR 1.65, 95% CI, 1.11 to 2.47, P = .014]). Findings were robust to sensitivity analysis in which patients who crossed over from pembrolizumab to pemetrexed/pembrolizumab were excluded. Estimated government payer spending on maintenance pemetrexed from 2017 to 2022 totaled $1.588 billion (2024 USD). CONCLUSION: Adding pemetrexed to maintenance pembrolizumab was not associated with improved survival but was associated with increased toxicity. Reassessing legacy chemotherapy components may improve the safety and cost-effectiveness of cancer care . Prospective evaluation of maintenance pemetrexed's incremental benefit in NSCLC in the immunotherapy era is needed.

Background: Circadian biology suggests that synchronizing immune checkpoint inhibitor (ICI) dosing with morning peaks in immune activation could improve clinical outcomes, but well-powered studies using appropriate causal inference methodology are sparse. Methods: We emulated a pragmatic randomized controlled trial of AM versus PM ICI infusions using Veterans Health Administration records from 2010 to 2024. In the emulated trial, stage IV non-small-cell lung cancer patients planned to undergo first-line or second-line ICI would have been randomized to receive the first three infusions in the AM (<12:00 PM) or PM (≥12:00 PM). The primary outcome was overall survival (OS). Marginal structural models with inverse probability of censoring weights estimated the per-protocol effect, accounting for baseline and longitudinal confounding. A historical chemotherapy cohort served as a negative control. Results: 4688 patients were eligible for the emulated trial; of these, 1171 received their first three infusions in the AM and 794 in the PM. Median follow-up was 4.7 years. Median survival was 10.3 months (AM) vs 8.1 months (PM). PM dosing was associated with worse OS (HR for PM versus AM 1.15, 95% CI 1.04 to 1.26, p=0.004). In 7951 chemotherapy controls (median follow-up 8.9 years), no time-of-day effect was detected (HR for PM vs AM 1.05, 95% CI 0.98 to 1.12, p=0.15). Results were robust in sensitivity analyses. Conclusions: Morning ICI infusions confer a modest but clinically meaningful survival benefit that is absent in chemotherapy controls, supporting a causal chronotherapeutic effect. Scheduling ICIs before noon represents a low-cost, immediately actionable strategy warranting prospective confirmation.

PURPOSE: Large language models (LLMs) may improve extraction of prognostic variables in prostate cancer from unstructured clinical text compared with traditional, rule-based natural language processing. METHODS: We used iterative prompt engineering with few-shot examples to develop LLM prompts for 30 phenotypes from prostate biopsy, radical prostatectomy (RP), and transurethral resection of the prostate (TURP) pathology reports, as well as magnetic resonance imaging (MRI) pelvis, computed tomography [CT] abdomen/pelvis, Tc-99m bone scan, and prostate-specific membrane antigen [PSMA] PET/CT reports. Data were drawn from >130 Veterans Affairs facilities (1999-2025). Inference was performed with Llama 3.3 70B or GPT-4o depending on the task. Performance was evaluated on independent test sets with metrics including overall accuracy, sensitivity, positive predictive value (PPV), negative predictive value (NPV), and macro-F1. RESULTS: Pathology extraction tasks achieved near-perfect accuracy. For prostate biopsy reports, exact extraction of total cores and involved cores was highly accurate (total cores: accuracy 98.0% [95% CI, 93.0 to 99.5]; involved cores: accuracy 95.0% [95% CI, 88.8 to 98.5]). Performance was similarly strong for RP and TURP reports. On MRI pelvis, extraction of PIRADS scores (accuracy 98.0% [95% CI, 93.0 to 99.5]), lesion locations (accuracy 100% [95% CI, 96.3 to 100]), and lesion dimensions (accuracy 100% [95% CI, 96.3 to 100]) was excellent. For PSMA PET/CT, PPVs were 100% (95% CI, 93.5 to 100) for nodal metastases and 97.9% (95% CI, 89.9 to 99.6) for bone metastases; Tc-99m bone scan performance was comparable. Lower PPVs were observed for nodal and bone metastases on pelvic MRI (84.2%-86.4%) and CT (88.0%-90.3%), largely due to ambiguous language in radiology report texts. CONCLUSION: LLMs can reliably extract key prostate cancer phenotypes from unstructured text across multiple pathology and radiology report types. Ambiguous or indeterminate language remains the principal challenge for optimal performance.