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Tumor histone H3 lysine 18 lactylation for the prediction of immunotherapy efficacy in patients with advanced non–small cell lung cancer.
e20676 Background: Clinical benefit from immune checkpoint inhibitors (ICIs) in advanced non–small cell lung cancer (NSCLC) remains heterogeneous, and current biomarkers such as PD-L1 and immune infiltration incompletely capture metabolism-driven immune suppression. Lactate metabolism may promote an immunosuppressive tumor microenvironment, partly through histone lactylation. We evaluated the clinical relevance of a proposed metabolism–epigenetics axis linking baseline serum lactate dehydrogenase (LDH) to tumor histone H3 lysine 18 lactylation (H3K18la) in patients receiving first-line ICI-based therapy. Methods: We retrospectively enrolled 52 patients with stage IIIB–IV NSCLC treated with first-line ICI monotherapy or ICI-based combination therapy (January 2019–December 2024). Baseline serum LDH was collected prior to treatment initiation. Tumor H3K18la and CD8⁺ tumor-infiltrating lymphocytes (TILs) were assessed by immunohistochemistry; H3K18la was scored using a semiquantitative immunoreactive scoring system (0–12). X-tile identified an OS-driven LDH cutoff of 319.0 U/L. Clinical endpoints included progression-free survival (PFS), overall survival (OS), and milestone outcomes (1-year PFS/OS). Survival analyses used Kaplan–Meier and Cox models; predictive performance was assessed by ROC/AUC for milestone endpoints. Results: Baseline LDH positively correlated with tumor H3K18la expression (p < 0.01). LDH-high (≥319.0 U/L) patients had inferior PFS (p = 0.007) and OS (p = 0.019); LDH predicted shorter PFS in univariable analysis (HR 2.91, 95% CI 1.29–6.54) with attenuated significance after multivariable adjustment. Low tumor H3K18la was associated with improved PFS (p < 0.0001) and OS (p = 0.039) and remained independently associated with PFS in multivariable models (HR 0.14, 95% CI 0.04–0.47; p = 0.001). Joint stratification by H3K18la and CD8⁺ TIL density defined distinct immunologic phenotypes with markedly different PFS (log-rank p < 0.0001); among CD8-high tumors, high H3K18la still conferred worse PFS. For predicting 1-year PFS, H3K18la showed higher AUC than PD-L1 TPS and CD8⁺ TIL density (0.747 vs 0.703 vs 0.658); the difference between H3K18la and PD-L1 was not statistically significant. Conclusions: Tumor H3K18la is a clinically relevant, metabolism-linked biomarker associated with ICI outcomes in advanced NSCLC and may complement conventional immunophenotypic markers. These findings support a model in which systemic lactate burden (LDH) relates to epigenetic remodeling (H3K18la) and immune resistance. Prospective, multicenter validation and harmonized assessment of H3K18la are warranted.
Timing of irAE and survival in NSCLC.
e20659 Background: Immune-related adverse events (irAEs) during immune checkpoint inhibitor (ICI) therapy are associated with improved outcomes in non-small cell lung cancer (NSCLC). However, factors influencing outcomes among patients with irAEs are not well established. This study assesses whether timing of irAEs is associated with outcomes in advanced NSCLC. Methods: This single-center retrospective cohort study included patients with advanced NSCLC treated with ICIs who developed ≥1 irAE. Kaplan–Meier estimates and multivariable Cox models (adjusted for age, sex, ECOG, PD-L1 status, smoking status, and line of therapy) were used to compare PFS and OS between patients with early-onset irAE (≤30 days after ICI start) versus late-onset irAE (>30 days). Immortal time bias was addressed via prespecified landmark analyses at 180 days and a modified 180-day landmark restricted to irAE onset <180 days. A post hoc analysis assessed outcomes following ICI discontinuation due to an irAE, comparing post-discontinuation PFS and OS (indexed from the date of ICI discontinuation) in patients with early versus late irAEs. Results: Of 117 patients (87% Stage IV), early-onset irAE predicted worse PFS (5.0 vs 22.0 mo; adjusted hazard ratio [aHR] 4.17; 95% CI 2.51-6.95) and OS (10.3 vs 35.2 mo; aHR 3.90; 95% CI 2.27-6.70). In the 180-day landmark analysis, early-onset irAE remained correlated with poorer PFS (13.6 vs 24.6 mo; aHR 2.20; 95% CI 1.06-4.57) and OS (18.4 vs 41.7 mo; aHR 2.65; 95% CI 1.36-5.16). Modifying the 180-day landmark analysis to restrict to patients with irAE onset <180 days attenuated the association for PFS (13.6 vs 18.3 mo; aHR 2.30; 95% CI 0.98–5.41), while OS remained significant (18.4 vs 30.9 mo, aHR 2.54; 95% CI 1.24-5.20). In the subgroup analysis of patients who discontinued ICI due to an irAE (n = 64), median ICI duration was 0.7 vs 6.9 mo for early and late irAEs, respectively (p < 0.001). Early irAEs were linked with markedly shorter median post-discontinuation PFS (2.5 vs 19.2 mo; aHR 4.00; 95% CI 1.82-8.80) and post-discontinuation OS (4.6 vs 27.8 mo; aHR 4.10; 95% CI 1.75-9.61). Conclusions: Among patients with advanced NSCLC who develop irAEs, onset within 30 days of ICI is associated with inferior survival, including in landmark analyses limiting immortal time bias. Rapid disease progression after early treatment discontinuation suggests that abbreviated ICI exposure may contribute to these outcomes. These findings support further investigation of strategies to extend ICI exposure after early irAEs. Analysis N Outcome Early irAE(median mo) Late irAE(median mo) aHR (95% CI) No landmark 117 PFS 5.0 22.0 4.17 (2.51-6.95) 117 OS 10.3 35.2 3.90 (2.27-6.70) > 180-day landmark 90 PFS 13.6 24.6 2.20 (1.06-4.57) 99 OS 18.4 41.7 2.65 (1.36-5.16) > 180-day modified landmark w/ irAE <180 days 52 PFS 13.6 18.3 2.30 (0.98-5.41) 61 OS 18.4 30.9 2.54 (1.24-5.20) ICI discontinuation due to an irAE 64 PFS from ICI stop 2.5 19.2 4.00 (1.82-8.80) 64 OS from ICI stop 4.6 27.8 4.10 (1.75-9.61)
Impact of poor performance status on outcomes with immune checkpoint inhibitors in advanced non–small cell lung cancer: A systematic review and meta-analysis.
e20617 Background: Immune checkpoint inhibitors (ICIs) have improved outcomes in advanced non–small cell lung cancer (NSCLC). However, patients with poor baseline performance status (ECOG ≥2) are commonly underrepresented in clinical trials, limiting the applicability of trial results to routine clinical practice. The prognostic significance of poor performance status in ICI-treated advanced NSCLC remains incompletely characterized. We conducted a systematic review and meta-analysis to evaluate the association between baseline ECOG performance status and survival outcomes in real-world patients receiving ICIs. Methods: We systematically identified observational and real-world studies reporting multivariable-adjusted hazard ratios (HRs for overall survival (OS) and/or progression-free survival (PFS) comparing ECOG ≥2 with ECOG 0–1 or < 2 in patients with advanced NSCLC treated with ICIs. Only studies with harmonizable ECOG contrasts and adjusted effect estimates were included in the quantitative synthesis. Hazard ratios were pooled on the logarithmic scale using the generic inverse-variance method. Random-effects models were applied using the DerSimonian–Laird estimator, with fixed-effect models calculated for comparison. Statistical heterogeneity was assessed using Cochran’s Q and the I² statistic. Results: Twenty studies met criteria for qualitative synthesis. Thirteen effect-size comparisons were eligible for quantitative analysis, including seven OS and six PFS evaluations. Across all OS studies, poor baseline performance status was consistently associated with inferior survival. Individual OS hazard ratios ranged from approximately 2.0 to nearly 4.0, indicating a substantially increased risk of death among patients with ECOG ≥2. In the random-effects model, ECOG ≥2 was associated with significantly worse OS (pooled HR 2.58, 95% CI 2.11–3.15), with moderate-to-substantial heterogeneity (I² = 70.0%). Six studies contributed to the PFS meta-analysis. In the random-effects model, poor performance status was associated with worse PFS (pooled HR 1.38, 95% CI 0.58–3.27), with substantial heterogeneity (I² = 95.2%). Conclusions: In real-world patients with advanced NSCLC treated with ICIs, poor baseline performance status is associated with significantly inferior overall survival and a trend toward worse progression-free survival. These findings highlight the prognostic importance of performance status in routine clinical practice and support the need for prospective studies and individualized treatment approaches for patients with impaired functional status.
Wait or treat? managing asymptomatic brain metastases in oncogene-mutated NSCLC: Results of a phase-III randomized controlled trial.
8624 Background: The timing of brain radiation therapy (RT) in patients with oncogene-mutated NSCLC with asymptomatic brain metastases (ABM) has been a matter of debate. No level 1 evidence supports delayed brain RT in ABM. This phase III, open-label, RCT (NCT05236946) evaluates Upfront Cranial RT (U-CRT) versus Delayed CRT (D-CRT) in ABM of oncogene-mutated NSCLC. Methods: Eligible patients (≥18 years, ECOG ≤2), with EGFR mutation or ALK gene rearrangement and completely ABM, were randomized to U-CRT vs D-CRT at intracranial progression (ICP), stratified by GPA score (0-2 vs > 2) and BM presentation (Synchronous vs Metachronous). Key exclusions include symptomatic BM, brainstem metastases, and prior cranial RT. All pts received standard systemic therapy (TKI ± CT). The primary endpoint is intracranial PFS with death treated as a competing event. Secondary endpoints included OS, PFS, and treatment toxicity. All patients underwent MRI brain every 3 months for 1 st year and 6 months thereafter, unless indicated clinically. Cumulative incidence functions were estimated, and subdistribution hazards were compared using the Fine and Gray model. With a planned enrollment of 208 patients and 139 target events, the study had 80% power to detect a hazard ratio of 0.62 at a two-sided alpha of 0.05. The icPFS was analyzed in intention-to-treat populations using Kaplan-Meier estimates and log-rank tests. Results: A total of 208 patients were randomized (105-U-CRT; 103-D-CRT). Baseline characteristics were well-balanced in both arms. The median age was 53 years (range, 26-83). EGFR and ALK mutations were seen in 87.6% and 12.4% in U-CRT and 79.6% & 20.4% in D-CRT arm. 1 st /2 nd generation TKIs ± CT were received by 58% & 72% pts, respectively and rest received 3 rd generation TKI. In U-CRT, 44.8% received SRS/SRT, 52.4% received WBRT± boost, and 3 pts did not receive RT. The median follow-up was 27.4 months (95%CI 26.2 -33). The cumulative incidence of ICP at 1 yr were 8.7% (95%CI 2.9%, 14.5%) & 25.7% (95%CI 16.8%, 34.7%), and at 2-yrs were 21.7% (95%CI 12.6%, 30.8%) & 50% (95%CI 39.2%, 60.9%) with sub-HR = 0.35 (95%CI 0.21, 0.59), p < 0.001. The median icPFS were 18 mo (95%CI 15.8, 23.5) and 14.3 mo (95%CI 12.6, 19.6) with HR-0.84 (95%CI 0.59, 1.20), p = 0.35. There was no difference in median PFS of 11.7 mo (95%CI 9.2, 14.1) & 12.0 mo (95% CI 9.8, 14.9), p = 0.37 and in median OS of 23.3 mo (95% CI 17.7-28.8) & 28.7 mo (95%CI 17.7, 39.7), p = 0.06, respectively. In the D-CRT arm, 39/47 who had ICP received salvage CRT. The incidence of grade ≤2 radiation necrosis was 25.4% and grade > 3 in 5.8% in upfront RT arm. Conclusions: In asymptomatic BM of oncogene-mutated NSCLC pts, upfront cranial RT significantly reduced the incidence of ICP; however, it did not improve the survival outcomes. The difference in survival may become more apparent as the OS data matures. Data on QOL, neurocognition, and molecular analysis will be reported later. Clinical trial information: NCT05236946 .
Omission of postoperative antibiotic prophylaxis after radical cystectomy: Interim results of the A-PURC phase III randomized non-inferiority trial.
e23314 Background: Urinary tract infection (UTI) is a common cause of readmission following radical cystectomy(RC). The optimal role of postoperative antibiotic prophylaxis remains uncertain. The A-PURCPhase III randomized non-inferiority trial evaluates whether omitting postoperative antibioticprophylaxis is non-inferior to standard prophylaxis in preventing UTIs after RC. Methods: Patients with muscle-invasive bladder cancer (MIBC) undergoing RC at the university ofMinnesota were randomized 1:1 to either a prophylaxis or control arm, stratified by urinarydiversion type—ileal conduit (IC) or neobladder (NB). The prophylaxis arm received dailynitrofurantoin until ureteral stent removal (10 days for IC; 21 days for NB). The primaryendpoint was 30-day UTI incidence. Secondary endpoints included 90-day UTI incidence andUTI-related readmission rates at 30 and 90 days. Logistic regression analysis and Kaplan-Meiercurves were used to compare UTI-free survival between the two groups.This is a prespecified interim analysis per protocol (data cutoff: December 31, 2025). Results: At interim analysis, 33 patients were enrolled: 17 prophylaxis (9 IC, 8 NB) and 16 control (12 IC,4 NB). The 30-day UTI rate was 12% in both arms. There was also no difference in 90-day UTIincidence (26% vs 24%; P = 0.99), 30-day UTI-related readmission rate (12% vs 6%; P = 0.6), or 90-day UTI-related readmission rate (26% vs 18%; P = 0.8) between the prophylaxis and controlarms. (Table 1) There was also no significant difference in UTI-free survival between arms. Conclusions: Interim findings from the A-PURC trial suggest that omission of postoperative antibioticprophylaxis after RC does not increase UTI or UTI-related readmission rates within 90 days.These results support a more selective, stewardship-driven approach to postoperativeantibiotic use after RC. The trial remains ongoing to confirm non-inferiority in an expandedcohort. Clinical trial information: NCT06190197 . Comparison of postoperative complications and UTI-related readmission betweengroups. Variable Control arm (n = 16) Prophylaxis arm (n = 17) P value Neoadjuvant chemotherapy, No. (%) 8 (50%) 9 (53%) 1 CCI (age-adjusted), median (IQR) 3 (2.5) 3 (1.5) 1 Length of stay (IQR), days 6.5 (4) 6 (3.5) 0.335 Overall complication rate (0–30 d), n (%) 9 (56%) 13 (76%) 0.282 UTI rate (0–30 d), n (%) 2 (12%) 2 (12%) 1 UTI related readmission rate (0–30 d), n (%) 2 (12%) 1 (6%) 0.601 Overall complication rate (31–90 d), n (%) 4 (25%) 10 (58%) 0.17 UTI rate (31–90 d), n (%) 2 (12%) 2 (12%) 0.99 UTI related readmission rate (31–90 d), n (%) 2 (12%) 2 (12%) 0.99 BMI, body mass index; IQR, interquartile range; UTI, urinary tract infection.
Clinicopathological features and prognosis of anaplastic and poorly differentiated thyroid carcinoma: Insights on treatment strategies from a 28-year real-world study spanning the immunotherapy era.
e18145 Background: Anaplastic thyroid carcinoma (ATC) and poorly differentiated thyroid carcinoma (PDTC) are rare and aggressive thyroid cancers, with limited data on their clinicopathological features and survival outcomes. This study aimed to characterize the real-world features of ATC and PDTC and identify prognostic factors, with an emphasis on evaluating therapeutic strategies. Methods: This retrospective study analyzed 92 ATC and 89 PDTC patients diagnosed at a tertiary institution between 1997 and 2025. Demographic, clinical, pathological, molecular, and treatment data were collected, including combined positive score (CPS), treatments (surgery, radiotherapy, chemotherapy, targeted therapies [TT], immunotherapy [IO]), and follow-up information. Overall survival (OS) was estimated using the Kaplan-Meier method and compared via the log-rank test. Prognostic factors were evaluated using univariate and multivariate Cox regression models. Results: The median OS for ATC and PDTC was 15 months and 62 months, respectively. ATC patients were older at diagnosis (p<0.001), presented with more advanced local disease (p=0.002), and exhibited fewer distant metastases (p=0.033) compared to PDTC patients. The ATC group showed higher gene mutation rates (p=0.009), more CPS-positive cases (CPS>1, p=0.035), and received more intensive treatments, including higher rates of IO (p=0.006), TT+IO (p=0.015), and multimodal therapy (≥3 modalities, p=0.001). Univariate and multivariate Cox regression analyses identified age, TP53 mutation, TT+IO, and multimodal treatment as significant prognostic factors for ATC. Multimodal treatment significantly improved survival in ATC (p=0.003), with surgery combined with TT+IO yielding better outcomes for metastatic ATC (p=0.019). TP53 mutation and co-mutation (≥3 mutations) were associated with significantly worse survival (p=0.003 and p=0.008). Metastatic PDTC patients benefited from IO-based multimodal therapies (p=0.031). Additionally, both ATC and PDTC showed improved survival post-2018, coinciding with the introduction of immunotherapy (p=0.017 and p=0.045). Conclusions: ATC and PDTC exhibit distinct clinicopathological features and survival outcomes. Multimodal treatment significantly benefits ATC patients, while TT+IO offers promising survival advantages for metastatic ATC. IO-based multimodal therapy shows potential efficacy for metastatic PDTC. These findings support a disease-specific, IO-based multimodal strategy, which warrants prospective validation and extended follow-up.
Discrepancy between plasma cell-free DNA and tissue-based analysis for detection of gene amplifications in non–small cell lung cancer.
8537 Background: Therapeutic strategies have been developed in patients with non-small cell lung cancer (NSCLC) harboring gene amplifications (amp) such as MET and HER2 . Although both plasma cell-free DNA (cfDNA) and tissue-based next-generation sequencing (NGS) are available for the detection of gene amp, the concordance between plasma cfDNA and tissue-based analysis for the detection of gene amp remains unclear. Methods: We investigated plasma cfDNA and tissue-based NGS concordance for detection of gene amp in NSCLC using a large-scale screening cohort (LC-SCRUM-Liquid). Paired blood samples were prospectively collected within 4 weeks of corresponding tumor tissue sampling from patients with advanced NSCLC. Guardant360 panel or Oncomine Precision Assay panel was used for plasma cfDNA NGS. Oncomine Comprehensive Assay panel or Oncomine Precision Assay was used for tissue-based NGS. The concordance of EGFR , MET and HER2 gene amp were evaluated. Results: A total of 1,133 pairs of blood and tissue samples were successfully analyzed between December 2017 and December 2024. The median age of the patients was 69 years (range 25-91), 60% were male, 68% were ever smokers, and 79% had a histopathological diagnosis of adenocarcinoma. The positive percent agreement (PPA) and positive predictive value (PPV) of plasma cfDNA analysis relative to tissue-based analysis are shown in the table. For detecting MET amp, the PPA of plasma cfDNA analysis relative to tissue-based analysis tended to be lower in the patients with metastases involving fewer than two organs compared to those with metastases involving two or more organs (25% vs. 63%, P = 0.07). Among the patients with EGFR , MET , or HER2 amp detected by either tissue-based or plasma cfDNA analysis, the correlation of the copy number variants between tissue-based and plasma cfDNA analysis was very weak (r = 0.20). Conclusions: The concordance between plasma cfDNA and tissue-based analysis for detecting gene amp is markedly low, particularly in patients with a low tumor burden. Detection of gene amp using plasma cfDNA analysis may be insufficient for accurately evaluating the efficacy of targeted therapies for patients with lung cancer harboring gene amp. Concordance of gene amp between plasma cell-free DNA and tissue-based analysis. Tissue PPA PPV + - cfDNA EGFR amp + 9 37 13% 20% - 60 1027 MET amp + 9 7 38% 56% - 15 1102 HER2 amp + 0 4 0% 0% - 3 1126
Baseline gut microbiome and metabolomic profiles associated with durable response to first-line third-generation EGFR-TKIs in patients with advanced EGFR-mutant NSCLC.
e20756 Background: First-line third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) are standard therapy for EGFR-mutant non–small cell lung cancer (NSCLC); however, clinical outcomes vary among patients with advanced disease. Increasing evidence suggests that the gut microbiome and its metabolites may influence treatment efficacy. This study investigated baseline gut microbiome and metabolomic features associated with durable response to first-line third-generation EGFR-TKIs in stage IV EGFR-mutant NSCLC. Methods: Baseline fecal samples were collected from 29 patients with stage IV EGFR-mutant NSCLC treated with first-line third-generation EGFR-TKIs. Patients were classified as durable responders (R, n = 19; median progression-free survival [PFS], 24 months) or non-responders (NR, n = 10; median PFS, 6 months). Shotgun metagenomic sequencing and untargeted metabolomics were performed, followed by differential abundance, diversity, and integrative microbiome–metabolome analyses. Results: Baseline gut microbiome and metabolomic profiles differed significantly between groups. Species-level α-diversity analysis demonstrated gut microbiome dysbiosis in the NR group, with higher microbial richness and diversity than in the R group (P < 0.05). Alistipes sp. HGB5, Eubacterium sp. AF22_9, and Tyzzerella nexilis were significantly enriched in the R group (all P < 0.05). Metabolomic profiling showed higher levels of chenodeoxycholic acid, testosterone glucuronide, and palmitic acid in responders (all P < 0.05). Integrative analysis identified Tyzzerella nexilis as a key species correlated with lipid and bile acid metabolism. Conclusions: Baseline gut microbiome and metabolomic profiles differed significantly between groups. Species-level α-diversity analysis demonstrated gut microbiome dysbiosis in the NR group, with higher microbial richness and diversity than in the R group (P < 0.05). Alistipes sp. HGB5, Eubacterium sp. AF22_9, and Tyzzerella nexilis were significantly enriched in the R group (all P < 0.05). Metabolomic profiling showed higher levels of chenodeoxycholic acid, testosterone glucuronide, and palmitic acid in responders (all P < 0.05). Integrative analysis identified Tyzzerella nexilis as a key species correlated with lipid and bile acid metabolism.
Multi-model prognostic evaluation of immunotherapy in advanced biliary tract cancer and development of the bedside biccaps score: A multicenter study.
e16183 Background: Immune checkpoint inhibitors (ICIs) have improved outcomes for advanced biliary tract cancer (BTC), but survival benefits remain modest and predictive biomarkers to guide clinical practice are lacking. Methods: We analyzed 588 advanced BTC patients receiving ICIs from a multicenter retrospective cohort and two prospective clinical trials. To address substantial multicollinearity among inflammation-, nutrition-, and liver function–related biomarkers, we adopted a rigorous three-stage feature selection pipeline integrating Boruta, LASSO regression, and akaike information criterion (AIC)-based best-subset selection. Cox proportional hazards regression and machine learning survival models were constructed, and an integer-based bedside scoring system (BICCAPS) was derived. Dynamic changes in prognostic nutritional index (PNI) and systemic inflammation response index (SIRI) from baseline to cycle 2–3 were evaluated for additional prognostic value. Results: Seven variables (ICI treatment line, carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA), peritoneal metastasis, SIRI, PNI and bilirubin) were incorporated into Cox proportional hazards regression model and random survival forest models, which showed good discrimination and calibration for OS across all cohorts. The BICCAPS score stratified patients into low-, intermediate- and high-risk groups with clearly separated median overall survival (OS) in the training (18.9, 10.5 and 6.8 months) and validation cohorts. Worsening PNI or SIRI during early treatment was associated with significantly shorter OS and progression-free survival. Conclusions: This study provides the first clinically implementable decision-making framework for immunotherapy in BTC. By translating complex statistical modeling into a simple bedside scoring system and incorporating dynamic biomarker assessment, the BICCAPS score offers a practical, low-cost, and accessible tool for individualized ICI management.
Tumor-informed ctDNA as a biomarker of outcomes following stereotactic body radiotherapy in metastatic urothelial carcinoma.
e16590 Background: Stereotactic body radiotherapy (SBRT) is used in metastatic urothelial carcinoma (mUC) to defer or augment systemic therapy, but biomarkers predicting outcomes after SBRT are lacking. Tumor-informed circulating tumor DNA (ctDNA) assays have prognostic value after cystectomy. We evaluated ctDNA for predicting outcomes following SBRT in patients (pts) with mUC. Methods: We retrospectively identified pts with mUC treated with SBRT who underwent tumor-informed ctDNA testing (Signatera, Natera) before and/or after SBRT between January 2023 and September 2025. Pts with < 3 months (mos) follow-up were excluded. Variables included number and location of metastatic sites, SBRT dose and fractionation, number of sites treated, and oligoprogressive (OP) versus oligometastatic presentation. OP disease was defined as ≤5 new lesions while on systemic therapy; pts with any number of metastases were eligible. ctDNA was assessed within 3 mos prior to SBRT and within 1 mos after SBRT. The primary endpoint was progression-free survival (PFS) from SBRT completion to radiographic progression or last follow-up. The secondary endpoint was time to next systemic therapy (TNST). Univariate Cox proportional hazards frailty models accounted for clustering of multiple lesions per patient. Results: Twenty-one pts underwent 34 SBRT courses targeting 72 metastases. Most pts were male (90.5%), had bladder primary tumors (80.0%), and had a median age of 74 years (IQR 66–78). Variant histology was present in 28.6%, and 70.8% had OP disease at SBRT. More than one-third (38.0%) had received ≥2 prior lines of systemic therapy. The median number of sites treated per SBRT course was 5 (IQR 3–7). Median SBRT dose was 35 Gy (range 18–54 Gy) in 5 fractions. Commonly treated sites included lymph nodes (47%), lung (19%), and bone (19%). At a median follow-up of 13.7 mos (IQR 9.5–15.2), median PFS was 2.9 mos (IQR 2.2–4.6). Median ctDNA at relapse was 7.02 MTM/mL. Subsequent management included new systemic therapy (38.9%) or repeat SBRT (37.7%). Median TNST was 3.4 mos (IQR 2.7–6.4). Baseline ctDNA was detectable prior to SBRT in 97.0% of courses, and ctDNA declined within 1 mos post-SBRT in 50% of cases. On univariate analysis, Hispanic ethnicity (p = 0.03), greater number of metastatic sites (p = 0.03), and OP disease (p < 0.01) were associated with shorter PFS. Pts with increased ctDNA within 1 mos after SBRT had significantly shorter PFS (1.3 vs 4.6 mos, p < 0.01) and TNST (2.6 vs 5.6 mos, p = 0.01). Absolute ctDNA levels at any time point and relative ctDNA changes were not associated with outcomes. Conclusions: Early post-SBRT increases in ctDNA are associated with inferior PFS and shorter time to next systemic therapy in pts with mUC, particularly those with OP disease. These findings suggest ctDNA kinetics may aid risk stratification after SBRT and warrant validation in larger cohorts.
Characterization of toxicities associated with sulfamethoxazole/trimethoprim (TMP-SMX) for pneumocystis jirovecii prophylaxis in patients with glioblastoma (GBM).
e14066 Background: Standard of care treatment for GBM includes temozolomide (TMZ) chemotherapy, which induces significant lymphopenia and reduction in CD4 counts. In the initial phase 2 trial of TMZ for GBM, 2 out of the first 15 patients developed pneumocystis pneumonia (PCP), and PCP prophylaxis became routine practice in patients receiving TMZ. However, a previous study demonstrated a number needed to treat of 288 to prevent one case of PCP in patients with GBM receiving TMZ. In addition, TMP-SMX, the most used prophylaxis, carries its own risks and adverse effects. This study aimed to identify the incidence of adverse events with TMP-SMX prophylaxis in a large cohort of GBM patients treated with TMZ. Methods: We conducted a retrospective, single-center, observational cohort study at the University of Pennsylvania. Patients included were 18 years or older, had a diagnosis of GBM, were treated with concomitant and/or adjuvant TMZ as part of first-line therapy between July, 2019, and July, 2024, and received TMP-SMX for PCP prophylaxis. Toxicities were graded using the Common Terminology Criteria for Adverse Events version 5.0. For toxicities based on serum values, patients without baseline serum values prior to treatment were excluded. The primary outcome was the incidence of dermatologic toxicity with secondary outcomes including the incidence of creatinine elevation, hyperkalemia, and liver injury defined by elevations in total bilirubin or transaminases. Results: Of the 354 patients who met the inclusion criteria, the mean age was 62.5 years and 59.9% were male. On average, patients completed 4 cycles of adjuvant TMZ. 17.2% of patients experienced a rash. The frequencies of additional key toxicities and the percent of toxicities that occurred during the concomitant phase are listed in the table. Creatinine and alanine aminotransferase (ALT) elevations were the most common adverse events. Grade 3 and 4 toxicities were infrequent with incidence of 3.0% for ALT, 1.1% for aspartate aminotransferase (AST), 0.75% for bilirubin, and 0.29% for creatinine elevations. 20.6% of patients discontinued TMP-SMX but only 23.3% resumed prophylaxis with an alternative agent. Conclusions: We demonstrate that hepatic, renal, and dermatologic toxicities associated with TMP-SMX prophylaxis among patients receiving TMZ for GBM are common although not usually severe. Although we cannot be certain that all toxicities were attributable to TMP-SMX, these data underscore the potential harms of PCP prophylaxis with TMP-SMX in patients with GBM receiving TMZ and challenge the paradigm of routine prophylaxis. Toxicity Any phase N, (%) Concomitant phase, % Creatinine elevation (grade ≥ 2 only) 112 (32.8) 49.1 ALT elevation 83 (31.2) 83.1 AST elevation 65 (24.4) 73.8 Hyperkalemia 74 (21.1) 70.3 Rash 61 (17.2) 63.9 Hyperbilirubinemia 32 (12.0) 59.4
Timing of TP53 mutation acquisition as a determinant of outcomes in patients with myeloproliferative neoplasms and myeloproliferative neoplasms/myelodysplastic syndromes.
6587 Background: While TP53 mutations have been studied in MDS and AML, their clinical significance in MPN and MDS/MPN remains incompletely understood. Emerging evidence suggests that TP53 mutations are often not present at diagnosis, acquired over the disease course, and enriched in older patients (pts). The primary objective of this study was to evaluate whether the interval between diagnosis and the detection of TP53 mutation impacts OS and/or PFS. Methods: All patients with a TP53 mutation were identified via our in-house NGS panel between 2018–2024 were included (n=497). Spearman correlation, Kruskal–Wallis, and chi-square tests were used to evaluate associations between age, VAF, and the presence of co-mutations with the interval from diagnosis to TP53 detection. The Kaplan–Meier method and Cox proportional hazards models were used to analyze OS and PFS. Results: A total of 54 pts, including ET (n=27), PV (n=7), MF (n=9), and CMML (n=9) were identified. The median age at diagnosis was 65.1 yrs, 56% were males (n=30), 81% Caucasian (n=44). 22% (n=12) of pts were diagnosed with their MPN or MDS/MPN at the time of TP53 identification. 52% pts were treated with hydroxyurea prior to TP53 identification. At the time of TP53 detection, 13 pts had progressed to AML and 11 pts to MF. The most common co-mutations were JAK2 (n=19), CALR (n=11), TET2 (n=10) and ASXL1 (n=9). The median time from initial diagnosis to TP53 detection was 6.7 yrs (interquartile range [IQR], 0.8–13.4; range, 0–38 yrs). Pts were divided into 4 quartiles depending on timing of TP53 acquisition, with 13 pts in the <6-mo, 15 pts in the 6 mo–7 yrs, 13 in the 7.1-14 yrs and 13 pts in the >14 yrs quartiles. Older pts had a significantly shorter interval between diagnosis and TP53 detection (Spearman r = −0.61, p < 0.0001). In addition to older age in TP53 time < 6 months (Median 74,9 vs 64.0, p=0.005), pts in the <6-month group also had higher VAF (> median of 41: 69.2% vs 43.9%) and had higher number of co-mutations at diagnosis (≥3: 53.8% vs 26.8%), although this did not reach statistical significance. Older age at TP53 detection was associated with significantly worse OS (3.6 vs 27.2 mo; p=0.002) and PFS (3.6 vs 17.5 mo; p<0.001). After adjusting for age at the time of TP53 detection, a longer interval between diagnosis and TP53 detection was associated with worse OS (HR for the 2nd, 3rd, and 4th quartiles vs. the 1st quartile: 1.2, 2.5, and 4.3; p for trend = 0.002) and worse PFS (HR 1.2, 2.9, and 4.5, p for trend = 0.001). Conclusions: This study demonstrates that after adjusting for age, a longer interval between MPN or MDS/MPN diagnosis and TP53 detection is associated with worse OS and PFS. Older age has previously been identified as an adverse prognostic factor, however our findings suggest that timing of TP53 acquisition may also be an important predictor of clinical outcomes in pts with MPNs and MDS/MPNs.
Incidence and genomic characteristics of a low homologous recombination deficiency score subgroup in <i>BRCA</i> -mutant ovarian cancer.
5584 Background: Homologous recombination deficiency (HRD) is a pivotal molecular phenotype in ovarian cancer (OC) and serves as a key biomarker for guiding PARP inhibitor (PARPi) therapy. Current clinical algorithms assess HRD status by integrating pathogenic BRCA1/2 mutations and genomic scar scores. Nevertheless, a paradoxical phenotype exists: BRCA mutations with a low HRD score. The incidence and genomic characteristics of this subgroup remain poorly understood. Methods: We retrospectively analyzed a cohort of OC patients tested at a centralized laboratory (2024-2025). A composite genomic instability score was calculated as the sum of three biomarkers: loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST). HRD positivity was defined as the presence of a BRCA1/2 pathogenic/likely pathogenic variant and/or a HRD score (LOH+TAI+LST) ≥ 42. Results: Among 441 ovarian cancer samples, 151 of 310 (34.24%, 151/441) BRCA wild-type patients had an HRD score ≥ 42, primarily driven by other homologous recombination repair (HRR) gene alterations. Conversely, among 131 BRCA-mutant patients, 30 (6.80%, 30/441) had an HRD score < 42. Notably, 13 patients (2.95%, 13/441) with pathogenic BRCA variants exhibited remarkably low HRD scores (< 10). This subgroup comprised 10 BRCA1 and 3 BRCA2 alterations, including: 4 somatic truncating mutations [Exon11 S1389* (VAF=4.41%; HRD=0), Exon11 D1868Vfs*5 (VAF=4.80%; HRD=4), Exon10 E597* (VAF=17.37%; HRD=3), Exon10 K339Rfs*2 (VAF=30.65%; HRD=6)]; 6 germline truncating mutations [Exon21 Q1785* (VAF=50.29%; HRD=9), Exon13 G1492* (VAF=47.61%; HRD=7), Exon10 L1086* (VAF=46.52%; HRD=2), Exon11 S1882* (VAF=50.83%; HRD=0), Exon10 Q1200* (VAF=49.37%; HRD=0), Exon11 L1908Rfs*2 (VAF=44.44%; HRD=0)]; and 3 germline copy number deletions (HRD=2, 2, 0). We hypothesize potential mechanisms for this discordance: 1) Monoallelic inactivation: Single-allele inactivation (first hit) without a complete loss-of-function second hit, leading to partial HR function retention. 2) Subclonal variants: Low VAF suggests BRCA mutations may reside in tumor subclones, not dominating the pan-tumor HRD phenotype, with signals diluted by HR-proficient cells. 3) Time-dependency: BRCA inactivation might occur late in tumor evolution, insufficient for accrual of HRD-associated genomic scars at testing. Conclusions: This study quantifies a rare subgroup (~3%) of OC with pathogenic BRCA mutations but low HRD scores. This suggests monoallelic BRCA mutation alone may be insufficient to induce high genomic instability, potentially contributing to primary resistance to PARPis, though validation with clinical outcome data is required. Future studies integrating multi-omics data are needed to precisely evaluate HR pathway status and guide individualized treatment decisions.
Correlation of Ki-67 with tumor fraction in metastatic HR-positive invasive lobular and no special type breast cancer.
e13014 Background: Invasive lobular carcinoma (ILC) is characterized by loss of E-cadherin, resulting in an infiltrative, discohesive growth pattern that complicates the monitoring of metastatic ILC (mILC). A pooled analysis of the SUCCESS trials showed that ILC patients tend to exhibit lower Ki-67 grade compared to no special type (NST) breast cancer although survival is comparable. This in part may be due to the heterogenous nature of ILC versus delayed detection. Circulating tumor DNA (ctDNA) analysis using liquid biopsy genomic sequencing provides a minimally invasive approach for disease monitoring. This study evaluated the relationship between tumor fraction (TFx) and Ki-67 index to potentially establish the added value for clinical utility in TFx-based ctDNA monitoring in metastatic breast cancer (mBC). Methods: From January 2016 – December 2025, 321 patients with mBC treated at UPMC Hillman Cancer Center underwent longitudinal liquid biopsy testing at times of clinical progression. Hormone receptor–positive (HR+) mILC and mNST cases with serial blood draws were selected, including 112 samples from 31 patients with mILC and 363 samples from 32 patients with mNST. Cell-free DNA underwent low-pass whole-genome sequencing with a mean coverage 0.21x. TFx was estimated using the ichorCNA algorithm. Ki-67 values at initial diagnosis and during clinical progression when available were collected. Treatment lines and clinical outcomes were abstracted from medical records. Results: Most samples were collected during first- to fourth-line metastatic therapy. TFx ranged from 0–65.12% (mean, 11.6%) in ILC and 0–67.43% (median, 12.97%) in NST, with no significant difference between HR+ mILC and mNST (p = 0.76). Baseline Ki-67 levels were available for 24 patients with ILC (range, 2–90%; mean, 26.3%) and 27 patients with NST (range, 0–80%; mean, 38.1%) and did not differ significantly between groups (p = 0.057), with a trend toward lower Ki-67 in mILC. Mean longitudinal TFx correlated with baseline Ki-67 in mNST (r = 0.403, p = 0.037) but not in mILC (r = 0.188, p = 0.390). Decreasing TFx was associated with radiographic response, whereas increasing TFx was observed with treatment resistance. Conclusions: Mean longitudinal TFx correlated with Ki-67 index in mNST but not in mILC although there was a trend towards significantly different Ki-67 levels between groups. A larger cohort is needed to establish this correlation. Nevertheless, TFx dynamics reflected disease progression in both mILC and mNST, suggesting the clinical value of earlier ctDNA monitoring, particularly in mILC where Ki-67 index may inadequately reflect prognosis and underscores the need for further genetic characterization of both subtypes.
Afatinib versus osimertinib for non–small cell lung cancer with uncommon epidermal growth factor receptor mutations: Real-world outcomes (HOT-Next001/HOT2501).
8605 Background: Non–small cell lung cancers (NSCLC) with uncommon epidermal growth factor receptor (EGFR) mutations exhibit considerable biological and clinical heterogeneity. Consequently, the optimal first-line EGFR tyrosine kinase inhibitor (EGFR-TKI) and the role of subsequent immune checkpoint inhibitor (ICI)–based regimens remain uncertain. Methods: This multicenter retrospective cohort study was conducted at 29 institutions in Japan and included patients with advanced or recurrent non-squamous NSCLC harboring uncommon EGFR mutations who received first-line afatinib or osimertinib between January 2015 and January 2024. Exon 20 insertions and de novo T790M mutations were excluded. Outcomes included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and the effectiveness of subsequent systemic therapies, including ICI plus platinum doublet chemotherapy (ICI-Chemo) and platinum doublet chemotherapy alone. To adjust for baseline imbalances, analyses used inverse probability of treatment weighting (IPTW) based on covariate-balancing propensity scores. Results: Among 162 patients, 95 received afatinib and 67 received osimertinib. After IPTW adjustment, no significant differences were observed in PFS (median, 11.3 vs 5.9 months; hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.60–1.80) or OS (28.0 vs 25.5 months; HR, 1.34; 95% CI, 0.73–2.44). Afatinib yielded a higher ORR (70.2% vs 47.2%) and DCR (93.7% vs 82.5%) than osimertinib, while adverse events requiring dose reduction were more frequent (76.8% vs 31.3%) but generally manageable. Subgroup analyses suggested greater benefit with osimertinib in L861X mutations and with afatinib in compound mutations. In patients with PD-L1 ≥50%, afatinib was associated with significantly longer PFS (15.5 vs 2.6 months; HR, 0.14; 95% CI, 0.04–0.46), whereas OS was numerically longer (30.5 vs 12.9 months; HR, 0.38; 95% CI, 0.07–1.93). Among 56 patients who received subsequent systemic therapy and were chemotherapy- and ICI-naïve, IPTW-adjusted analyses showed that ICI-Chemo did not improve outcomes compared with platinum doublet chemotherapy: median PFS, 6.7 vs 7.3 months (HR, 1.08; 95% CI, 0.53–2.19) and post–EGFR-TKI OS, 14.6 vs 19.7 months (HR, 1.30; 95% CI, 0.63–2.68). Conclusions: In one of the largest multicenter real-world cohorts, afatinib and osimertinib demonstrated comparable survival outcomes as first-line EGFR-TKIs in NSCLC with uncommon EGFR mutations, with treatment effects modulated by mutation subtype and PD-L1 expression. ICI-based regimens did not improve outcomes compared with platinum doublet chemotherapy and conferred no meaningful clinical benefit as post–EGFR-TKI therapy in this population.
Real-world impact of human papillomavirus vaccination on cervical cancer incidence and prevalence: A large electronic health record analysis.
e17521 Background: Human papillomavirus (HPV) vaccination is a key preventive strategy against cervical cancer; however, real-world population-level data comparing cervical cancer burden among vaccinated and unvaccinated individuals remain limited. Large electronic health record databases provide an opportunity to evaluate the epidemiologic impact of HPV vaccination in routine clinical practice. Methods: We conducted a retrospective incidence and prevalence analysis using the TriNetX Global Collaborative Network, comprising de-identified electronic health records from 169 healthcare organizations. Adult female patients (≥9 years) with at least one healthcare encounter between January 1, 2015, and December 21, 2025, were included. Two cohorts were constructed: HPV-vaccinated patients identified by CPT codes 90649, 90650, or 90651, and unvaccinated patients with no record of HPV vaccination. Invasive cervical cancer was identified using ICD-10 codes C53.*, including endocervical and exocervical subtypes. Incidence proportion, prevalence, and incidence rates were calculated using TriNetX’s validated incidence–prevalence framework with an applied lookback period. Analyses were stratified by age, race, and ethnicity. Results: The unvaccinated cohort included 94,899,368 adult women, whereas the vaccinated cohort included 798,346 patients. Among unvaccinated individuals, the incidence proportion of invasive cervical cancer was 0.00163 with a prevalence of 0.00218 and an incidence rate of 1.13×10⁻⁶ cases per person-day. In contrast, HPV-vaccinated individuals demonstrated a substantially lower incidence proportion of 5.54×10⁻⁴, prevalence of 6.50×10⁻⁴, and incidence rate of 1.85×10⁻⁷ cases per person-day. Across both cohorts, cervical cancer incidence increased with age, peaking in middle-aged and older adults. Racial and ethnic disparities persisted in both groups, with higher incidence observed among American Indian or Alaska Native patients. Conclusions: In this large real-world analysis, HPV vaccination was associated with markedly lower incidence and prevalence of invasive cervical cancer compared with unvaccinated populations. These findings provide robust population-level evidence supporting the effectiveness of HPV vaccination in reducing cervical cancer burden while highlighting the continued importance of equitable vaccine uptake and routine screening across demographic groups.
Neighborhood deprivation and nativity in breast cancer stage at diagnosis among U.S.- and Latin America–born women.
e13512 Background: Stage at diagnosis strongly predicts breast cancer outcomes. Socioeconomic and structural factors affect access to screening, yet the relative impact of neighborhood deprivation versus immigration status on stage at presentation remains unclear. Methods: We conducted a retrospective cohort study of women ≥18 years diagnosed with breast cancer (2010–2024) at a South Florida cancer center. Analyses included U.S.-born women and women born in Latin America. Neighborhood deprivation was measured using the Area Deprivation Index (ADI), categorized into quartiles (Q1 least deprived–Q4 most deprived). Late-stage diagnosis (LSD) was defined as stage III–IV. Multivariable logistic regression assessed associations between ADI, nativity, and late-stage diagnosis, adjusting for age, with tests for trend. Results: Among 1,235 women (726 Latin America–born; 509 U.S.-born), 20.4% presented with LSD. LSD did not differ by nativity (22.1% U.S.-born vs 19.2% Latin America–born; p = 0.24), and nativity was not independently associated with LSD after adjustment (OR 1.27, 95% CI 0.96–1.69). Higher neighborhood deprivation was strongly associated with LSD, with increasing odds across ADI quartiles (Q2 vs Q1 OR 1.51, Q3 vs Q1 OR 2.49; p-trend < 0.001). In secondary analyses, U.S.-born women had higher adjusted odds of all-cause mortality (OR 1.72, 95% CI 1.04–2.88), while ADI was not independently associated with mortality. Conclusions: Neighborhood deprivation was independently associated with breast cancer LSD, whereas nativity was not. U.S.-born women demonstrated higher all-cause mortality in secondary analyses. Together, these findings highlight the dominant role of neighborhood-level socioeconomic conditions in breast cancer disparities, independent of nativity. Cohort characteristics and outcomes. Characteristic / Outcome Estimate Measure Total analytic cohort 1,235 women — Latin America–born 726 (58.8%) — U.S.-born 509 (41.2%) — Late-stage disease (overall) 252 (20.4%) — Late-stage disease by nativity 22.1% vs 19.2% p = 0.24 Late-stage disease by ADI Increasing Q1→Q4 p < 0.001 ADI (per quartile increase) OR 1.51 (95% CI 1.25–1.83) p-trend < 0.001 All-cause mortality (overall) 66 (5.2%) — Mortality by nativity (adjusted) OR 1.72 (95% CI 1.04–2.88) p < 0.05
Sensitivity of CA-125 by ovarian cancer histology.
e17557 Background: Women with ovarian cancer may have subtle symptoms, delaying diagnosis to late stage. Guidelines recommend use of cancer antigen 125 (CA-125) in the work up of suspected ovarian cancer, especially for which patients need referral to gynecologic oncology. Yet “normal” CA-125 thresholds of 35 units/mL in practice were developed in 1980s in a homogenous group of women with different distribution of ovarian cancer histologies than current. Our objective was to compare the sensitivity of different CA-125 thresholds across ovarian cancer histologies. Methods: We identified patients with newly-diagnosed ovarian cancer from the Penn Medicine Cancer Registry, 2009-2023 (n=2,785) supplemented with patients identified by ICD codes, 2020-2023 (n=1,342). CA-125 values obtained within 60 days of diagnosis were abstracted from the electronic health record. We examined the sensitivity of current CA-125 thresholds by histology. Results: Among 1670 patients with ovarian cancer and CA-125 at diagnosis, the median CA-125 at diagnosis was 255.0 (interquartile range 49.0-955.0) in epithelial tumors compared to 41.0 (IQR 26.0-264.8) for germ cell and 23.2 (IQR 16.0-53.5) for sex cord stromal tumors. Within epithelial tumor types, CA-125 ranged from 31.2 (IQR 21.0,92.0) in mucinous tumors, 34.0 (IQR 21.0,104.0) in borderline tumors, 193.0 (IQR 35.0,807.6) in low-grade serous to 466.0 (IQR 112.0,1328.0) in high-grade serous tumors. At diagnosis, 50% of patients with ovarian cancer had CA-125 <35 units/mL, including 20% of epithelial tumors. Lowering CA-125 threshold to 15 units/mL improved sensitivity to 92%. Conclusions: Current thresholds of abnormal CA-125, used for gynecologic oncology referral, miss up to half of individuals with ovarian cancer. Sensitivity is lowest for mucinous and borderline tumors that are increasingly common. Updated thresholds are needed to avoid delays in diagnosis, and strengthen the potential for cure, in ovarian cancer.
Impact of immunotherapy era on survival in stage IV non–small cell lung cancer.
8562 Background: The introduction of immunotherapy (IO) has transformed treatment paradigms in Stage IV non-small cell lung cancer (NSCLC). However, large-scale population-based evidence quantifying its impact on survival remains limited. We evaluated overall survival trends before and after the IO era using SEER data. Methods: We identified patients diagnosed with Stage IV NSCLC from 2006 to 2020 in the SEER 17 database. Patients were grouped by era: pre-IO (2006–2014) and post-IO (2015–2020). Demographics, histology, and socioeconomic variables were included. Overall survival (OS) was assessed using Kaplan-Meier analysis. Multivariable Cox proportional hazards models estimated hazard ratios (HRs) with 95% confidence intervals (CIs) adjusting for age, sex, race, and histology. Results: A total of 101,243 Stage IV NSCLC patients were included. The post-IO era was associated with a 19% reduction in mortality compared to the pre-IO era (HR 0.81; 95% CI 0.79–0.82; p<0.001). Older age (≥75 years) conferred increased mortality risk (HR 1.32; 95% CI 1.30–1.34; p<0.001), while younger patients (<65 years) had better outcomes (HR 0.91; 95% CI 0.89–0.93; p<0.001). Male sex (HR 1.16; 95% CI 1.14–1.17; p<0.001), non-adenocarcinoma histology (HR 1.30; 95% CI 1.28–1.32; p<0.001), and Black race (reference group) were independently associated with worse survival. White (HR 0.83; 95% CI 0.81–0.85; p<0.001) and Other races (HR 0.75; 95% CI 0.73–0.77; p<0.001) demonstrated survival advantages. Kaplan-Meier curves confirmed significantly improved OS in the post-IO era (median OS 8 vs 10 months, log-rank p<0.001). Conclusions: This large population-based study confirms a significant survival benefit in Stage IV NSCLC patients diagnosed in the immunotherapy era, alongside expected demographic and histologic disparities. These findings support the real-world impact of immunotherapy and underscore the need for continued efforts to address survival inequities.
A SEER-based Joinpoint analysis investigating the effect of shared decision-making on prostate cancer stage at diagnosis.
10521 Background: Prostate cancer screening recommendations in the United States have evolved over the last two decades. The U.S. Preventive Services Task Force (USPSTF) recommended against routine prostate-specific antigen (PSA) screening for men ≥75 in 2008 and for all men in 2012 (Grade D), followed by a transition to shared decision-making for men ages 55–69 in 2018 (Grade C). These changes have raised concern for later-stage presentation Few analyses have leveraged national data through 2022 to evaluate whether the 2018 guideline modification has affected stage-specific incidence. Methods: We queried the Surveillance, Epidemiology, and End Results (SEER) Program for malignant prostate cancer cases diagnosed from 2000–2022 using the SEER 17 Registries Research Data (November 2024 submission), which provides population-based incidence coverage for approximately 26% of the United States. Cases were limited to men aged ≥55 at diagnosis. Age-adjusted incidence rates (per 100,000; 2000 U.S. standard population) were extracted separately for localized and distant Prostate malignancies (Summary Stage 2000+) using SEER*Stat incidence rate sessions. Annual rates and standard errors were exported for analysis. Joinpoint regression (Joinpoint v5.4.0) was used to estimate Annual Percent Change (APC) for each trend segment, with model selection determined by the Bayesian Information Criterion and weighting by standard error. Up to four joinpoints were permitted, and the software automatically selected the optimal number. Average Annual Percent Change (AAPC) was calculated to summarize overall trends. Results: Localized prostate cancer incidence declined significantly from 2004–2022 (APC = –3.12%; p < .05). Distant prostate cancer incidence decreased from 2000–2010 (APC = –0.95%; p < .05), followed by a significant increase from 2010–2022 (APC = +6.04%; p < .05). Joinpoint analysis identified a statistically significant inflection point near 2010 that temporally follows USPSTF recommendations discouraging routine PSA screening. No additional joinpoint or attenuation in distant-stage incidence was observed following the 2018 guideline revision. Conclusions: Using up-to-date national registry data through 2022, our analysis corroborates prior work demonstrating rising distant-stage prostate cancer incidence following guideline changes that reduced PSA screening. The absence of a joinpoint following the 2018 revision suggests that the shift to shared decision-making has not yet reversed or slowed this trend.