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Cardiomyopathy mortality among U.S. adults with breast cancer: A 25-year CDC WONDER study.
e13139 Background: Cardiovascular disease is an increasingly recognized contributor to mortality among cancer patients. Arrhythmias may represent an underappreciated cause of death in breast cancer, particularly among older individuals and those receiving cardiotoxic therapies. We examined national multiple cause of death data to characterize the burden and demographic patterns of arrhythmia-associated mortality in breast cancer. Methods: This retrospective population-based study used CDC WONDER death certificate data. Deaths with breast cancer (ICD-10 C50) as the underlying cause and arrhythmias (ICD-10 I47–I49) as contributing causes were identified. Age-adjusted mortality rates (AAMRs) per 100,000 population were calculated using the 2000 U.S. standard population. Analyses followed STROBE guidelines and were stratified by age, sex, race/ethnicity, and urbanization. Temporal trends were evaluated descriptively using AAMRs with 95% confidence intervals. Results: Arrhythmia-associated mortality in breast cancer patients remained substantial throughout the study period. AAMRs increased with advancing age, with the highest rates among individuals aged ≥65 years. Racial disparities were observed, with White decedents showing higher absolute AAMRs compared with other groups. Although breast cancer predominantly affects women, sex-stratified analyses showed a notable burden of arrhythmia-related mortality. Mortality rates were higher in metropolitan areas compared with non-metropolitan regions. Temporal analyses indicated persistent arrhythmia-associated mortality over the study period. Conclusions: Arrhythmias are a significant and persistent contributor to mortality among patients with breast cancer. The age-related increase and observed demographic disparities highlight the importance of cardiovascular risk assessment and arrhythmia monitoring in this population. These findings support the integration of cardio-oncology strategies to reduce non-cancer mortality among patients with breast cancer.
A real-world analysis of ctDNA methylation-based histology prediction and associated clinical characteristics in non–small cell lung cancer (NSCLC).
8539 Background: The treatment of NSCLC differs by histologic subtype, though traditional histologic review faces several challenges including insufficient tissue and intratumoral heterogeneity. The circulating tumor DNA (ctDNA) assay Guardant360 Liquid (G360) now includes a molecular tumor type (TT) and lung subtype (ST) predictor based on DNA methylation patterns. This study aimed to evaluate the concordance between G360 TT/ST prediction and tissue-based histology in a real-world sample of patients (pts) with NSCLC. A comparative analysis was conducted to understand differences in clinical characteristics between pts with and without G360 TT/ST prediction. Methods: This retrospective study included pts with NSCLC who underwent G360 testing from May to October of 2025. G360 predicted TT and ST (proportion of adenocarcinoma (AD), squamous cell carcinoma (SQ), and small cell carcinoma (SC)). Dominant TT was defined as the top cancer of origin prediction. Dominant ST was defined as a proportion >80%. G360 TT/ST was compared to tissue histology to determine concordance using Cohen’s kappa coefficient. Demographic and clinical characteristics were collected, and statistical differences (p<0.05) between pts with and without TT/ST prediction were evaluated. Results: Of 145 pts who underwent a combined 176 G360 assays, 47 (32%) had assays predicting TT/ST, including 9 pts with TT prediction only and 38 with both. Of these 38 pts, 32 had tissue-proven AD, 3 had SQ, and 3 had poorly differentiated NSCLC. The overall accuracy of G360 TT prediction was 100% (47/47). The accuracy of ST prediction, excluding the 3 pts with poorly differentiated NSCLC, was 94% (33/35, k=0.72), with 2 discordant cases. One case was a pt with AD whose G360 at diagnosis predicted AD, but 4 months later predicted a SC component (40%). Both pts with discordant subtyping died within 4 months of their G360 result. Pts with TT/ST prediction were statistically younger, had more advanced disease, higher extra-thoracic metastatic burden, and higher ctDNA tumor fraction (TF) than pts without TT/ST prediction (Table 1). Conclusions: In this real-world analysis, G360 TT/ST prediction demonstrated good concordance with tissue-based histology, though prediction was more likely in pts with more advanced disease and higher TF. In the future, ctDNA-based TT/ST prediction may be a useful noninvasive tool to confirm primary lung cancer, classify histologic subtype, and identify histologic transformation, particularly during periods of disease progression, leading to better therapeutic decisions. Baseline pt characteristics. (+) G360 TT/ST prediction (n=47) (-) G360 TT/ST prediction (n=98) P -value Median age (IQR) 68 (64-77) 71 (60-74) 0.03 Female (%) 27 (57.4) 60 (61.2) 0.66 Stage III/IV (%) 46 (97.9) 67 (68.4) <0.0001 Extra-thoracic metastases (%) 35 (74.5) 20 (20.4) <0.0001 TF (%) 3.9 0.7 0.01
Disproportionate reporting of ischemic gastrointestinal injury associated with lenvatinib: A FAERS pharmacovigilance analysis.
e23416 Background: Vascular endothelial growth factor (VEGF)–targeted tyrosine kinase inhibitors (TKIs) are widely used across solid tumors. While end-stage gastrointestinal (GI) complications such as perforation and fistula formation have been described, ischemic GI injury (e.g., ischemic colitis and mesenteric ischemia) represents a distinct vascular toxicity phenotype that has not been systematically characterized in post-marketing pharmacovigilance data. We assessed disproportionate reporting of ischemic GI injury associated with VEGF-targeted TKIs in the FDA Adverse Event Reporting System (FAERS). Methods: We analyzed quarterly ASCII FAERS data from October–December 2012 through October–December 2024. Reports were deduplicated at the case level by retaining the most recent FDA receipt date per CASEID. Exposure was defined as primary suspect reports for VEGF-targeted TKIs (lenvatinib, cabozantinib, axitinib, tivozanib; generic and brand names). Ischemic GI injury was identified using MedDRA Preferred Terms including ischemic colitis, mesenteric ischemia, and intestinal, bowel, or colonic ischemia. Disproportionality was assessed using reporting odds ratios (RORs) with 95% confidence intervals, applying Haldane–Anscombe correction for sparse events, within a real-world pharmacovigilance framework for post-marketing safety signal detection. Results: Among 15,473,015 deduplicated FAERS cases, 3,540 reports included ischemic GI injury terms, with 71,838 VEGF-targeted TKI primary suspect reports. At the class level, VEGF-targeted TKIs were not associated with significantly increased reporting of ischemic GI injury (ROR 1.37, 95% CI 0.91–2.08; 22 events). In drug-specific analyses, lenvatinib demonstrated a significant disproportionality signal (10/22,143 reports; ROR 2.08, 95% CI 1.13–3.81). No significant signal was observed for cabozantinib (6/33,859; ROR 0.84, 95% CI 0.39–1.81) or axitinib (6/14,639; ROR 1.94, 95% CI 0.90–4.19). Tivozanib analyses were limited by sparse events (0/1,197; ROR 1.82, 95% CI 0.11–29.19). Conclusions: In FAERS data from 2012–2024, ischemic GI injury did not demonstrate a class-wide disproportionality signal among VEGF-targeted TKIs; however, a significant drug-specific signal was observed with lenvatinib. These findings support heightened clinical vigilance for ischemic GI presentations in patients receiving lenvatinib and highlight the need for confirmation in longitudinal real-world datasets. As with all spontaneous reporting systems, causality and incidence cannot be inferred. As a real-world pharmacovigilance study, these findings identify a severe but underrecognized ischemic gastrointestinal injury reporting signal associated with lenvatinib, informing post-marketing safety surveillance, clinical recognition, and timely treatment interruption in routine practice.
Classification tree phenotypes for early treatment-limiting toxicity after androgen receptor pathway inhibitor initiation in metastatic hormone-sensitive prostate cancer from the IRONMAN registry.
5095 Background: Androgen receptor pathway inhibitors (ARPIs) improve survival in metastatic hormone-sensitive prostate cancer (mHSPC), but early treatment-limiting toxicity remains common. Using the IRONMAN (International Registry for Men with Advanced Prostate Cancer; NCT03151629) registry, we developed an interpretable classification tree that yields simple rule-based 1-year risk strata for a composite adverse outcome (AO) after ARPI initiation. Methods: Men with mHSPC initiating first-line ARPI with at least 12 months follow-up or AO within 365 days were included (n=583). AO was the first serious adverse event (SAE) or ARPI discontinuation for toxicity or other non-progression reasons; progression-attributed events were not counted. Candidate peri-ARPI initiation predictors (demographics, labs, treatments/medications, patient-reported outcomes) were screened for missingness, imbalance, and collinearity, reduced by stepwise logistic regression, and entered a recursive-partitioning classification tree with restricted depth and node size. Discrimination was summarized by area under the receiver operating characteristic curve (AUC) and repeated 3-fold cross-validation. Terminal nodes were collapsed into low, intermediate, and high-risk strata by predicted 1-year AO. Results: Overall, 122/583 men (20.9%) had AO within 1 year (85 SAEs; 37 discontinuations [28 toxicity, 9 other non-progression]). AO-free survival did not differ by ARPI agent (log-rank p=0.40); ARPIs were pooled. Peri-ARPI docetaxel exposure (triplet therapy) was uncommon (2.4%). The final tree retained nine predictors, including European Organization for Research and Treatment of Cancer global health rating (1-7), hemoglobin, worst pain (0-10), lactate dehydrogenase (LDH), age, docetaxel, and opioid agonist and systemic steroid use. In-sample AUC was 0.76 (95% CI 0.71-0.81); cross-validated AUC was 0.60 (95% CI 0.55-0.65). Collapsed strata showed distinct 1-year AO risk (Table 1). High-risk phenotypes reflected poor health/symptoms with anemia and/or elevated LDH, and a treatment-intensity phenotype with triplet therapy plus opioids and steroids. Conclusions: A small classification tree identified three clinically transparent phenotypes of early AO after ARPI initiation in mHSPC and can be applied as simple decision rules to support monitoring and shared decision-making. External validation is needed. Tree risk strata and 1-year AO risk. Risk stratum n (%) 1-year AO %, (95% CI) Low 422 (72) 10.7 (7.7–13.6) Intermediate 80 (14) 26.3 (16.6–35.9) High 81 (14) 69.1 (59.1–79.2)
Efficacy and safety of cabozantinib (CABO) in advanced neuroendocrine tumors (NET) according to hormone functional status: Subgroup analysis of phase 3 CABINET trial (Alliance A021602).
4178 Background: In the CABINET trial, CABO significantly prolonged progression-free survival (PFS) compared to placebo (PB) in patients (pts) with advanced, previously treated extrapancreatic NET (epNET) or pancreatic NET (pNET) (Chan et al., NEJM, 2025). Here we report outcomes according to functional status based on NET hormone secretion. Methods: Pts with locally advanced or metastatic epNET or pNET were randomized 2:1 in separate cohorts to receive CABO 60 mg daily vs PB. Eligibility included progression by RECIST within 12 months (mo) before registration, ≥ 1 prior systemic therapy not including somatostatin analogs (SSA). Pts with functional NET due to hormone secretion and non-functional NET were included. In this post hoc subgroup analysis, we analyzed PFS by blinded independent central review and adverse events for pts receiving CABO vs PB based on functional status. Cox regression models were used with stratification on primary tumor site (epNET vs pNET). Subset analyses to evaluate treatment arm differences were conducted in pts with functional and non-functional tumors. Due to small numbers, separate results for those with unknown functional status are not included. Results: Of the total 298 pts enrolled in both cohorts, 74 had a functional NET (CABO, n = 47; PB, n = 27); 179 had a non-functional NET (CABO, n = 123; PB, n = 56); 45 had unknown functional status (CABO, n = 28; PB, n = 17). For functional NET, primary tumor sites were GI tract (n = 50; 68%), pancreas (n = 15; 20%), unknown (n = 4; 5%), lung (n = 3; 4%), and thymus (n = 2; 3%). Secreted hormones that were reported included serotonin (55%), somatostatin (18%), gastrin (16%), glucagon (4%), insulin (4%), ACTH (1%), and vasoactive intestinal peptide (1%). For non-functional NET, primary tumor sites were pancreas (n = 75; 42%), GI tract (n = 42; 23%), lung (n = 30; 17%), unknown (n = 17; 9%), thymus (n = 8; 4%), and other (n = 7; 4%). Concurrent SSA was received by 91% and 53% of pts with functional and non-functional NET, respectively. In both subgroups, CABO was associated with improved PFS compared to PB (for functional NET: stratified hazard ratio [sHR], 0.40; 95% confidence interval [CI]: 0.20-0.82, P = 0.012; for non-functional NET: sHR, 0.26; 95% CI: 0.17-0.41, P < 0.001). The most frequent grade 3/4 adverse events (AEs) attributed to CABO vs PB in pts with functional NET included hypertension (21% vs 11%), diarrhea (9% vs 11%), and fatigue (2% vs 15%); in pts with non-functional NET, grade 3/4 AEs included hypertension (21% vs 4%) and fatigue (18% vs 4%). Conclusions: Subset analyses of the CABINET trial suggest that CABO is an effective treatment option for pts with functional and non-functional epNET or pNET. Efficacy and safety results for pts with functional or non-functional NET treated with CABO are consistent with results for the entire trial. Clinical trial information: NCT03375320 .
Fuzuloparib combined with abiraterone acetate and prednisone (AA-P) as first-line (1L) treatment for metastatic castration-resistant prostate cancer (mCRPC): Interim results from the FUZUPRO trial.
5008 Background: The combination of PARP inhibitors with standard AA-P may offer enhanced antitumor activity over AA-P. We conducted FUZUPRO, an international, randomized, double-blind, placebo-controlled phase 3 trial, to compare the efficacy of fuzuloparib, a novel PARP inhibitor, plus AA-P vs AA-P as 1L treatment for mCRPC. Methods: 1L mCRPC patients were randomized (1:1) to orally receive fuzuloparib 150 mg BID plus AA-P (abiraterone acetate 1000 mg QD; prednisone 5 mg BID) or placebo plus AA-P. Randomization was stratified by DNA-repair gene defect (DRD) status (positive vs negative/unknown) and other factors. Primary endpoint was blinded independent central review (BICR)-assessed radiographic progression-free survival (rPFS) per RECIST v1.1 and PCWG3. As of March 23, 2025, 259 (85% of total expected) BICR-assessed rPFS events occurred, and a prespecified interim analysis was conducted. Results: 496 patients were randomized to fuzuloparib-AA-P (n = 249) or AA-P (n = 247). Median follow-up was 33.3 mo. Fuzuloparib-AA-P significantly prolonged rPFS compared with AA-P (median, 24.8 mo vs 19.9 mo; HR 0.71, 95% CI 0.55-0.91; 1-sided p = 0.0034). rPFS benefit with fuzuloparib-AA-P was generally consistent across clinically relevant subgroups. Among DRD-positive patients (n = 116), median rPFS was 27.7 mo and 13.9 mo in the fuzuloparib-AA-P and AA-P groups, respectively (HR 0.51, 95% CI 0.31-0.85; 1-sided p = 0.0039). Subgroup analysis suggested improved rPFS among DRD-positive patients regardless of their BRCA1/2 mutation status. Among DRD-negative/unknown patients (n = 380), median rPFS was 22.8 and 21.2 mo, respectively. Overall survival showed a benefit trend in favor of fuzuloparib-AA-P (Table). Treatment-related adverse events (TRAEs) were reported by 81.9% and 76.0% of patients in the two groups, respectively. The most common grade ≥3 TRAEs were mainly hematological toxicities, including anemia (20.1%), decreased white blood cell count (5.6%), decreased platelet count, and decreased neutrophil count (5.2% for each). Conclusions: Fuzuloparib plus AA-P as 1L treatment significantly prolonged rPFS in patients with mCRPC. The combination showed acceptable safety and tolerability with no new safety signals identified. Clinical trial information: NCT04691804 . Overall DRD-positive DRD-negative/unknown Fuzuloparib-AA-P(N = 249) AA-P (N = 247) Fuzuloparib-AA-P (N = 60) AA-P (N = 56) Fuzuloparib-AA-P (N = 189) AA-P (N = 191) rPFS, mo, median (95% CI) 24.8 (20.4, 30.4) 19.9 (15.2, 22.2) 27.7 (17.7, NR) 13.9 (8.3, 24.9) 22.8 (19.9, 30.2) 21.2 (16.5, 24.6) HR (95% CI), vs. AA-P 0.71 (0.55, 0.91) 0.51 (0.31, 0.85) 0.81 (0.61, 1.08) Overall survival, mo, median (95% CI) 41.9 (31.1, NR) 36.8 (28.7, NR) NR (27.0, NR) 36.8 (24.7, 40.3) 37.3 (29.0, NR) 36.8 (28.7, NR) HR (95% CI), vs. AA-P 0.96 (0.73, 1.24) 0.76 (0.44, 1.32) 1.00 (0.74, 1.35) NR, not reached.
Intrapatient comparative analysis of tumor-informed ctDNA and ctHPV-DNA in patients with HPV-driven OPSCC.
6075 Background: The rising incidence of oropharyngeal squamous cell carcinoma (OPSCC) is largely attributable to human papillomavirus associated (HPV+) disease, which accounts for ~70% of OPSCC cases. Circulating tumor (ct)DNA has the potential to enable more accurate treatment response assessment, guide response-adaptive management, and detect minimal residual disease to indicate persistence or recurrence. Both mutation-based tumor-informed ctDNA and ctHPV-DNA testing have demonstrated utility in HPV+ disease, but prospective intrapatient evaluations remain limited. A direct comparison of these approaches is essential to determine redundancy versus complementarity and to guide optimal integration into OPSCC patient management. Methods: In an ongoing prospective study, serial plasma samples were obtained from patients with stages I-IV OPSCC undergoing curative intent treatment. Up to 50 patient specific somatic variants were selected based on tumor whole exome sequencing to develop a personalized tumor-informed next generation sequencing (NGS) ctDNA assay (Haystack MRD) for plasma analysis. In patients with HPV+ disease (determined via ISH, IHC, and/or NGS), plasma was also analyzed using an NGS-based assay interrogating 13 high-risk HPV strains (Haystack HPV). Paired intrapatient samples were analyzed using percent agreement with 95% confidence intervals and Cohen’s kappa; concordance of dynamic changes was assessed using Spearman’s correlation. Results: As of January 2026, ctDNA results were available for 111 serial timepoints from 26 patients. The median number of timepoints per patient was 4 (range 1-9). Seventeen patients (65%) had HPV+, and 9 (35%) had HPV− disease. In HPV+ patients, across 85 longitudinal samples collected during multimodal treatment and post-treatment surveillance, mutation-based ctDNA and ctHPV demonstrated high concordance (91%; 95% CI, 82.5–95.2; κ=0.80). Of 30 ctDNA+ samples, 28 were ctHPV+ (93%; 95% CI, 78.7–98.2%), while 49 of 55 ctDNA- samples were ctHPV- (89%; 95% CI, 78.2–94.9%). Discordance was infrequent (8/85, 9.4%), predominantly ctHPV+/ctDNA- (6/85, 7.1%). All ctHPV+/ctDNA- cases occurred during neoadjuvant treatment monitoring and reflected earlier clearance of ctDNA, with ctHPV clearance lagging by several weeks to months. Two low-level (<100 parts per million) ctDNA+/ctHPV- cases were observed in the adjuvant setting. When both analytes were present, dynamic changes in ctDNA and ctHPV levels were highly concordant (Spearman’s ρ=0.94), although ctHPV was consistently detected at higher absolute levels. Conclusions: In HPV-driven OPSCC, tumor-informed ctDNA and ctHPV show high longitudinal concordance and distinct clearance kinetics, with earlier ctDNA clearance. Ongoing analyses will define how these assays can be optimally integrated into response assessment, treatment adaptation, and surveillance strategies.
Germline pathogenic/likely pathogenic (P/LP) variants in epithelial neuroendocrine neoplasms: The case for universal germline genetic testing.
4182 Background: Current National Comprehensive Cancer Network (NCCN) guidelines for germline testing in neuroendocrine neoplasms (NENs) rely on organ-specific, syndrome-driven algorithms that may not adequately capture hereditary risk. We sought to analyze prevalence of P/LP germline variants in epithelial NENs and investigate relevant associations. Methods: Germline genetic testing results were analyzed from 3,611 probands. Cohort 1 included 3,409 patients identified by ICD-10 code C7A (2015–2025), and Cohort 2 included 201 consecutively curated patients with pathology information (2019–2021). Patients with paraganglioma, pheochromocytoma, or medullary thyroid carcinoma were excluded. Except 59 single-gene tests, multigene panels included a mean of 67 and 62 genes in Cohorts 1 and 2, respectively. Data were classified as P/LP, variant of uncertain significance (VUS), or negative. Comparisons of variant classification frequencies between cohorts were performed using chi-square or Fisher’s exact tests. Multivariable logistic regression evaluated clinical and demographic predictors of P/LP variant detection, with results reported as likelihood ratios (LR) and two-sided p-values ( < 0.05 considered significant). Results: Among all 3,611 probands, mean age was 56 years in Cohort 1 and 53 years in Cohort 2, with females comprising 63% and 71%, respectively. VUS and negative results differed between cohorts (VUS 21.9% vs 32.9%, p = 0.002; negative 67.4% vs 55.0%, p < 0.001), while P/LP rates were similar (10.6% vs 12.1%, p = 1.0), permitting pooled analysis. Overall, 387 patients (10.7%) harbored P/LP variants, with 399 P/LP variants identified across 49 genes. Sixty percent of P/LP variants were accounted for by CHEK2, MEN1, BRCA2, ATM, FH, HOXB13, PALB2, and BRCA1 . Clinically actionable variants per NCCN guidelines were identified in 348 patients (9.6%). Among 479 probands with curated family history, meeting NCCN criteria for multigene testing or having a family history of NEN was not predictive of P/LP detection. Logistic regression demonstrated that male sex was a significant predictor of P/LP variants (LR = 4.538, p = 0.03), while age at NEN diagnosis and primary NEN site were not predictive, nor were the interaction terms significant. Conclusions: In this 10-year, multicohort study of patients at a commercial laboratory, more than one in ten patients with epithelial NENs harbored a germline P/LP variant, frequently outside classic hereditary NEN syndromes and inadequately predicted by NCCN criteria, family history, age, or tumor site. These findings suggest that current germline testing frameworks may miss clinically relevant hereditary cancer risk. Broader approaches to germline testing in these patients may be needed to improve identification of hereditary cancer risk and enable personalized prevention and surveillance strategies.
Xerostomia following lutetium-177 PSMA radioligand therapy in metastatic prostate cancer: Associations with accelerated fatigue and dental treatment onset in a propensity-matched real-world analysis.
e24086 Background: Radioligand therapy (RLT) with lutetium-177 (177Lu)-labeled prostate-specific membrane antigen (PSMA) ligands is an effective treatment for metastatic castration-resistant prostate cancer (mCRPC), but xerostomia is a frequent adverse effect due to off-target salivary gland uptake, with prevalence rates of 22% to 87%. The long-term implications of xerostomia on patient outcomes, such as electrolyte imbalances, fatigue, neurological disorders, mortality, and need for dental treatments, remain understudied. Methods: This retrospective cohort study used deidentified electronic health records from the TriNetX federated network ([Deprecated 11-20-2024] COVID-19 Research Network, 88 healthcare organizations). Cohorts included patients with prostate cancer (ICD-10-CM C61 or C80.1) who received 177Lu-PSMA-617 or 177Lu-dotatate (HCPCS A9607 or A9513). Cohort 1 (non-xerostomia) excluded xerostomia codes (K11.7, R68.2, T66.XXXA); Cohort 2 included them. Propensity score matching (PSM) balanced cohorts on demographics, diagnoses, and laboratory values. Analysis was conducted on January 24, 2026. Results: Pre-PSM, Cohort 1 had 1875 patients; Cohort 2 had 122. Post-PSM, both had 122 patients (predominantly White [81.1%]). Malaise/fatigue had higher risk in xerostomia group (29.5% vs 44.8%; RR, 0.658; 95% CI, 0.376-1.152; P = .153) and shorter median survival (1280 vs 372 days; log-rank P = .052). No significant differences in fluid/electrolyte imbalance risk (28.9% vs 31.8%; risk ratio [RR], 0.909; 95% CI, 0.558-1.481) or median survival (1182 vs 609 days; log-rank P = .239). Nervous system disorders showed similar risk (22.4% vs 35.7%; RR, 0.629; 95% CI, 0.302-1.309; P = .209) and median survival (not reached vs 728 days; log-rank P = .066). Mortality was identical (36.9% both; RR, 1.000; 95% CI, 0.720-1.389). Dental treatments showed similar risk (15.9% vs 24.5%; RR, 0.650; 95% CI, 0.317-1.334; P = .237) and median survival (1316 vs 479 days; log-rank P = .063). Conclusions: Xerostomia after 177Lu-RT was associated with increased fatigue risk and earlier onset, leading to an increase in the burden of illness on the patient. Other associations were not found but can be due to the small number of patients that were used in this retrospective study. This preliminary finding highlights the need for further research to identify other associations and/or disparities.
Is language barrier a mere proxy?: Psychological distress among non–English-speaking prostate cancer patients receiving radiation therapy—A prospective cohort study.
5113 Background: Cancer patients experience depression and anxiety at elevated rates, with minority and non-English-speaking populations disproportionately affected. Prior research at our institution demonstrated elevated distress among Spanish-speaking breast cancer patients undergoing radiation therapy. However, limited data exist on language-related disparities in prostate cancer patients undergoing radiation therapy. We investigated this while exploring the mediating role of social determinants of health (SDOH). Methods: We enrolled prostate cancer patients initiating radiation therapy at an urban safety-net hospital. We assessed anxiety (GAD-2), depression (PHQ-2), and SDOH including food and housing insecurity, and transportation barriers at baseline and treatment completion. Comparisons used t-tests and Mann-Whitney U tests; correlations used Spearman coefficients with statistical significance p < 0.05. Results: Of 84 patients enrolled (mean age 70.3±8.0 years), 49 (58.3%) were English-speaking and 35 (41.7%) were non-English-speaking (Spanish n = 20, Haitian Creole n = 13, Portuguese n = 2). The sample was predominantly Black/Caribbean (64.3%). Non-English speakers had fewer years in the US (41.1 vs. 50.3 years, p = 0.016) and lower educational attainment (25.7% vs. 0% elementary school only, p = 0.006). At baseline, non-English speakers showed numerically higher anxiety (GAD-2: 1.31±2.13 vs. 1.08±1.72) and depression (PHQ-2: 1.09±1.87 vs. 0.84±1.57), though this was not statistically significant (p > 0.50). Notably, Spanish-speaking patients demonstrated the highest distress (GAD-2: 2.00±2.45; PHQ-2: 1.40±1.98), with 30.0% screening positive for clinical anxiety vs. 16.3% of English speakers. SDOH factors were significantly correlated with distress: housing insecurity (ρ = 0.42, p < 0.001), food insecurity (ρ = 0.37, p = 0.001), and transportation worry (ρ = 0.38, p < 0.001). In multivariable regression adjusting for age, stage, race, ethnicity, and education, language was not independently associated with anxiety (B = -0.64, 95% CI: -1.76 to 0.48, p = 0.26). Among 73 patients with paired data, distress remained stable from baseline to treatment completion. Conclusions: While non-English-speaking prostate cancer patients reported higher psychological distress during radiation therapy, SDOH factors emerged as the strongest predictors of distress regardless of language. Interventions targeting social vulnerability may be more impactful than language services alone. SDOH screening should be integrated into oncology care at safety-net institutions serving diverse populations.
Adjuvant chemoradiotherapy versus radiotherapy alone in high-risk endometrial cancer: Updated meta-analysis of randomized trials.
e17635 Background: The survival benefit of adjuvant chemoradiotherapy compared with radiotherapy alone in high-risk endometrial cancer (EC) remains debated. With updated PORTEC-3 results and maturation of earlier randomized clinical trials (RCTs), a contemporary quantitative reassessment is warranted. Methods: A PRISMA-compliant systematic review and meta-analysis of RCTs compared adjuvant chemoradiotherapy versus radiotherapy alone after surgery in high-risk EC. Kaplan–Meier curves were digitized using ScanIt, and individual patient data were reconstructed with IPDfromKM, with validation by log-rank test, root mean square error, and Kolmogorov–Smirnov test. Overall survival (OS) and disease-free survival (DFS) were pooled using random-effects models and expressed as hazard ratios (HRs) with 95% CIs. Trial-level weighted meta-regressions explored effect modification by FIGO stage, histologic subtype, tumor grade, and extent of lymphadenectomy. Safety outcomes were summarized using pooled risk ratios (RRs). Results: Six RCTs including 2,105 patients were analyzed, with OS effects ranging from negative in earlier trials to improved survival in contemporary combined-modality studies. In pooled analysis, chemoradiotherapy was associated with a borderline improvement in OS (HR 0.83, 95% CI 0.69–1.01; p=0.06; I²=0%). DFS was consistently improved with chemoradiotherapy across trials, yielding a statistically significant pooled benefit (HR 0.75, 95% CI 0.63–0.91; p<0.01; I²=0%). Trial-specific DFS HRs ranged from approximately 0.60 to 0.85, favoring combined treatment in the majority of comparisons, including PORTEC-3–eligible populations. Meta-regression analyses demonstrated limited explanatory power for OS according to FIGO stage I–III, tumor grade, or non-endometrioid histology, with low coefficients of determination across models (R²≤0.31). In contrast, DFS benefit showed a strong association with extent of lymphadenectomy (R²=0.85), suggesting greater relative benefit in comprehensively staged patients. Chemoradiotherapy increased acute grade ≥3 hematologic and gastrointestinal toxicity compared with radiotherapy alone, while late grade ≥3 adverse events were infrequent and similar between groups. Conclusions: In high-risk EC, adjuvant chemoradiotherapy significantly improves DFS and confers a borderline OS benefit compared with radiotherapy alone, with acceptable long-term toxicity. The magnitude of benefit appears more closely related to surgical staging quality than to histology or tumor grade, supporting combined-modality therapy in selected patients.
Multilevel disparities in HIV-associated gastrointestinal cancer mortality in the United States, 1999–2020.
e15688 Background: Although gastrointestinal (GI) cancers are more common in people living with HIV (PLWH), it is unclear how HIV-related mortality disparities differ by race, sex, age, and geography. Methods: From 1999 to 2020, we examined U.S. death certificate data from the CDC WONDER Multiple Cause of Death database. The esophagus, stomach, colon/rectum, anus, liver, and pancreas were among the GI cancers. ICD-10 codes B20–B24 were used to identify HIV. Rate ratios (RR) by race and cancer site were estimated using age-adjusted mortality rates (AAMR). Log-linear regression was used to calculate the annual percent change (APC) in mortality, stratified by race, sex, age group, and U.S. Census region. Results: HIV infection was linked to a significantly increased mortality rate from GI cancers, with substantial variation based on race. The most pronounced HIV-related excess was observed in esophageal cancer among American Indian/Alaska Native individuals (RR 1.56, 95% CI 1.17–2.07), surpassing the rate seen in White individuals (RR 1.08, 95% CI 1.05–1.10). Furthermore, Black PLWH exhibited heightened mortality rates for both esophageal (RR 1.16, 95% CI 1.08–1.24) and colorectal cancers (RR 1.08, 95% CI 1.04–1.13). Elevated mortality from liver cancer associated with HIV was evident across all racial groups.Notwithstanding these disparities, improvements were noted in several subgroups. Among Black Americans, the mortality rate from GI cancer decreased in PLWH (APC −1.97%/yr), while it increased in those without HIV (APC +2.06%/yr). This resulted in a −4.02% annual reduction in the disparity related to HIV. Analyses by sex showed a decrease in HIV-related mortality for both men (APC −1.94%/yr) and women (APC −0.88%/yr), whereas non-HIV GI cancer mortality increased in both groups. Age-specific trends revealed the most significant improvements in PLWH aged 50–59 (APC −3.12% to −2.87%/yr), while declines were slower in those aged 60–64. Regionally, the burden of HIV-associated GI cancer increased most rapidly in the U.S. South (APC +7.65%/yr), which was much greater than the non-HIV trend (+0.55%/yr). Conclusions: HIV infection is linked to significantly increased mortality from GI cancers, exhibiting notable disparities based on race, age, sex, and geographic region. Despite the observed decline in HIV-associated mortality across numerous subgroups within the contemporary antiretroviral treatment landscape, the burden is escalating rapidly in the Southern United States, and disparities persist among the American population. Indian/Alaska Native and Black populations highlight the need for targeted, region-specific HIV-oncology interventions.
Does a statin a day keep prostate cancer (PC) away?: Statin use and disease progression in patients receiving androgen deprivation therapy (ADT) after radical prostatectomy (RP) in SEARCH.
5091 Background: Prior studies suggest statin use may improve PC outcomes, including PC specific mortality (PCSM) and disease progression in patients receiving ADT. However, prior studies compared patients taking vs not taking statins at the time of ADT, ignoring that many statin non-users initiate statins later on. We evaluated the association between statin use and PC outcomes using both baseline (yes/no) and time-dependent exposure definitions in patients initiating ADT after RP. Methods: We conducted a retrospective cohort study of 9,931 patients with PC treated with RP between 1988 and 2020 at 9 VA hospitals from SEARCH Database. Patients who received ADT for biochemical recurrence after 2000 were included. Those with known metastasis prior to ADT or missing covariates of interest were excluded. Characteristics at ADT were stratified by statin use at time of ADT and compared with rank-sum for continuous variables and chi-square for categorical. Univariable and multivariable Cox models tested associations between statin use at ADT and time to metastasis, castration-resistant PC (CRPC), PCSM and all-cause mortality (ACM), adjusted for clinicopathological variables. As ~50% of non-statin users initiated statins after ADT, additional models treated statin use as time-dependent covariate. Results: Among 1,274 patients treated with ADT, 784 (62%) used statins at time of ADT. Users were older (median 67 vs 65), initiated ADT in more recent years (median 2013 vs 2010), had longer time from RP to ADT (median 39 vs 21 months), and had higher obesity rates (38% vs 25%). PC characteristics were similar between groups, except users had lower rates of positive nodes (11% vs 17%) and seminal vesicle invasion (28% vs 33%). Statin use at ADT was not significantly associated with time to metastasis, CRPC, PCSM or ACM, though HRs indicated lower risk for statin users (all HRs 0.89-0.98, all p>0.2; see table). On time-dependent multivariable analysis, statin use was significantly associated with lower risk of CRPC (p=0.019), PCSM (p=0.020) and ACM (p<0.001). Similar results were seen for metastases, though this did not reach significance (p=0.058) (see table). Conclusions: Statin use at ADT was not associated with PC outcomes after RP. However, accounting for statin initiation during ADT, statin use was associated with notably lower rates of CRPC, PCSM and ACM, with a trend towards reduced metastasis. These findings support the potential role of statins in slowing PC progression and highlight the need for prospective randomized trials of statins in patients initiating ADT. Outcome Statin at ADT, HR (95% CI) p Time-varying statin, HR (95% CI) p Metastasis 0.92 (0.71, 1.20) 0.541 0.74 (0.55, 1.01) 0.058 CRPC 0.95 (0.73, 1.24) 0.702 0.69 (0.51, 0.94) 0.019 PCSM 0.98 (0.70, 1.39) 0.920 0.62 (0.42, 0.93) 0.020 ACM 0.89 (0.73, 1.08) 0.229 0.51 (0.40, 0.64) <0.001
Surgical efficacy and complications of cytoreductive surgery with HIPEC for colorectal cancer patients with peritoneal carcinomatosis.
e15549 Background: Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal peritoneal carcinomatosis has been a contentious issue due to concerns regarding its oncologic efficacy weighed against high surgical complication rates. The present retrospective analysis aims to reappraise the clinical and surgical outcomes in these patients. Methods: Patients with pathologically confirmed colorectal adenocarcinoma and clinical peritoneal carcinomatosis who underwent cytoreductive surgery with HIPEC were retrospectively included. The exclusion criteria were: (1) repeat HIPEC procedures; and (2) an American Society of Anesthesiologists (ASA) score ≥4. Patients were stratified according to the Completeness of Cytoreduction (CC) score (CC-0, CC-1, CC-2). Major complications were defined as Clavien-Dindo grade ≥3. Surgical efficacy and complications were compared among the groups. Results: Between 2015 and 2025, a total of 142 patients were included. The median follow-up was 17.2 months (range: 0.5–111.9). The overall complication rate was 48.6%, with a major complication (Clavien-Dindo grade ≥3) rate of 21.1%. When stratified by Completeness of Cytoreduction (CC) score, median overall survival (OS) was not reached (NR) for CC-0, 18.4 months (95% CI: 10.8-77.0) for CC-1, and 7.1 months (95% CI: 1.1-69.6) for CC-2 (p = 0.0002). The 5-year OS rate for the CC-0 group was 61.5% (95% CI: 47.5–72.8%). Major complication rates differed significantly among the groups (CC-0: 12.6%, CC-1: 31.6%, CC-2: 41.2%; p = 0.0057). Further analysis was performed according to PCI thresholds: < 12, 12–24, and > 24. In the high-PCI subgroup ( > 24, n = 24), CC-0 was achieved in only 4.2% (1/24), compared to 58.3% for CC-1 and 37.5% for CC-2. In this challenging setting, the median OS for the three groups was NR, 18.8 (95% CI: 10.1-26.9), and 17.3 months (95% CI: 6.4-NA), respectively (p < 0.0001) with major complication rates of 15.4%, 26.0%, and 37.5% (p = 0.4572). The 5-year OS rate for the PCI < 12 group was 67.6% (95% CI: 54.1–77.8%). Conclusions: The present study confirms the significant clinical efficacy and acceptable complication rates for patients undergoing cytoreductive surgery with HIPEC for colorectal cancer with peritoneal carcinomatosis. We advocate that this treatment is worthy of recommendation for selected patients, even in cases with high PCI scores.
Malignant Leydig cell tumor: A population-level demographic study using the National Cancer Database.
e17010 Background: Leydig cell tumors (LCTs) are typically rare testicular neoplasms arising from androgen-producing interstitial cells and account for 1–3% of testicular tumors. Although most cases are benign, a subset malignantly transforms, and the resulting mortality increases sharply, with many patients dying within two years. Malignant LCTs respond poorly to platinum-based chemotherapy and radiation, and metastasectomy rarely achieves lasting disease control. Given the rarity of malignant LCTs, demographic and epidemiological data are limited, and population-level patterns remain poorly defined. This study used the National Cancer Database (NCDB) to further characterize demographic trends in malignant LCT. Methods: A retrospective cohort study from the NCDB identified patients with histologically confirmed malignant LCT (ICD-O-3 Code 8650) from 2004–2020 (N = 526). Demographic variables were analyzed, including age, sex, race, ethnicity, education, insurance, facility type, residential distance, tumor size, stage, treatment, education status, income, and Charlson–Deyo score. Incidence trends were evaluated using regression analysis and descriptive statistics. Results: A total of 526 cases were identified. Incidence showed moderate variability with no consistent trend (R² = 0.50). The cohort was overwhelmingly male (95%), predominantly White (74.7%), and largely non-Hispanic (87.8%), with a mean age of 47.6 years. An atypical percentage of patients lived in metropolitan counties with ≥1 million population (54.1%) and were concentrated in the highest income (≥ $74,063; 42.6%) and education quartiles ( < 5% without a high school degree; 28.5%). Treatment most commonly occurred in comprehensive community cancer programs (39.3%) or academic/research programs (38.2%), and private insurance was the primary payer for 61.6% of patients. Early mortality was rare (0.4% at 30 days; 0.6% at 90 days). Almost all patients (99.8%) received no palliative care. Surgery was the primary treatment, with 92.8% achieving negative margins; nonsurgical therapies were uncommon (radiation 2.7%, chemotherapy 3.2%, hormone therapy 1.0%, immunotherapy 0.4%). Tumors averaged 30.6 mm in size, and most were NCDB Analytic Stage I (70.7%). Mean survival was 165.4 months, with estimated two, five, and 10-year survival rates of 92.0%, 87.0%, and 79.0%. Conclusions: To our knowledge, this is the first NCDB analysis focused on malignant LCT, addressing a major gap in the epidemiologic characterization. Unlike prior reports, these cases occurred predominantly in middle-aged men in the early stages. This study provides the first nationwide description of socioeconomic patterns, demonstrating concentration in high-income, educated urban populations. Further research is needed to determine how demographic and socioeconomic factors shape diagnostic timing, treatment selection, and long-term outcomes.
Effect of dual immune checkpoint inhibitors (ICI) by the time of infusion in advanced non–small cell lung cancer (NSCLC): A secondary analysis of CCTG BR34 trial.
8566 Background: There is increasing evidence suggesting the impact of circadian biology on ICI efficacy in solid tumours, though evidence for dual checkpoint blockade is limited. We conducted a secondary analysis of BR.34 to assess whether time of infusion (TOI) correlates with outcomes with durvalumab–tremelimumab ± platinum chemotherapy in advanced EGFR/ALK-negative NSCLC. Methods: Patients were classified into the AM group when ≥80% of the PD-1 inhibitor infusions were started before 13:00 (threshold based on prior literature); otherwise, they were placed into the PM group. OS and PFS were analyzed using Cox models adjusted for imbalanced baseline factors. Sensitivity analyses were performed to assess correlations with other TOI thresholds. Results: TOI was evaluable for 296/301 patients; 186 were AM and 110 PM. PM infusion was associated with longer median OS (19.1 vs 13.4 months (m); HR 0.58, 95% CI 0.41–0.82) and median PFS (8.3 vs 4.1 m; HR 0.67, 95% CI 0.51–0.88). The improvement in OS associated with the PM group was consistent across both arms. In the multivariable analyses, PM administration remained associated with improved OS (adjusted HR (aHR) 0.62, 95% CI 0.44–0.88) and PFS (aHR 0.73, 95% CI 0.55–0.96). Sensitivity analyses using an alternative threshold of ≥60% of the PD-1 inhibitor infusions started before 1300 yielded consistent trends. Using a median TOI of 11:00 AM as an additional threshold, later infusions were also associated with longer OS (HR 0.77, 95% CI 0.56–1.05), with similar trends across both treatment arms. There was no apparent difference in fatal adverse events (n = 4), with two in the AM and two in the PM group. Serious adverse effects that led to therapy discontinuation also did not significantly differ between AM vs. PM in the IO-alone group (3 vs. 5) or the IO-chemo group (6 vs. 4). Conclusions: Afternoon infusion of dual ICI ± chemotherapy was associated with improved survival in BR.34, in contrast to earlier reports with anti-PD-1 therapy. These findings highlight the potential for regimen- and disease-specific chronotherapeutic effects and support the need for prospective trials across tumour types and of different checkpoint inhibitor combinations. References: 1. Leighl NB, et al. J Thorac Oncol. 2022;17(3):434–445. 2. Karaboué A, et al. Br J Cancer. 2024;131:783–796. Baseline factors. Baseline Factors IO-AM (n) IO-PM (n) IO-CHEMO-AM (n) IO-CHEMO-PM (n) Sex (F/M) 41/54 28/25 42/49 27/30 Age (<65/ ≥ 65) 48/47 84/64 36/55 32/25 ECOG (0/1) 22/73 23/30 26/65 20/37 Disease Stage (IVA/IVB) 26/69 22/31 34/57 19/38 Histological subtype (NSq/Sq) 77/18 44/9 73/18 48/9 Liver Metastases (N/Y) 78/17 42/11 68/23 50/7 Brain Metastases (N/Y) 76/19 45/8 82/9 44/13 PD-L1 Expression (<1/1-49/ ≥ 50%/Unknown) 37/25/20/13 23/19/7/4 33/27/16/15 22/17/13/5 TMB (<20/≥20 mut/MB) 74/21 39/14 69/22 46/11 Nsq = non-squamous, Sq = squamous.
Validation of pathology-based triage for the 21-gene recurrence score: A meta-analysis and qualitative synthesis of the Magee equations.
1591 Background: The 21-gene OncotypeDX (ODX) recurrence score (RS) is the standard for chemotherapy decision-making in HR+/HER2- early breast cancer (EBC), but cost limits accessibility in resource-constrained settings. The Magee equations (MEs) use routine pathology features (Nottingham grade and IHC; ER/PR/HER2/Ki-67) to estimate RS. We performed a meta-analysis to validate MEs performance as a triage tool for ODX testing and a qualitative synthesis to identify sources of discordance, highlighting the transition toward objective digital pathology AI models. Methods: A systematic review identified validation studies comparing MEs with RS in HR+ EBC. Studies with sufficient data to construct a 2X2 contingency table were included; neoadjuvant trials were excluded. Primary outcomes were Negative Predictive Value (NPV) for identifying low-risk cases (RS <26 for the current TAILORx cutoff and RS<31 for the historical cutoff) and ODX test sparing rate (TSR). Data were pooled using random-effects models. Qualitative themes regarding interpretation variability were extracted from study results and discussion sections. Results: Thirteen studies met the inclusion criteria, representing 5396 patients in global cohorts from the USA, Mexico, Colombia, Jordan, France, Belgium, and Canada. For RS >26, Magee <18 achieved pooled NPV of 0.96 (95% CI: 0.94-0.97) and TSR 61% (95% CI:51%-69%). For RS >31, NPV increased to 0.99 (95% CI: 0.97-1.00) and TSR 52% (95% CI: 44%-59%). Pooled diagnostic performance for Magee <18 predicting RS <26 demonstrated 83% sensitivity and 71% specificity (AUC 0.81, LR+:2.53, LR-:0.28). Qualitative analysis of discordance identified: (1) Inter-observer variability: Nottingham mitotic counts and Ki-67 scoring were the primary drivers of score fluctuations. (2) IHC quantification: Variations in H-score calculation and Allred-to-H-score conversion introduced heterogeneity (3) Pre-analytical and biological factors: Inflammation and stromal proliferation occasionally inflated genomic RS; selection of non-representative blocks and intratumor heterogeneity further contributed to discordance (4) Technological solutions: Digital pathology and AI models emerge as solutions to standardize these variables. Conclusions: Magee-based triage provides a safe and cost-effective strategy for HR+ EBC risk stratification, with NPV up to 99% for excluding high-risk disease and sparing up to 61% of ODX testing. These results confirm a robust histopathological signal. Transitioning to objective digital pathomics provides a pathway to reduce manual subjectivity and democratize precision oncology globally. Pooled diagnostic accuracy of Magee equations by cutoff. Magee score and RS cutoff Number of studies Total patients Pooled NPV (95% CI) ODX test sparing rate (95% CI) Magee <18/ RS>26 8 4153 0.96 (0.94-0.97) 61% (51%-69%) Magee <18/ RS>31 5 1243 0.99 (0.97-1.00) 52% (44%-59%)
Precision histopathologic classification of epithelial ovarian cancer subtypes using a computationally efficient multilayer perceptron framework with global validation.
5605 Background: Epithelial ovarian cancer is the leading cause of gynecologic cancer mortality, with treatment and prognosis strongly dependent on accurate histopathologic subtype classification. The five major epithelial subtypes—high-grade serous, low-grade serous, endometrioid, mucinous, and clear cell carcinoma—exhibit distinct clinical behaviors, yet conventional interpretation is limited by subjectivity and interobserver variability. Although deep learning has advanced digital pathology, most high-performing models require substantial computational resources, limiting clinical scalability. We evaluated whether a lightweight multilayer perceptron (MLP) combined with structured dimensionality reduction could enable accurate and globally deployable ovarian cancer subtyping. Methods: We analyzed 9,521 anonymized histopathology image patches representing five epithelial ovarian cancer subtypes from publicly available datasets with expert pathologist consensus ground truth. Images underwent Gaussian random projection followed by principal component analysis to preserve discriminative morphologic features. A feedforward MLP (2,048→1,024→512→5 neurons) with batch normalization and dropout (p=0.3) was trained using AdamW optimization with cosine annealing over 50 epochs on 80% of the data. External validation was performed on independent datasets. Performance metrics included accuracy, sensitivity, specificity, F1 score, and AUROC. The model was deployed on a cross-platform digital pathology system and evaluated by pathologists across six continents. Results: The MLP achieved 97.4% test accuracy with balanced subtype performance. Sensitivity ranged from 94.2% to 99.3%, with a macro-averaged F1 score of 0.993 and AUROC >0.99 for all classes. External validation accuracy ranged from 91% to 93% across heterogeneous staining protocols. Sensitivity for low-grade serous carcinoma (92.1%) exceeded reported interobserver agreement (52–73%). Inference time averaged 0.33 seconds per image on standard CPU hardware. Pathologists rated the system clinically useful in >90% of evaluations. The model contained 2.8 million parameters, representing an 89% reduction compared with conventional convolutional architectures. Conclusions: A computationally efficient MLP enables accurate and reproducible epithelial ovarian cancer subtype classification while substantially reducing computational complexity. This approach mitigates interobserver variability and supports scalable AI-assisted pathology deployment. Prospective multicenter studies are warranted to assess integration into routine diagnostic workflows and impact on treatment stratification.
Sintilimab in combination with cetuximab and chemotherapy as first-line treatment for microsatellite stable/pMMR and RAS/BRAF wild-type metastatic colorectal cancer (CALLIOPSIS): An open-label, non-comparative, phase Ib/II dose escalation and expansion trial.
e15537 Background: Immunotherapy offers limited therapeutic benefit in microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Priorstudies indicate that anti- epidermal growth factor receptor (EGFR) antibody combined with chemotherapy might enhance malignant tumor immunogenicity. This study aims to evaluate the safety and efficacy of Sintilimab, a PD-1 inhibitor, combined with Cetuximab and chemotherapy, as a first-line treatment for pMMR/MSS and RAS/BRAF wild-type mCRC. Methods: A phase Ib/II dose escalation and expansion trial was conducted. Patients received 6 cycles of Sintilimab 200mg ivgtt q3w, cetuximab and chemotherapy q2w for at least 8 cycles, followed by maintenance therapy with capecitabine ±cetuximab for those whose best response is complete response (CR), partial response (PR) or stabel disease (SD) until disease progression or intolerable toxicity. Primary endpoints included safety and objective response rate (ORR). In the dose escalation phase (3+3 design), patients received cetuximab (500 mg/m², Q2W) and investigator-chosen chemotherapy regimens (mFOLFOX6, CAPEOX), with Sintilimab tested at 100 mg, 150 mg, and 200 mg (Q3W). The recommended phase II dose was 200 mg Q3W. Results: Between December 26, 2023, and December 31, 2025, 25 eligible patients were enrolled (72.0% male, 16.0% ECOG PS 0, median age 54 years， 60 % liver metastasis, 48% peritoneal metastasis, 24% PD-L1 CPS≥5 ). In the dose escalation phase, 88.9% of patients experienced grade 3/4 treatment-related adverse events, with 55.6% requiring dose adjustments for chemotherapy-related issues. No immune-related grade 3/4 adverse events were observed. The overall ORR was 76.0%, with 68.4% for the 200 mg Sintilimab cohort. The median progression-free survival (PFS) was not reached. Surgical resection was feasible in 10 patients (40.0%, 1 planned ,9 R0 resection, including 1 ypT0N0). Treatment was well tolerated, with 72.0% of patients experiencing ≥ grade 3 adverse events, most commonly neutropenia (36.0%), rash (8.0%). Conclusions: The combination of Sintilimab with cetuximab and chemotherapy shows manageable safety and efficacy in advanced pMMR/MSS and RAS/BRAF wild-type mCRC. The overall ORR was 76.0%% and 40.0% of patients achieved surgical resectability. Further clinical data are needed to confirm these findings. Clinical trial information: NCT06776757 . Treatment outcomes and surgical conversion outcomes. Therapeutic outcome N=25(%) ORR (Objective response rate) 19(76) DCR (Disease Control Rate) 25(100) SCR (Surgical conversion rate) 8(32) Surgical outcome N=9(%) Complete resection rate R0 9(100) R1 0(0) R2 0(0) Tumor regression grade TRG1 3(34) TRG2 2(22) TRG3 3(33) TRG4 1(11)
Staging, surgery, and relapse patterns in uterine sarcomas: A single-institution cohort.
e23553 Background: Uterine sarcomas are rare gynecologic malignancies and are frequently misdiagnosed as benign uterine disease, which may lead to incomplete staging, delays, and suboptimal surgery. Methods: We performed a retrospective descriptive study of patients with uterine sarcoma discussed at a multidisciplinary tumor board (Oct/2014–Oct/2024). We analyzed tumor characteristics, diagnostic workup, surgical approach, time intervals, and treatments, and explored associations with relapse-free survival (RFS) and overall survival (OS). Survival was estimated using the Kaplan–Meier method and compared using Cox regression; categorical variables were compared using chi-square tests. Results: Thirty-one patients were included (median age 54.6±12.6 years). The most common presenting symptom was abnormal uterine bleeding (58.1%). Transvaginal ultrasound was the first imaging test in 64.5%. Abdominal staging imaging was completed in 67.7%, but only 32.3% underwent preoperative chest CT. Radiologically, 71% of lesions were interpreted as benign. Twenty-six patients underwent surgery; 26.9% had incomplete initial surgery (polypectomy, myomectomy, or morcellation), requiring reintervention. The most frequent histology was leiomyosarcoma (41.9%), followed by low-grade endometrial stromal sarcoma (19.4%), adenosarcoma (16.1%), and high-grade endometrial stromal sarcoma (12.9%). On surgical specimens, 32.3% were hormone receptor–positive and 38.7% had a high mitotic index (>10 mitoses per 10 high-power fields). Two patients received adjuvant radiotherapy. Five patients did not undergo surgery due to unresectable locally advanced disease (n=1) or metastatic disease (n=4). Among operated patients, 13 relapsed, 76.9% with oligoprogression (1–5 lesions). Relapse sites were lung (53.8%) and peritoneum (46.2%). First relapse treatment included surgery (38.5%), surgery plus chemotherapy (23.1%), chemotherapy (30.8%), and endocrine therapy (7.7%). In advanced stages, patients received a median of 2 systemic chemotherapy lines (range 0–5). High mitotic index versus low/unknown was associated with shorter RFS (median 31.3 vs 152.8 months; p=0.012), with no significant association with OS (p=0.39). No statistically significant associations with RFS or OS were observed for radiologic benign vs malignant suspicion, preoperative chest CT, tumor size, or symptom-to-surgery interval >12 months. Conclusions: In this real-world cohort, uterine sarcomas were frequently interpreted as benign on preoperative imaging and showed substantial variability in staging and initial surgical management. Standardized diagnostic pathways and increased radiologic suspicion may reduce incomplete upfront surgery and optimize multidisciplinary care.