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Trends in non-epithelial ovarian malignancies in patients younger than 51 from 2004 to 2022 in the United States.
e17554 Background: Non-epithelial ovarian cancers (NOCs) are rare but disproportionately affect younger patients (pts), where diagnosis delays can limit fertility-preserving options or result in early menopause. With increasing cancer rates in younger pts, trends in NOC case volume and stage at presentation remain poorly defined. Therefore, the objective of this study was to examine national trends of NOC in pts under 51 years of age from 2004 to 2022 in the United States. Methods: Pts diagnosed with NOC between 2004 and 2022 under the age of 51 were identified using the National Cancer Database. Demographic and clinicopathologic variables were collected. Trends in incidence were evaluated by year of diagnosis and stratified by age group, stage, and histology. Comparisons across groups were performed using Pearson Chi-Square tests with likelihood ratio Chi-Square also reported when appropriate. Temporal trends over time were assessed using linear-by-linear association. Statistical significance was defined as p<0.05. Results: Between 2004 and 2022, a total of 6,863 pts were diagnosed with NOC, including 4,078 (59.4%) germ cell tumors (GCT), 2,687 (39.2%) sex-cord stromal tumors (STC), and 98 (1.4%) ovarian sarcomas. The number of pts diagnosed with NOC increased by 72% during the study period, rising from 257 pts in 2004 to 442 pts in 2022 (p<0.001). Overall, 4,622 (67.3%) pts were diagnosed with stage I, 595 (8.7%) pts with stage II, 1,271 (18.5%) with stage III, and 375 (5.5%) stage IV. During the study period, while the number of GCT remained stable, the number of STC nearly tripled (from 86 pts diagnosed in 2004 to 243 in 2022) and the number of pts diagnosed with ovarian sarcoma substantially increased (1 in 2004 to 12 in 2022)( p<0.001). The rise in new diagnoses was driven largely by older pts, with the 35–44 age group increasing from 22.6% to 32.8% and with the 45–51 age group increasing from 15.6% to 19% between 2004 and 2022 (p<0.001). In terms of stage, pts were more likely to be diagnosed with stage IV if they were diagnosed later in our study period (4.2% vs 6.4%, p<0.001) and less likely to be diagnosed with stage I (69.1% vs 66%, p<0.001). Conclusions: In our young pt cohort, NOCs have rising national case volume, driven mainly by increasing SCSTs and a relative increase in ovarian sarcomas. The shift toward older age and more advanced stage at diagnosis suggests delayed recognition and fewer opportunities to prevent treatment-induced menopause. These trends underscore the need to streamline evaluation and referral to specialty centers, improve NOC-specific symptom recognition, and expand registries and trial networks to better address a growing burden of rare ovarian cancers in younger pts.
Trends and disparities in lung cancer and renal failure–related mortality in the United States, 1999-2023.
e23372 Background: Lung cancer is the leading cause of oncological mortality in the U.S, a burden frequently increased by co-occurring renal failure, which impairs systemic drug metabolism and significantly elevates the risk of treatment-related complications. This study aims to analyze and interpret annual mortality trends and disparities among adults in the United States from 1999 to 2023, for various demographic and geographic factors. Methods: The mortality data from the CDC WONDER multiple cause of death files for adults aged ≥25 years were used to analyze age-adjusted and crude mortality rates (AAMRs and CMRs) per 1,000,000 through ICD 10 code: C34 (lung cancer) and ICD 10 code: N17-N19 (renal failure), stratified by year, gender, race/ethnicity, place of death and geography. Joinpoint regression was used to estimate average annual percent change (AAPC) and annual percent change (APC) with 95% confidence intervals (CIs). Statistical significance was defined as p < 0.05. Results: From 1999 to 2023, a total of 93,566 deaths were reported where lung cancer and renal failure co-occurred, most occurring among medical facility inpatient settings. The overall AAMR increased from 14.21 in 1999 to 18.67 in 2023 (AAPC: 0.93; 95% CI: -0.44 to 2.33; p = 0.18). An initial decline in AAMR was observed between 2011 and 2017 (APC: -6.61; p = 0.004), followed by a notable increase through 2023 (APC: 6.71; p < 0.001). The overall annual rise in mortality was significant among women (AAPC: 2.43; p < 0.001), although AAMR was higher in men than women (24.74 vs 11.07). Adults aged 65 and above experienced the highest CMR (69.52). By race, non-Hispanic (NH) Blacks had the highest AAMR (28.28), while NH Asians had the lowest (11.41). Geographic disparities were evident, with the Midwest having the greatest AAMR (18.38) and the West having the least (14.97). Non-metropolitan areas had a higher AAMR than metropolitan areas (18.63 vs 15.91), along with a steeper rise in mortality (AAPC: 0.52 vs -0.49). At the state level, Kentucky and Indiana ranked highest, both falling within the top 90th percentile during 1999–2020 and 2021–2023, respectively. Conclusions: Mortality related to lung cancer and co-occurring renal failure has increased over the past two decades, with disproportionate burden among older adults, men, NH Black individuals, those residing in non-metropolitan areas, and the Midwest region. This underscores the need for targeted prevention, early detection, and provision of equitable healthcare. Average annual percent change (AAPC) of Lung Cancer and Renal Failure related age-adjusted mortality rates in the United States, 1999 to 2023. Variable Deaths AAPC (95%CI) Overall 93,566 0.93 (-0.44 to 2.33) Male 58,332 -0.34 (-2.73 to 2.11) Female 35,234 2.43 (0.95 to 3.93) Non-metropolitan areas 15,768 0.52 (-2.05 to 3.16) Metropolitan areas 62,525 -0.49 (-2.70 to 1.76)
Early intravenous immunoglobulin use in multiple myeloma patients treated with talquetamab: Effect on risk of infections and mortality.
7573 Background: Bispecific T-cell–engaging (BiTE) antibodies have transformed the treatment of relapsed or refractory multiple myeloma (MM) but are associated with high rates of infectious complications. Talquetamab, a GPRC5D-directed BiTE, induces immune dysfunction but has been shown to be associated with less infection risk than anti-BCMA BiTEs. Although there is evidence supporting prophylactic intravenous immunoglobulin (IVIG) use for pts receiving anti-BCMA BiTEs, there is limited data assessing the benefit of early IVIG use in patients treated with talquetamab. Methods: A retrospective multicenter cohort study using the TriNetX Research Network to evaluate outcomes among adults with MM treated with talquetamab. Patients who received IVIG within 4 weeks of talquetamab initiation were compared to those who did not receive IVIG within 4 weeks. Propensity score matching was performed which included comorbidities, demographics, prior therapies (PIs, ImIDs, anti-CD38 abs, other BiTEs, belantamab, SCTx and CAR T), lab markers of disease severity, IgG levels, EM disease and plasma cell leukemia. Primary outcomes were 1-year all-cause mortality and infection incidence. Secondary outcomes included infection subtypes and ICU admission. Multivariable Cox proportional hazards models were used to identify independent associations. Results: Among 834 pts treated with talquetamab, 305 received IVIG within 4 wks of initiation. After propensity score matching, 271 patients remained in each cohort with balanced baseline characteristics. Early IVIG use was associated with lower 1-year mortality (14.8% vs. 26.7%; OR, 0.48; 95% CI, 0.31–0.74) and fewer infections of any type (41.7% vs. 55.0%; OR, 0.59; 95% CI, 0.42–0.82). Reductions were most pronounced for respiratory and bloodstream infections. In multivariable analysis, early IVIG remained independently associated with lower hazard of mortality (HR, 0.52; 95% CI, 0.37–0.73). In addition, a sub-analysis comparing early IVIG with no IVIG exposure within 1 year found similar findings. Conclusions: Early IVIG administration following talquetamab initiation was associated with reduced infection risk and improved survival in a large real-world cohort. These findings support consideration of early IVIG as part of routine supportive care for patients receiving talquetamab. Outcome (after propensity matching) IVIG within 4 weeks (n=271) No IVIG within 4 weeks (n=271) OR 95% CI P-value 1-year mortality 40 (14.8) 72 (26.7) 0.48 0.31–0.74 0.0008 Any infection 113 (41.7) 149 (55.0) 0.59 0.42–0.82 0.002 Respiratory infections 37 (13.6) 55 (20.3) 0.62 0.39–0.98 0.04 Bloodstream infections 39 (14.4) 61 (22.5) 0.58 0.37–0.90 0.016 Opportunistic infections 13 (4.8) 10 (3.6) 1.31 0.57–3.05 >0.2 Skin & Soft Tissue infections 12 (4.4) 10 (3.6) 1.21 0.51–2.85 >0.2 Urinary tract infections 12 (4.4) 13 (4.8) 0.92 0.41–2.05 >0.2
Identification of checkpoint inhibitor resistance mechanisms in leiomyosarcoma through enrichment of active chromatin-associated cell-free DNA.
11545 Background: Leiomyosarcoma (LMS) is a sarcoma subtype with poor metastatic outcomes and limited treatment options. Checkpoint inhibitors (CPI) combination therapy may benefit LMS patients (pts). We previously showed (Lopes, ASCO 2025) that a liquid biopsy assay enriching for active chromatin–associated cell-free DNA (cfDNAac) identified biomarkers predicting clinical benefit in LMS pts treated with durvalumab plus olaparib or cediranib (NCT03851614). Here, we report longitudinal cfDNAac findings at baseline and progression. Methods: Plasma samples at baseline (n=30) and disease progression (n=22) were analyzed using a cfDNAac capture platform. Univariate analysis and recursive feature elimination identified genomic features associated with clinical benefit rate (CBR; complete response/partial response or stable disease >6 months). Molecular transcriptomic profiles, pathway enrichment, and copy number variation (CNV) were analyzed and correlated with CBR and progression-free survival (PFS). Linear mixed-effects models assessed temporal differences in cfDNAac-derived biomarkers between CBR and non-CBR groups. Results: A total of 1,570 baseline cfDNAac features distinguished pts who achieved CBR from those who did not (n=8 vs 22, p < 0.01). Pts with CBR exhibited enrichment of immune-related signatures (i.e., B and T-cell activation, lymphocyte differentiation, and a decrement of extracellular matrix organization [ECM]), all of which were individually significantly associated with longer PFS (p < 0.05). Upon progression, B-cell and T-cell activation significantly decreased, whereas ECM-related signatures increased in CBR compared to non-CBR group, the latter of which remained stable. A higher baseline tumor fraction (>5%) was also associated with reduced CBR (p < 0.05) and shorter PFS (HR = 3.33; CI: 1.32-8.40 p < 0.01). Recurrent CNV losses on chromosome 15 correlated with improved PFS (HR = 2.48; 95% CI: 0.99-6.22; p = 0.052) and CBR (p = 0.0073). At progression, these CNV reverted in CBR pts but remained stable in non-CBR patients. Conclusions: This active chromatin-associated cell-free DNA profiling enables a non-invasive monitoring of dynamic tumor microenvironment remodeling over time and provides insights into emerging mechanisms of resistance to CPI in LMS pts.
Technical performance of online adaptive radiotherapy in managing inter-fractional anatomical deformation during moderately hypofractionated prostate cancer treatment.
e23158 Background: Inter-fractional variability of pelvic organ anatomy introduces non-linear geometric uncertainty that challenges the reliability of conventional margin-based radiotherapy planning. Online adaptive radiotherapy (oART) enables real-time plan modification to address such variability. This study evaluates the operational robustness and geometric dose-stabilization capability of an artificial intelligence–driven oART workflow under routine clinical care conditions. Methods: A retrospective fraction-level analysis was performed on 185 treatment fractions from 9 patients with prostate cancer treated using moderately hypofractionated oART (60–68 Gy). Rectal and bladder anatomical variation was quantified for each fraction using absolute volumetric deviation (cc) relative to reference planning geometry. Fractions were categorized by deformation severity as minor ( < 10 cc), moderate (10–30 cc), or major ( > 30 cc). Workflow performance and dose-control reliability were evaluated using D15%, defined as the dose received by 15% of the organ-at-risk (OAR) volume, extracted from dose–volume histograms for each fraction. Fraction-level dosimetric impact was assessed by comparing adapted plans with corresponding non-adaptive scheduled plans (ΔD15% = Adapted − Scheduled). Results: The oART workflow demonstrated 100% mechanical and delivery reliability across all 185 fractions. Moderate-to-major anatomical deformation (≥10 cc) was observed in 118 fractions (63.8%), including 53 fractions (28.6%) with major deformation ( > 30 cc). Mean rectal and bladder volume changes were 12.8 cc and approximately 75 cc, respectively. Despite substantial anatomical variability, oART stabilized high-dose organ exposure. Median ΔD15% was −1.0 cGy for rectum and approximately +5 cGy for bladder across all fractions. Increasing deformation magnitude did not result in proportional dose escalation, indicating effective truncation of extreme organ-at-risk dose excursions that would otherwise reach up to ~70 cGy per fraction in non-adaptive scenarios. Conclusions: In the presence of frequent and clinically significant inter-fractional pelvic anatomical deformation, artificial intelligence–driven online adaptive radiotherapy demonstrated robust workflow reliability and effective geometric dose stabilization. These findings support oART as a reliable care-delivery strategy providing non-linear geometric dose control beyond conventional margin-based planning in moderately hypofractionated prostate radiotherapy.
Real-world overall survival with platinum–pemetrexed chemotherapy versus ipilimumab–nivolumab in peritoneal mesothelioma: A propensity-matched multicenter analysis.
e23442 Background: Peritoneal mesothelioma is a rare malignancy with limited data guiding optimal first-line systemic therapy. Platinum–pemetrexed has historically been the standard regimen. Dual immune checkpoint inhibition with ipilimumab plus nivolumab is now guideline-recommended, largely based on pleural mesothelioma data. Comparative real-world effectiveness data in peritoneal mesothelioma are limited. We compared outcomes between these two first-line strategies. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, identifying adults with peritoneal mesothelioma who received first-line platinum–pemetrexed or ipilimumab plus nivolumab. The index date was treatment initiation. Baseline characteristics were assessed. One-to-one propensity score matching was performed using demographics and major comorbidities. Overall survival (OS) was evaluated using Kaplan–Meier methods with log-rank testing over the full follow-up period and at fixed time points (6 months, 1 year, and 3 years). Results: Before matching, 389 patients received platinum–pemetrexed and 108 received ipilimumab–nivolumab. The immunotherapy cohort had a higher burden of comorbidities, including heart failure and chronic kidney disease. After matching, 88 patients per cohort were included with balanced baseline characteristics. No significant difference in OS was observed. Death occurred in 48/88 (54.5%) in the chemotherapy cohort and 42/88 (47.7%) in the immunotherapy cohort (risk ratio 1.14, 95% CI 0.86–1.53; log-rank p = 0.36). Median OS was 609 days with chemotherapy and 426 days with immunotherapy. Survival probabilities at the end of follow-up were 28.4% and 17.6%, respectively. At 6 months, OS was 72.6% with chemotherapy and 66.3% with immunotherapy (p = 0.42). At 1 year, OS was 54.4% versus 56.5% (p = 0.94). At 3 years, OS was 34.4% versus 37.7% (p = 0.94). No time point demonstrated a statistically significant survival difference between the two cohorts. Conclusions: In this real-world multicenter analysis, ipilimumab plus nivolumab did not demonstrate a significant overall survival advantage compared with platinum–pemetrexed after propensity score matching. Outcomes were comparable across early and long-term time points. Prospective, peritoneal mesothelioma–specific trials are needed to define optimal first-line therapy. Overall survival comparison after propensity score matching. Time Point Chemotherapy OS (%) ICI OS (%) Risk ratio (95% CI) Log-rank p 6 months 72.6 66.3 0.89 (0.55-1.42) 0.42 1 year 54.4 56.5 1.16 (0.80-1.69) 0.94 3 years 34.4 37.7 1.26 (0.93-1.71) 0.94 Overall follow-up 28.4 17.6 1.14 (0.86- 1.53) 0.36
Randomized, double-blind phase 3 trial of the fixed-dose combination fosrolapitant/palonosetron (HR20013) plus dexamethasone for prevention of nausea and vomiting in patients receiving moderately emetogenic chemotherapy.
11006 Background: Despite antiemetic guidelines, ~50% of patients (pts) receiving moderately emetogenic chemotherapy (MEC) still experience chemotherapy-induced nausea and vomiting (CINV), mainly in the delayed phase (DP, 24-120 h). HR20013 is a fixed-dose IV formulation providing dual NK1 and 5-HT3 receptor blockade in a single dose and showed efficacy in preventing CINV following highly emetogenic chemotherapy in the phase 3 PROFIT trial (Zhou et al., JCO 2025). This study is the first pivotal phase 3 trial to evaluate the efficacy and safety of single-dose HR20013 plus dexamethasone (DEX) in the MEC setting. Methods: In this multicenter, randomized, double-blind, active-controlled phase 3 trial, chemotherapy-naïve adults with solid tumors scheduled for single-day MEC were randomized (1:1) to receive single-dose HR20013 (fosrolapitant 218 mg + palonosetron [PALO] 0.25 mg IV) or placebo + PALO prior to chemotherapy on D1. All pts also received oral DEX 7.5 mg on D1. Primary endpoint was complete response (CR; no emesis, no rescue therapy) in the DP (24–120 h). Key secondary endpoint was CR in the overall phase (OP; 0–120 h). Results: Of 706 randomized pts, the ITT population included 348 in the HR20013+DEX group and 352 in the PALO+DEX group. Baseline characteristics were well balanced. HR20013 showed statistically superior and clinically meaningful efficacy vs active control. CR rate in the DP was 79.0% (95% CI 74.4–83.2) with HR20013+DEX vs 61.4% (95% CI 56.1–66.5) with PALO+DEX (difference 17.8%, 95% CI 11.1–24.4; P < 0.0001). CR rate in the OP was 75.6% (95% CI 70.7–80.0) vs 59.9% (95% CI 54.6–65.1) (difference 15.7%, 95% CI 9.0–22.5; P < 0.0001). HR20013 also showed improved CR rate in acute phase (0-24 h; 92.5% vs 86.1%; P = 0.0052) and consistently showed higher rates across efficacy assessments including no significant nausea, complete protection, and total control in all phases. Time to treatment failure analysis favored HR20013 (HR 0.52, 95% CI 0.40–0.69). Functional Living Index-Emesis indicated that a greater proportion of pts receiving HR20013+DEX reported no impact on daily life in the DP (e.g., 90.2% vs 75.9% in the vomiting domain). The incidence of TRAEs were similar between groups (25.1% for HR20013 vs 21.4% for PALO). Most common TRAEs with HR20013 were constipation (8.9%), hypertriglyceridemia (4.0%), and hiccups (3.5%). Grade ≥3 TRAEs were infrequent (1.2% vs 1.4%). No new safety signals were identified. Conclusions: In pts receiving MEC, a single dose of fixed-dose combination HR20013 plus DEX was well tolerated and demonstrated superior efficacy in preventing CINV compared to the standard regimen of PALO+DEX, with improved patient-reported outcomes. This single-dose, dual-pathway antiemetic offers a more effective and convenient prophylactic option for MEC. Clinical trial information: NCT06554184 .
Germline <i>RET</i> variants in medullary thyroid carcinoma: A single-center experience from 2019 to 2025.
e18051 Background: Medullary thyroid carcinoma (MTC) accounts for approximately 1–2% of all thyroid cancers and is hereditary in up to 25% of cases, most commonly due to germline mutations in the RET proto-oncogene. Systematic genetic testing is recommended for all patients diagnosed with MTC to identify hereditary forms and guide familial screening. We report our institutional experience with germline RET testing in patients with MTC over a six-year period. Methods: Between 2019 and 2025, a total of 28 patients diagnosed with MTC were referred for germline genetic testing. The cohort included 22 women and 6 men, with a median age at diagnosis of 40 years. Germline analysis of the RET gene was performed using Sanger sequencing, covering exons 10, 11, 13, 15 and 16. Clinical, pathological, and genetic data were retrospectively reviewed. Results: Pathogenic or likely pathogenic germline RET mutations were identified in 6 of 28 patients (21.4%), including 3 women and 3 men. Notably, all detected mutations were located in exon 11 of the RET gene. Among mutation carriers, 19 had clinical features suggestive of hereditary disease, including [pheochromocytoma / hyperparathyroidism / family history / bilateral disease?], while 9 cases appeared sporadic at presentation. Conclusions: In this single-center cohort, approximately one-fifth of patients with medullary thyroid carcinoma harbored a germline RET mutation, consistent with reported international data. The exclusive involvement of exon 11 in mutation-positive cases highlights its critical role in hereditary MTC and supports systematic germline RET testing in all patients, regardless of clinical presentation. Early identification of mutation carriers enables appropriate familial counseling, targeted surveillance, and personalized management.
EMITT-1: Clinical and pharmacodynamic activity with the oral ERAP1 inhibitor GRWD5769 and cemiplimab in 6 completed phase 1b expansion cohorts in solid tumors with anti–PD-1 resistance or MSS-CRC.
2500 Background: Resistance to anti-PD-1 therapy remains a major unmet need. GRWD5769 is a first-in-class oral Endoplasmic Reticulum Amino Peptidase 1 inhibitor (ERAP1i) that modulates tumor antigen presentation on MHC-I. Dosing GRWD5769 Q3W on/off generates 2 alternating antigen repertoires (AgR) that could both broaden T cell responses and avoid T cell exhaustion from chronic tumor antigen exposure. We report clinical and translational results from 6 completed stage 1 expansion cohorts of combination GRWD5769 with cemiplimab in patients (pts) with secondary resistance to anti-PD1 and in MSS-CRC (NCT06923761). Methods: Pts with NSCLC, Urothelial (UC), HCC, Cervical & SCCHN with secondary resistance to ≥3 month 1 st line aPD-1 or MSS-CRC without liver mets received 400 mg BD GRWD5769 and cemiplimab. ORR, Durable Clinical Benefit (DCB; defined as CR, PR or SD lasting ≥6 months) and PFS were assessed. T cell repertoire and immune phenotype changes were evaluated longitudinally. Results: All 6 cohorts are fully recruited (n= 81) with median follow up of 6.0 months at this interim analysis. Durable responses were observed in all cohorts (Table 1) with ORR 10-33%; DCB 26-57%. Median PFS ranged from 1.9-7.5 months across evaluable cohorts. Therapy was well tolerated with no observed safety signals. imARs were reported in 12 pts, with only 1 ≥Gr3 event (immune hepatitis) which required drug discontinuation. ≥Gr3 TRAEs occurred in 3% of pts. TCR repertoire diversity increased substantially in pts who achieved clinical benefit, driven by expansion of low-frequency, putative de novo TCR clonotypes. Responders exhibited cyclical Vß gene-usage dynamics indicative of broad T cell clonal expansion and contraction, consistent with AgR shifts resulting from ERAP1i. Dynamic activation of T cell associated genes further supported antigen-driven T-cell remodelling. Conclusions: GRWD5769 with cemiplimab demonstrated broad, durable activity across all 6 phase 1b expansion cohorts in pts with ≥2 prior lines of therapy and secondary anti-PD-1 resistance, or MSS-CRC. Translational analyses suggest that GRWD5769 exerts a dual mechanism of action, both reprogramming antigen-experienced T cells and inducing de novo T cell responses, in keeping with its potential to address both primary and secondary resistance to anti-PD-1 therapy. Based on the efficacy and tolerability of the combination, stage 2 cohort expansions are now ongoing, to inform a randomized Phase 2 study. Clinical trial information: NCT06923761 . Summary of expansion cohort efficacy by iRECIST. Dosed n Evaluable* n ORR%confirmed ORR%unconfirmed DCB % PFS m NSCLC 14 14 14 21 54 7.5 UC 14 12 25 33 44 2.1 HCC 15 14 14 14 32 3.9 MSS-CRC 12 7 29 29 57 2.1 SCCHN 11 7 14 14 26 3.7 Cervix 15 10 10 10 - 1.9 Data snapshot Jan 26, update for presentation. *≥1 scan or PD or death before 1st scan.
Outcomes of systemic therapy followed by surgery for synchronous liver metastases from pancreatic cancer: A multicenter retrospective cohort study.
e16365 Background: The role of surgical intervention in pancreatic ductal adenocarcinoma with synchronous liver metastases (sPDACLM) remains controversial. While systemic therapy is the mainstay, select patients demonstrating significant response may benefit from surgery. This study aimed to identify optimal criteria for selecting patients with sPDACLM for conversion surgery. Methods: This multicenter, retrospective cohort study analyzed patients with sPDACLM from seven Chinese centers (2017-2025). Key inclusion criteria were age ≥18, ECOG 0-1, biopsy-proven PDAC with liver metastases, and completion of ≥4 cycles of first-line systemic therapy. Patients were stratified by primary tumor resectability into an "Intention-to-Conversion Surgery (ITCS)" group (resectable/borderline resectable primary tumor) and a "Maintenance Therapy" group (unresectable primary tumor). Treatment response was assessed radiographically (RECIST 1.1 Partial Response [PR]) and biochemically (CA19-9 decline > 85% or normalization); patients meeting both criteria were classified as "Dual Responder." The primary endpoint was overall survival (OS). Results: Of 175 eligible patients, 135 were in the ITCS group and 40 in the maintenance therapy group. The median OS for the entire cohort was 13 months. The ITCS group had significantly longer median OS than the maintenance therapy group (14.0 vs. 11.4 months, P = 0.015). Multivariate analysis confirmed biochemical response, radiographic response, and baseline neutrophil-to-lymphocyte ratio (NLR) as independent prognostic factors for OS. "Dual responder" (n = 46/175, 26.3%) had a significantly superior median OS of 23.0 months compared to 11.0 months in non-responders (P < 0.001). Within the ITCS group (n = 135), "Dual responder" (n = 46, 34.1%) achieved a median OS of 24.8 months versus 11.0 months in non-responders (P < 0.001). Among these 46 "Dual responder," those who underwent surgery (n = 22) had a significantly longer median OS than those who did not (31.9 vs. 18.0 months, P = 0.05), with a 5-year survival rate of 19%. In contrast, for patients not meeting the dual criteria (n = 89), surgery did not confer a significant long-term OS benefit despite potential short-term improvement. Conclusions: The "Dual response" criteria—combining radiographic partial response (RECIST 1.1 PR) and a major biochemical response (CA19-9 decline > 85% or normalization)—effectively identifies a subgroup of patients with sPDACLM who may derive significant survival benefit from conversion surgery. Surgical intervention is not recommended for patients who fail to meet these dual criteria. These findings provide a practical framework for patient selection in the multimodal management of pancreatic ductal adenocarcinoma with synchronous liver metastases.
Distribution of BRAF functional classes across select tumor lineages with implications in current targeted therapy paradigms.
e15176 Background: BRAF -driven oncogenesis is biologically heterogeneous, and the clinical relevance of non-V600E BRAF alterations remains incompletely integrated into routine practice. Methods: Comprehensive genomic profiling was performed on 8,337 solid tumor samples using a NGS assay capable of detecting BRAF single-nucleotide variants, indels, and gene fusions. Among BRAF -mutant tumors, alterations were classified by functional class and distributions of V600E versus non-V600E alterations were compared across tumor lineages using Fisher’s exact test. Results: Among 266 BRAF -mutant tumors (3.2%), Class I alterations accounted for 66.5%, driven predominantly by V600E (59.8%). Notably, 40.2% of BRAF -mutant tumors harbored non-V600E alterations that fall outside current V600E-directed therapeutic paradigms, including non-V600E codon 600 variants (6.8%), Class II mutations and fusions (24.8%), and Class III variants (9.0%). Among Class II alterations, recurrent events included K601E/N (28.8%) and G469A/V/E (24.2%), along with diverse BRAF fusions (31.8%). Marked tumor-type–specific differences were observed. Tumors with high BRAF prevalence -melanoma (24.2%), thyroid (21.3%), colorectal (7.5%), CNS (5.8%), and lung (3.0%)- were predominantly V600E-driven (60–92%). In contrast, tumors with low BRAF prevalence, including pancreatic (2.8%), gastric (2.2%), uterine (1%), breast (0.4%) and ovary (0.2%) were enriched for non-V600 BRAF biology. In pancreatic cancer, 78% of BRAF -positive tumors harbored Class II alterations, while gastric cancers showed predominantly non-V600 alterations (60% Class II, 40% Class III). Grouped lineage analysis confirmed significant enrichment of non-V600E alterations in pancreatic, gastric, uterine, breast, and ovarian cancers compared with melanoma, thyroid, colorectal, CNS, and lung cancers (OR ≈ 18.1; Fisher’s exact p < 0.0001). Conclusions: BRAF functional class distribution is strongly tumor-type dependent. While tumors with high BRAF prevalence are largely V600E-driven, tumors enriched for non-V600 BRAF alterations occur less frequently overall but represent a disproportionate unmet clinical need, supporting lineage-informed therapeutic development and trials targeting non-V600E BRAF biology. Distribution of BRAF alteration classes across most represented tumor types in the cohort (distributions among BRAF -mutant tumors). Tumor Type Overall N BRAF mutant (%) Overall Class I (%) V600E (%) Non-V600E Codon 600 (%) Class II (Non-Fusion) (%) Class II Fusion (%) Class III (%) Lung 2117 3 70 60 10 19 8 3 Breast 1136 0.4 20 20 0 40 40 0 Colorectal 965 8 81 81 0 11 1 7 Ovary 498 0.2 0 0 0 0 0 100 Head & Neck 366 1 25 25 0 0 25 50 Sarcoma 359 1 50 50 0 0 50 0 Pancreas 318 3 11 11 0 78 0 11 CUP 282 10 75 46 29 11 4 11 CNS 257 6 67 67 0 7 27 0 Gastric 231 2 20 20 0 60 0 40 Biliary Tract 107 4 0 0 0 50 25 25
Transcriptomic profiling to identify cancer–immune meta-programs in penile squamous cell carcinoma.
e17035 Background: Penile squamous cell carcinoma (PSCC) is a rare malignancy with substantial heterogeneity in tumor-intrinsic biology & the immune microenvironment. While genomic studies have identified recurrent alterations, how cancer & immune programs jointly shape PSCC ecosystems & outcomes remain poorly defined. Methods: We profiled 67 PSCC tumors using the nCounter PanCancer Immune Profiling Panel, interrogating cancer-relevant genes & curated immune-response pathways. The cohort included 29 HPV-positive tumors (43.3%) & was balanced across stage (33 stage I–II; 34 stage III–IV). Highly variable genes (HVGs) were identified, followed by unsupervised clustering, pathway-based analyses using 61 curated canonical gene sets, & survival analyses for recurrence-free survival (RFS) & overall survival (OS). To model joint cancer–immune ecosystems, non-negative matrix factorization (NMF) was applied to derive cancer–immune meta-programs with program-level signals interpreted using independent single-cell RNA sequencing data. Results: HVG analysis revealed transcriptional variability spanning inflammatory & myeloid-associated genes, interferon & antigen-presentation genes, tumor-intrinsic epithelial & cancer-testis antigens. Unsupervised expression-based clustering identified four major transcriptional clusters that were not strongly associated with any clinical covariates. Pathway-level analyses demonstrated distinct transcriptional programs associated with stage, HPV status and smoking history. Survival analyses identified Th17 signaling & canonical PI3K signaling associated with RFS in univariable analyses, canonical PI3K signaling & cytotoxic cell signatures remaining associated with RFS in multivariable models. NMF resolved this heterogeneous landscape into three orthogonal cancer–immune meta-programs that captured coordinated transcriptional structure across tumors. Program 1 was enriched for interferon-α & complement pathways, Program 2 for interferon-γ signaling, & Program 3 for E2F targets & epithelial–mesenchymal transition. These meta-programs showed clear prognostic stratification with Program 2 associated with favorable RFS and OS, whereas Program 3 associated with adverse outcomes. Integration with single-cell PSCC data demonstrated preferential enrichment of Program 1 in myeloid compartments, Program 2 across B cells, myeloid cells, and subsets of T cells, & Program 3 predominantly within epithelial, fibroblast, and endothelial compartments. Conclusions: Transcriptomic analysis in PSCC identifies coordinated cancer–immune meta-programs that define biologically distinct tumor ecosystems & stratify clinical outcomes beyond conventional clinical features supporting a promising framework for understanding penile cancer molecular heterogeneity, motivating ecosystem-informed biomarker & therapeutic strategies.
Behavioral predictors of pain control among adult cancer survivors: Examining the impact of smoking, physical activity, and alcohol consumption.
12048 Background: Cancer-related pain remains a prevalent and debilitating symptom among adult cancer survivors, substantially impairing quality of life. While pharmacologic therapies are central to pain management, growing evidence suggests that modifiable lifestyle behaviors may influence pain outcomes. This study examined the association between smoking status, alcohol consumption, physical activity, and pain control among adult cancer survivors in the United States. Methods: We conducted a cross-sectional analysis using data from the 2022 Behavioral Risk Factor Surveillance System (BRFSS), a nationally representative survey of U.S. adults. The study population included adults aged ≥18 years with a history of cancer who reported physical pain attributable to cancer or its treatment. The primary outcome was self-reported pain control (controlled vs uncontrolled). Primary predictors included smoking status (current, former, never), heavy alcohol consumption (men >14 drinks/week; women >7 drinks/week), and physical activity in the past 30 days outside of regular employment. Multivariable logistic regression models were used to estimate odds ratios (ORs) with adjustment for age, sex, race/ethnicity, educational attainment, and household income. Sampling weights were applied to account for the complex survey design. Results: A total of 1,380 cancer survivors with cancer-associated pain were included. Most participants were aged ≥60 years (62.4%), female (63%), and non-Hispanic White (78.9%). Overall, 76% reported controlled pain, while 24% reported uncontrolled pain. Compared to current smokers, participants who had never smoked had significantly lower odds of having uncontrolled pain (OR=0.45; 95% CI 0.25 – 0.81, p=0.001). Former smokers had a 41% lower odds of having uncontrolled pain than current smokers (OR=0.59; 95% CI 0.33 – 0.94, p=0.04). Heavy alcohol consumption was not significantly associated with pain control (OR=1.03, 95% CI 0.48 – 2.21, p=0.94). Physical inactivity was significantly associated with poorer pain outcomes; participants who were inactive in the past 30 days had 72% higher odds of uncontrolled pain compared with those who engaged in physical activity (OR=1.72, 95% CI 1.11 – 2.67, p=0.01). Conclusions: Smoking and physical inactivity are significantly associated with poor pain control among adult cancer survivors. Incorporating smoking cessation and exercise promotion into survivorship care plans may enhance pain management and overall quality of life among cancer survivors.
ASP2998, a trophoblast cell-surface antigen 2 (TROP2)–targeted immunostimulatory antibody-drug conjugate with dual payloads, in patients with locally advanced unresectable or metastatic solid tumors: A phase 1b/2 study.
TPS2665 Background: TROP2 is a type I transmembrane glycoprotein involved in cell proliferation, migration, and survival, that is upregulated in and is associated with poor prognosis in patients (pts) with several malignancies including urothelial carcinoma, non-small cell lung cancer, gastric cancer and breast cancer. TROP2 antibody drug conjugates (ADCs) have demonstrated clinical efficacy and are approved for metastatic breast cancer and epidermal growth factor receptor-mutated non-small cell lung cancer. ASP2998 is a dual-payload (topoisomerase I inhibitor plus stimulator of interferon genes [STING] agonist) immunostimulatory ADC targeting TROP2. ASP2998 monotherapy has shown preclinical antitumor activity in a syngeneic mouse model bearing human TROP2-expressing tumors that was superior to single-payload topoisomerase I inhibitor TROP2 ADCs. Methods: This first-in-human, multicenter, open-label, phase 1b/2 dose escalation (DESC) and expansion (DEXP) study, is evaluating the safety, tolerability, recommended phase 2 dose (RP2D) and/or maximum tolerated dose (MTD), preliminary antitumor activity, and pharmacokinetic profile of ASP2998 in pts with locally advanced unresectable or metastatic solid tumors. Initial DESC of ASP2998 includes 6 dose levels (n≥3 per dose level) to determine the RP2D and/or MTD. Eligible pts (aged ≥18 years) include those with urothelial carcinoma, non-small cell lung cancer, gastric/gastroesophageal junction cancer, or locally confirmed human epidermal growth factor receptor 2-negative breast cancer, who have progressed on, are ineligible for, or have refused all available standard therapies per investigator’s decision. At DEXP, multiple dose levels of ASP2998 may be evaluated based on the totality of data to optimize dosage in at least one tumor type (n≤40 per dose level per tumor type). Eligible DEXP pts with non-small cell lung include those who have received ≤3 prior lines of therapy and known programmed death-ligand 1 status, without actionable oncogenic alterations, who have progressed on or after platinum-based chemotherapy and/or checkpoint inhibitors. Eligible DEXP pts with urothelial carcinoma include those who have received ≤3 prior lines of therapy and progressed on or after enfortumab vedotin plus pembrolizumab. Prior exposure to TROP2, STING agonists or topoisomerase I inhibitor-directed therapy is permitted at DESC but not DEXP. Tumor-specific backfill pts can be enrolled in the DESC cohorts at dose levels that are deemed safe and tolerable, and will be counted towards the corresponding tumor-specific DEXP cohorts. Recruitment is ongoing with 196 planned pts (36 in DESC; 160 in DEXP). ClinicalTrials.Gov Identifier: NCT07287995. Clinical trial information: NCT07287995 .
Organ-specific progression and AI-based prognostic modeling in metastatic NSCLC treated with chemo-immunotherapy.
e20585 Background: Organ-specific progression patterns and survival outcomes in metastatic non–small cell lung cancer (NSCLC) treated with chemo-immunotherapy are not well defined, and prognostic tools capable of predicting disease trajectories remain limited. This study evaluated organ-specific metastatic behavior, associated clinical outcomes, and machine-learning–based prognostic models in patients with advanced NSCLC. Methods: We retrospectively analyzed stage IV NSCLC patients without targetable mutations who received systemic chemo-immunotherapy at MD Anderson Cancer Center (2009–2025). Clinical and demographic variables, baseline metastatic sites, and first sites of progression were collected. Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan–Meier analyses. LASSO-Cox regression identified independent prognostic factors. Twelve machine-learning models were trained to predict disease progression and mortality, and model performance was evaluated using ROC curves, calibration, and SHAP-based feature interpretation. Results: Among 7,049 patients screened, 4,332 eligible stage IV patients were included. Progression most commonly occurred at the primary tumor (60.8%), lung (25.4%), bone (29.9%), brain (16.1%), liver (14.5%), and adrenal glands (12.7%). Liver progression was associated with the poorest outcomes (median PFS 5.07 months; median OS 11.80 months; P < 0.001). Patients with liver or bone progression experienced significantly shorter survival than those without involvement. Independent predictors of shorter PFS included ≥2 prior therapy lines, non-targetable EGFR mutations, adenocarcinoma, and baseline pleural metastasis. Poor OS was associated with baseline bone or liver metastasis, M3 stage, adenocarcinoma, and STK11 mutations. Of the twelve models evaluated, the ExtraTrees algorithm demonstrated the highest predictive accuracy for progression (AUC 0.935) and mortality (AUC 0.995). Conclusions: Organ-specific progression patterns strongly influence outcomes in metastatic NSCLC treated with chemo-immunotherapy, with liver progression conferring the worst prognosis. The high-performing, interpretable machine-learning models developed in this study may support personalized treatment planning for advanced NSCLC.
Predictive factors of biochemical recurrence after robot-assisted radical prostatectomy: Results from a monocentric cohort.
e17128 Background: Robot-assisted radical prostatectomy is a modern surgical approach for the treatment of localized prostate cancer. Despite technological advances, biochemical recurrence (BCR) remains a frequent event, warranting the identification of reliable predictive factors. Early identification of such predictors is essential to refine risk stratification, personalize postoperative monitoring, and guide additional therapeutic decisions. Methods: The PROROB study is a retrospective, single-center analysis including 75 consecutive patients treated with robot-assisted radical prostatectomy in the urology department of Sens Hospital between Febrary 2023 and Febrary 2025. Concordance between preoperative and postoperative ISUP grades was assessed using the Kappa coefficient. The association between a preoperative PI-RADS 5 score and a high postoperative ISUP grade (4 or 5) was tested using a Chi-square test. Biochemical recurrence-free survival was estimated using the Kaplan-Meier method and compared using the log-rank test. A multivariable Cox regression model was used to identify independent predictors of recurrence. Results: The median age was 71 years (52–79), with a median PSA of 7.7 ng/mL (2.5–26) and a median delay between diagnosis and surgery of 2 months (1–38). Clinically, 48% were staged T1c on digital rectal examination. MRI showed a PI-RADS score of 4 or 5 in 76% of cases. Capsular invasion was reported in 5.3%. Most tumors were ISUP 1 or 2 at biopsy (83%). Postoperative complications occurred in 9 patients (12%) with 4 cases of hemorrhage (5.3%). Positive surgical margins were observed in 26.7% of cases, and pelvic lymph node dissection was performed in 66.7%. Postoperative urinary incontinence was reported in 21% of patients. Median follow-up was 13 months. Biochemical recurrence occurred in 11 patients (14.7%). A significant association was found between a PI-RADS 5 MRI score and a postoperative ISUP grade of 4 or 5 (p < 0.001). Concordance between pre- and postoperative ISUP scores was moderate (Kappa = 0.395). The 24-month biochemical recurrence-free survival rate was estimated at 82.2% (95% CI: 72.8%–92.8%). Positive surgical margins and postoperative urinary incontinence were significantly associated with BCR. In multivariate analysis, only positive margins remained an independent predictor of BCR (HR = 4.14; 95% CI: 1.14–15.09; p = 0.031). Conclusions: In this cohort, positive surgical margins and a PI-RADS 5 score were the main factors associated with BCR. The moderate concordance between biopsy and surgical ISUP grades highlights the limitations of biopsy alone for tumor risk stratification. These findings support the relevance of comprehensive preoperative imaging and reinforced postoperative follow-up in high-risk patients, particularly in the presence of positive margins or elevated MRI scores.
Association of progression-free survival (PFS) with microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) status determined by single vs dual validated companion diagnostic (CDx) assays: CheckMate-8HW post hoc analyses.
3531 Background: First-line (1L) nivolumab (NIVO) + ipilimumab (IPI) showed PFS benefit vs chemotherapy (chemo) in patients (pts) with MSI-H or dMMR metastatic colorectal cancer (mCRC) in the phase 3 CheckMate 8HW trial. Using post hoc analyses, we examined the association of PFS with single and dual positivity in validated CDx MSI (polymerase chain reaction; PCR) or MMR (immunohistochemistry; IHC) central assays. Methods: Study details were published previously (Andre T et al. NEJM 2024). Pts with unresectable or mCRC with MSI-H or dMMR per local testing were randomized 2:2:1 to NIVO + IPI, NIVO, or chemo. Tumor tissue samples were tested centrally using validated Idylla (CDx MSI PCR; Biocartis) and Dako (CDx MMR IHC; Agilent) assays post randomization. Clinical trial assay positive (CTA+) pts were those with locally diagnosed MSI-H/dMMR mCRC randomized to NIVO + IPI or chemo. PFS and hazard ratios (HR) were evaluated in CTA+ pts; pts positive using a single central assay (CDx MSI or CDx MMR); and pts positive in both central assays (CDx dual positive). Results: Of the 303 pts randomized to 1L NIVO + IPI or chemo, 301 had locally diagnosed MSI-H/dMMR (CTA+; 2 randomized pts missed local testing and were excluded in the analysis). 263 pts had valid CDx MSI results, 284 had valid CDx MMR results; 208 were CDx dual positive (Table); result missingness was mainly due to lack of tissue samples. PFS benefit was noted with NIVO + IPI vs chemo in CTA+ pts (HR, 0.32; Table). Greater PFS benefit with NIVO + IPI vs chemo was seen in pts positive with single CDx MSI or CDx MMR assays (HR, 0.20 and 0.22, respectively), and was consistent with those from CDx dual positive pts (HR, 0.20; Table). Pts with microsatellite stable (MSS) or mismatch repair proficient (pMMR) status were low, so these data should be interpreted with caution (Table). Conclusions: In this post hoc analysis, dual positivity from CDx MSI and CDx MMR assays did not offer greater PFS benefit with 1L NIVO + IPI vs chemo over positivity from a single CDx MSI or MMR assay. Single CDx MSI or CDx MMR assays provided similar PFS benefit with 1L NIVO + IPI vs chemo in pts with MSI-H/dMMR mCRC. Clinical trial information: NCT04008030 . NIVO + IPI(n = 202) Chemo(n = 101) HR (95% CI) a n (%) Median PFS (95% CI) n (%) Median PFS (95% CI) CTA+ 200 (99) NR (34.3–NE) 101 (100) 6.2 (4.7–9.0) 0.32 (0.22–0.45) CDx b MSI+: MSI-H 147 (73) NR (38.4–NE) 71 (70) 6.2 (4.7–9.0) 0.20 (0.12–0.31) CDx b MSI−: MSS 30 (15) 1.8 (1.5–5.8) 15 (15) 7.4 (4.0–12.9) 1.51 (0.68–3.33) CDx b MMR+: dMMR 163 (81) NR (38.4–NE) 82 (81) 5.9 (4.4–7.8) 0.22 (0.14–0.34) CDx b MMR−: pMMR 27 (13) 1.8 (1.5–5.8) 12 (12) 11.5 (2.0–NE) 1.39 (0.57–3.40) CDx b : dual positive 139 (69) NR (38.4–NE) 69 (68) 6.2 (4.9–9.2) 0.20 (0.13–0.32) a Cox proportional hazards model stratified by tumor sidedness. b By central assay. NE, not estimable; NR, not reached.
Does the FIGO 2018 cervical cancer staging system need revision? Insights from a global survey.
e17513 Background: FIGO 2018 incorporated imaging and nodal status into cervical cancer staging; however, concerns remain regarding prognostic discrimination, imaging-related pitfalls, and global feasibility. We conducted a global multidisciplinary survey to identify key limitations of FIGO 2018 and priorities for future revision. Methods: A structured, web-based survey (20 items across 6 domains) was distributed internationally to gynecologic oncologists, radiation oncologists, radiologists, and pathologists. Domains included parametrial laterality, nodal site and burden, extranodal extension (ENE), imaging pitfalls, feasibility in low- and middle-income countries (LMICs), and comparison with AJCC/UICC TNM 9th edition. Descriptive statistics were reported as frequencies and percentages. Associations between categorical variables were assessed using chi-square or Fisher’s exact tests as appropriate. Ordinal Likert-scale responses were analyzed using trend analysis and collapsed agreement categories. Statistical significance was defined as p <0.05. Results: A total of 228 complete responses were analyzed. FIGO 2018 was considered inadequate for differentiating unilateral versus bilateral parametrial involvement by 80.3%. MRI overstaging of bilateral parametrial disease due to inflammatory changes was reported by 82.5% and was significantly associated with dissatisfaction regarding parametrial stratification ( p <0.001). Failure to distinguish micro- versus macrometastases was identified as a major limitation by 88.6%, while 79.4% supported incorporation of pelvic nodal burden into staging. Inguinal lymph nodes were variably classified, most commonly as distant metastases (56.6%), suggesting a lack of consensus. ENE was considered inadequately addressed by 84.6%, with 68.9% supporting automatic upstaging. Imaging-based nodal overstaging due to reactive nodes was reported by 76.8%, and 69.3% cited significant inter-observer MRI variability. Implementation challenges included limited imaging availability (41.2%) and pathology infrastructure (27.6%). Resource-stratified staging was supported by 89.5%. TNM 9th edition was perceived as providing superior nodal and prognostic stratification by 58.8%, with 87.7% favoring a complementary role. Conclusions: Global expert consensus indicates that FIGO 2018 is clinically practical but prognostically oversimplified. Revision incorporating nodal burden, ENE, imaging reliability, and resource-stratified frameworks is strongly supported. Domain Result Parametrial laterality Inadequate 80.3% (χ² p<0.001) MRI parametrial overstaging 82.5% No micro/macro nodal split 88.6% (χ² p<0.001) Nodal number ignored 79.4% (χ² p<0.01) ENE not addressed 84.6% (χ² p<0.001) Resource stratification needed 89.5% Global survey shows strong statistical support for FIGO 2018 revision.
Uncoupling of MT1E transcription and translation in high-CNA colorectal cancer: A proteostatic adaptation as driver of aggressiveness.
e15577 Background: Somatic copy number alterations (CNAs) drive chromosomal instability in colorectal cancer (CRC). We aimed to determine the prognostic value of CNA burden and elucidate its underlying molecular adaptations, focusing on the discovered RNA-protein decoupling of metallothionein (MT1E). Methods: Genome-wide CNA burden was analyzed in 78 CRC patients (Taipei Veterans General Hospital) via targeted NGS and validated in 437 patients (TCGA-COAD). Multi-omic integration screened for critical dysregulated targets in high-CNA tumors. Findings were validated by examining MT1E protein expression using immunohistochemistry and digital pathology in an independent cohort (n = 189). Results: High CNA burden was mutually exclusive with MSI-high status and consistently predicted inferior overall survival in both cohorts (TVGH: HR = 1.80, p = 0.019; TCGA: HR = 1.71, p = 0.009). Notably, integrative analysis revealed a striking discordance regarding MT1E: while high-CNA tumors exhibited significant downregulation of MT1E mRNA (logFC = −1.13; FDR = 4.23×10⁻¹²), protein-level analysis demonstrated that high MT1E protein expression was paradoxically associated with aggressive disease and worse survival (p = 0.028). This suggests that post-transcriptional stabilization of MT1E acts as a critical stress-adaptive mechanism specific to genomically unstable tumors. Conclusions: High CNA burden serves as a robust prognostic biomarker in CRC, identifying a high-risk subgroup characterized by stress-adaptive MT1E protein stabilization despite transcriptional repression. These findings expose a potential proteostatic vulnerability in chromosomal-unstable CRC that could be exploited therapeutically.
Survival outcomes in individuals with cancer and pre-existing autoimmune disease receiving immune checkpoint inhibitors: A multicenter, propensity-matched real-world survival analysis.
11098 Background: Autoimmune disease (AID) affects approximately 5–10% of individuals with cancer. Although immune checkpoint inhibitors (ICIs) have transformed cancer therapy, individuals with pre-existing AID are routinely excluded from clinical trials due to concerns about immune-related adverse events. Consequently, long-term real-world survival outcomes in this population remain incompletely defined, limiting evidence-based risk–benefit assessment. Methods: We conducted a retrospective, multicenter cohort study using a large U.S.-based real-world oncology network derived from harmonized electronic health records across academic and community cancer centers. Adults (≥18 years) with solid tumors who received at least one immune checkpoint inhibitor (PD-1, PD-L1, or CTLA-4) were included. Individuals were classified by the presence or absence of documented pre-existing AID prior to ICI initiation. Cohorts were matched 1:1 using propensity scores based on age, sex, race, and baseline comorbidities, including cardiovascular disease, diabetes, chronic kidney disease, chronic obstructive pulmonary disease, cerebrovascular disease, and heart failure. Survival outcomes at 1, 3, and 5 years from ICI initiation were evaluated using Kaplan–Meier methods and Cox proportional hazards models. Results: After propensity score matching, 13,800 adults were included (6,900 with AID and 6,900 without), with excellent balance across baseline covariates. All-cause mortality was higher among individuals with pre-existing AID at 1 year (36.7% vs 32.6%), 3 years (48.3% vs 44.7%), and 5 years (50.1% vs 47.0%). Pre-existing AID was independently associated with worse overall survival at all time points (HR 1.15; 95% CI 1.09–1.22 at 1 year; HR 1.15; 95% CI 1.10–1.21 at 3 years; HR 1.15; 95% CI 1.09–1.20 at 5 years; all P < 0.001). Kaplan–Meier analyses demonstrated early separation of survival curves that persisted through long-term follow-up (log-rank P < 0.001). Conclusions: In this large, multicenter, real-world cohort, pre-existing autoimmune disease was associated with a modest but durable reduction in survival among individuals treated with immune checkpoint inhibitors, persisting through 5 years of follow-up. These findings do not contraindicate ICI use but highlight the need for individualized risk stratification, multidisciplinary collaboration, proactive toxicity surveillance, and informed shared decision-making when initiating immunotherapy in this population.