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Trends in lung adenocarcinoma incidence among younger adults in the United States: A SEER-based Joinpoint analysis.
e20113 Background: Patterns of lung adenocarcinoma (LUAD) incidence among younger adults remain underexplored, particularly across racial and ethnic subgroups. We sought to evaluate long-term incidence trajectories by stage, sex, and race/ethnicity to identify populations with emerging risk. Methods: Using SEER 17 Registries (Nov 2023 submission), we identified LUAD cases diagnosed between 2000–2021 in patients aged 15–49. Age-adjusted incidence rates were calculated with the 2000 US standard population. Cases were stratified by age (15–39 vs 40–49), sex, race/ethnicity (NHW, NHB, NHAPI, Hispanic), and stage (localized, regional, distant). Joinpoint regression estimated annual percent change (APC) and average annual percent change (AAPC). Statistical significance was defined as p-value < 0.05. Results: Overall cancer incidence among individuals aged 15–39 years remained stable during the study period (AAPC –0.47, p = 0.39). When stratified by race/ethnicity, a modest but statistically significant decline was observed among non-Hispanic White individuals (AAPC –1.506, p = 0.047), whereas incidence trends among non-Hispanic Black (AAPC +0.99, p = 0.43) and Hispanic populations (AAPC +1.656, p = 0.266) did not demonstrate significant changes. Stage-specific analyses showed a significant decline in regional-stage disease overall (AAPC –4.44, p = 0.025). In contrast, trends in localized and distant-stage incidence were not statistically significant across the overall population or when stratified by sex and race/ethnicity. Sex-specific analyses similarly revealed no significant changes in overall incidence among males or females. Among individuals aged 40–49 years. Non-Hispanic White (AAPC –3.59, p < 0.001) and non-Hispanic Black populations (AAPC –4.25, p < 0.001) demonstrated significant decreases, while Hispanic incidence remained stable (AAPC –0.87, p = 0.18). Notably, non-Hispanic Asian or Pacific Islander females exhibited a significant increase in distant-stage incidence (AAPC +2.41, 95% CI 0.66–4.22, p = 0.007). Regional-stage incidence declined across most groups (AAPC –6.53, p < 0.001). Conclusions: Lung adenocarcinoma incidence among younger adults has remained largely stable over the past two decades. A modest but significant decline was observed among non-Hispanic White individuals and in regional-stage disease, while no significant temporal changes were identified across other racial/ethnic, sex-specific, or stage-specific subgroups. Continued surveillance is warranted to monitor potential emerging disparities in this population.
A Ki-67/CD34 prognostic model for risk stratification in resected gastrointestinal stromal tumors.
e23515 Background: Accurate risk stratification is essential for guiding postoperative adjuvant therapy in resected gastrointestinal stromal tumors (GIST). Traditional Joensuu criteria rely mainly on mitotic count, together with tumor size and primary site. While immunohistochemistry is routinely used for diagnosis, integrating biomarkers into prognostic assessment may improve identification of patients at high risk of recurrence after curative resection. We developed a prognostic model incorporating a proliferation marker (Ki-67) and a vascular marker (CD34) to improve postoperative risk stratification. Methods: We retrospectively collected 634 patients with localized GIST who underwent curative resection at the National Cancer Center of China. The primary endpoint was disease-free survival (DFS). A multivariable Cox regression model including Ki-67 index, CD34 expression, tumor size, and sex was developed; mitotic count and tumor site were evaluated for inclusion. Discrimination was compared with the modified Joensuu criteria using Harrell’s concordance index (C-index) and log-rank tests. Results: In this cohort, the Joensuu criteria showed limited DFS separation between intermediate- and high-risk groups (log-rank P=0.17). In multivariable analysis, Ki-67 index and CD34 positivity were independent prognostic factors. Mitotic count and tumor site were evaluated but were not retained in the final multivariable model. The integrated model achieved a C-index of 0.766 (95% CI, 0.632–0.877), higher than the Joensuu criteria (C-index 0.694; 95% CI, 0.573–0.795). In multivariable Cox regression for DFS (Table), higher Ki-67 index and larger tumor size were associated with increased risk, whereas CD34 positivity and female sex were protective. The model provided improved discrimination among higher-risk patients, with significant separation between intermediate- and high-risk groups (P=0.002), whereas DFS was similar between low- and intermediate-risk groups (P=0.86). Conclusions: A prognostic model integrating Ki-67 and CD34 may refine DFS risk stratification after GIST resection, particularly at the intermediate- versus high-risk boundary where standard criteria show limited discrimination. This approach may support more tailored selection of patients for postoperative adjuvant therapy. Multivariable analysis of factors associated with DFS. Variable HR 95% CI P value Ki-67 index (per 1% increase) 1.04 1.01-1.07 0.007 Tumor size (per 1 cm increase) 1.08 1.01-1.16 0.019 CD34 positive (vs negative) 0.36 0.16-0.81 0.014 Female (vs male) 0.37 0.17-0.81 0.013
Tislelizumab Combined With Induction Chemotherapy and Concurrent Chemoradiotherapy in Locally Advanced Esophageal Squamous Cell Carcinoma: A Multicenter, Randomized, Phase II Trial (EC-CRT-002)
PURPOSE To evaluate the efficacy and safety of adding tislelizumab to induction chemotherapy and concurrent chemoradiotherapy (CRT), with or without maintenance immunotherapy, in patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC). METHODS This multicenter, randomized, open-label, phase II trial was conducted across four academic hospitals in China (ClinicalTrials.gov identifier: NCT05520619 ). Participants were adults age 18-70 years with newly diagnosed, unresectable, stage II to IVB ESCC. Patients were randomly assigned (1:1) to receive two cycles of paclitaxel/cisplatin induction chemotherapy followed by concurrent CRT in combination with tislelizumab for 16 cycles in group A (two induction, two concurrent, and 12 maintenance) or four cycles in group B (two induction and two concurrent). The primary end point was progression-free survival (PFS) in the intention-to-treat population, compared with historical control. RESULTS Between October 2022 and October 2024, 114 patients were randomly assigned to group A (n = 57) or group B (n = 57). After a median follow-up of 22.7 months (IQR, 16.2-28.2), group B demonstrated significantly better PFS versus controls (1-year: 71.9% [95% CI, 61.1 to 84.6] v 56.4% [95% CI, 44.7 to 71.1]; hazard ratio [HR], 0.54 [95% CI, 0.32 to 0.94]), while group A showed no PFS benefit (1-year: 52.6% [95% CI, 41.4 to 67.3]; HR, 1.06 [95% CI, 0.67 to 1.68]). Overall survival was also significantly better in group B (HR, 0.42 [95% CI, 0.22 to 0.82]). Grade ≥3 adverse events occurred in 86.0% of group A and 80.7% of group B, with the most common being lymphopenia (77.2% and 73.7%, respectively). Comprehensive biomarker analyses revealed that PD-L1 expression, CD8 + T-cell density, NRF2 pathway mutations, and dynamic changes in circulating tumor DNA were associated with treatment efficacy. CONCLUSION The addition of tislelizumab to induction chemotherapy and concurrent CRT without maintenance immunotherapy demonstrated superior efficacy and manageable toxicity in locally advanced ESCC.
To re-test or not: Evaluating candidacy for precision therapy in breast cancer.
e12599 Background: Breast cancer is one of the most common types of cancer as well as a leading cause of cancer death among women in the United States. Receptor status (estrogen receptor ER, progesterone receptor PR, HER 2) carries both prognostic and predictive value in breast cancer and testing for these findings is essential in order to identify appropriate candidates for endocrine therapy (ET) and/or HER2 directed treatment (HDT), respectively. There have been numerous studies evaluating receptor testing between primary breast and synchronous lymph nodes with varying levels of discordance ranging from 3-50%. Across Tufts Medicine, patients whose primary breast biopsy shows an ER- or PR-negative and/or HER2-negative invasive cancer often have a second specimen (e.g., either axillary node or final breast specimen) re-tested. We report the proportional discordance between primary and secondary samples among people newly diagnosed with de novo non-metastatic breast cancer. Methods: This study involved a retrospective review of patients with a new diagnosis of breast cancer at an academic health system between 2023-2025. All patients had breast biopsy testing available and underwent a second round of testing as part of initial evaluation of breast cancer. We excluded patients with de novo metastatic (stage IV) breast cancer. We compared ER/PR and HER2 testing between serial pathology specimens to determine concordance and how the information was ultimately utilized in individual patient treatment. Results: We identified 74 patients who underwent multiple receptor testing. Age ranged from 25-86 years and the cohort was predominantly female. Patients identified as 61% white, 12% African American, 18% Asian, and 8% Hispanic/Latino. 41.9% of patients had simultaneously performed breast and axillary core biopsies performed while 54% of patients had these done sequentially. The rate of concordance was 94.6% for ER, 84.8% for PR and 94.6% for HER2. Based on initial biopsy, 79.7% and 17.6% of patients were eligible for ET and/or HDT, respectively. Secondary testing increased candidacy to 81.1 (+1.4%) and 23 (+5.4%) for ET and HDT. Of the 19 patients who received neo-adjuvant chemotherapy and had repeat HER2 testing of their surgical specimen, two patients had HER2 negative disease at initial biopsy and HER2 positive disease following neoadjuvant therapy. One patient with HER2 positive disease at diagnosis continued with adjuvant targeted therapy despite repeat negative testing. Conclusions: Re-testing of ER/PR and HER2 in the context of a new diagnosis of breast cancer changes management in very few patients. However, given the predictive value of this information, it may be warranted in select patients, especially when the goal of treatment is cure. Our data suggests that repeat testing for HER2 may prove to be more valuable, given that four patients (5.4%) were deemed candidates for HDT despite negative HER2 results on breast biopsy.
Early mortality and contemporary survival in intravascular large B-cell lymphoma: A population-based SEER study.
e19089 Background: Intravascular large B-cell lymphoma (IVLBCL) is a rare and aggressive extranodal lymphoma that frequently presents with nonspecific symptoms, often leading to delayed diagnosis and poor outcomes. Prior population-based SEER analyses described survival through 2013; however, outcomes in the modern treatment era and prognosis among longer-term survivors remain incompletely characterized. We evaluated contemporary survival, early mortality, temporal patterns, and clinical presentation in a national cohort. Methods: We conducted a retrospective study of adults with IVLBCL in SEER (17 registries, 2000–2022) using ICD-O-3 histology code 9712/3. Demographic and clinical variables, including age, sex, stage, and receipt of systemic therapy per the SEER chemotherapy recode, were collected. Cutaneous phenotype was defined as primary skin involvement. Early mortality was assessed at 30 and 90 days. Overall survival was estimated using Kaplan–Meier methods. Survival was compared by diagnosis era (2000–2013 vs 2014–2022). Conditional survival was calculated at 12- and 24-month landmarks. Results: A total of 123 patients were included. Median age was 66 years, and 46% were male. Sixty-five percent received systemic therapy, and 16% had localized disease at diagnosis. Early mortality was substantial, with 30- and 90-day mortality rates of 29% and 32%. Median overall survival was 22 months, with 1- and 2-year survival of 56% and 49%. Survival appeared longer in the contemporary era (median 35 vs 17 months). Conditional 1-year survival was 88% among patients alive at 12 months and 95% among those alive at 24 months. Cutaneous-limited disease represented 6% of cases and showed longer survival, although estimates were exploratory, and cutaneous presentations may be undercaptured in SEER. Conclusions: IVLBCL remains associated with substantial early mortality despite modern therapy. Outcomes appear more favorable in recent years, and patients who survive the first 1–2 years have an improved subsequent prognosis. These findings provide contemporary population-level benchmarks to guide counseling and risk stratification and should be interpreted in the context of potential registry misclassification and coding limitations. Patient characteristics and outcomes in IVLBCL (SEER 2000 to 2022). Characteristic Value Patients, n 123 Median age, years 66 Male sex, % 46 Received systemic therapy, % 65 Localized stage at diagnosis, % 16 30-day mortality, % 29 90-day mortality, % 32 Median overall survival, months 22 Conditional 1 year survival among 12-month survivors, % 88 OS, overall survival. Systemic therapy includes chemotherapy or chemoimmunotherapy per SEER coding.
EIF4B expression in lung squamous cell carcinoma using bulk and single-cell transcriptomic profiling.
e20537 Background: Dysregulated translation initiation is a hallmark of cancer progression and therapeutic resistance. Eukaryotic initiation factor 4B (EIF4B) enhances cap-dependent translation by promoting mRNA recruitment and helicase activity within the eIF4F complex. While epithelial–mesenchymal transition (EMT) and drug resistance critically drive lung squamous cell carcinoma (LUSC) aggressiveness, the contribution of EIF4B to these processes remains unclear. Methods: EIF4B expression was analyzed using TCGA-LUSC bulk RNA-seq data and single-cell RNA-seq data (GSE148071). Tumor–normal expression differences were assessed, and correlations with EMT scores and drug-resistance markers (ABCB1, CD44, ALDH1A1) were evaluated using Spearman analysis. Differential expression and Hallmark gene set enrichment analyses were performed comparing EIF4B-high versus EIF4B-low tumors. Single-cell analyses mapped EIF4B expression across cellular subpopulations and assessed co-expression with EMT and stemness signatures. Results: EIF4B expression was significantly reduced in LUSC tumors compared with normal tissue (p < 0.001). Despite this global downregulation, EIF4B-high tumors demonstrated significantly elevated EMT scores (ρ = 0.16, p = 0.0001) and positive correlations with ABCB1 (ρ = 0.35), CD44 (ρ = 0.32), and ALDH1A1 (ρ = 0.22). Gene set enrichment analysis revealed activation of xenobiotic metabolism and coagulation pathways, alongside suppression of E2F and G2/M checkpoint programs. Single-cell profiling identified EIF4B enrichment within EMT-active epithelial and stem-like subpopulations, with significant correlations to cell-level EMT and resistance scores. Conclusions: Although globally downregulated in LUSC, EIF4B selectively marks mesenchymal and drug-resistant tumor subpopulations. Integrated bulk and single-cell analyses implicate EIF4B as a functional mediator of EMT-associated therapeutic resistance, highlighting its potential as a target to overcome treatment-refractory LUSC phenotypes.
Reporting of patient-reported outcomes in randomized phase 3 clinical trials of FDA-approved medications in breast cancer.
e12693 Background: Patient-reported outcomes (PROs) capture symptoms, functional limitations, and quality of life directly from patients and complement traditional efficacy and safety endpoints in the FDA registration drug trials. PRO data is relevant in breast cancer treatment selection as therapies may require prolonged treatment and offer modest survival gains. Despite the increasing recognition of the importance of PROs, it remains unclear whether PRO data in registration clinical trials of FDA-approved breast cancer medications are prioritized, consistent and reported in a timely manner. Methods: The FDA’s drug database was queried to identify breast cancer drug approvals between 2011 and 2024, and the corresponding clinical trial publications were identified through systematic searches of EBSCO and PubMed. Manuscripts were included if they reported PRO data from FDA registration clinical trials in breast cancer that were associated with drug approval. Extracted variables included PRO endpoint classification, trial characteristics, sample size, time to PRO publication, and reporting of missing data. Descriptive statistics were used to summarize PRO reporting outcomes. Results: Thirty-six randomized breast cancer trials supporting 34 FDA approvals were identified, corresponding to 45 manuscripts reporting PRO data. PROs were included as secondary or exploratory endpoints in most trials; however, one-quarter of trials (9/36, 25%) did not explicitly list any PROs as endpoints. Trials included a median of 3 PRO measures most commonly the EORTC QLQ-C30, FACT-B/FACIT scales. Among 26 PRO-specific manuscripts, the median time from publication of the primary trial results to PRO publication was 18 months, with 6 trials reporting PRO after two years or longer. Missing PRO data were reported in 16 manuscripts (36%), while only 5 (31%) provided reasons for the missing data. Conclusions: In FDA-approved breast cancer trials, patient-reported outcomes are commonly collected; however, they are frequently developed with inconsistent trial standardization, published with substantial delay, and reported without adequate transparency. Future work should focus on standardization to enable meaningful comparison and regulatory relevance. Reporting of patient-reported outcomes in FDA-approved breast cancer trials. Variable Value FDA approvals included (n) 34 Clinical trials included (n) 36 Trials with PROs as secondary endpoint (n, %) 23 (64%) Trials with PROs as exploratory endpoint (n, %) 3 (8%) Trials with PROs not prespecified (n, %) 9 (25%) Time (months) to PRO publication (median, range) 18 (0–44) Manuscripts reporting missing PRO data (n, %) 16 (36%)
Denosumab as an immune modulator: Results of a window-of-opportunity study in early breast cancer.
e12540 Background: Denosumab, a RANK ligand inhibitor, has been shown to improve disease free survival when given adjuvantly with an aromatase inhibitor to hormone receptor-positive breast cancer (BC) patients. Preclinical models have suggested that RANK signaling plays a crucial role in regulation of the tumor immune microenvironment. Methods: 31 pts with early stage BC were enrolled on window of opportunity study receiving 1 dose of denosumab, with paired biopsy and surgical specimens assessed by immunohistochemistry (RANK, RANKL, CD3, CD8, CD68, FOXP3, CD163, CD33, CSF1R, HLADR) and transcriptomic (NanoString BC-360 panel) methods. A cohort matched for menopausal status and BC subtype of untreated pts were included for comparative purposes. Results: Immune subset analysis by immunohistochemistry demonstrated lower CD68 expression in the surgical specimens of denosumab-treated patients as compared to untreated control patients (p = 0.0099). Multivariate DEG analysis did not demonstrate any statistically significant differences in single gene expression. However, differences in gene set enrichment analysis were detected on univariate analysis including an increase in antigen presenting signature (log fold change 1.61, p = 0.03), PD-L1 (logFC 1.1, p = 0.01) and TGF-Beta (logFC 1.5, p = 0.01) in the denosumab treated cohort. Conclusions: This presurgical study allowed for evaluation of the mechanism of denosumab’s antitumor effect, which suggests a more favorable switch in the immune profile of patients treated with this agent in the early stage setting. Denosumab-treated patients had different expressions of several gene signatures known to affect the tumor immune microenvironment including APM, PD-L1 and TGF-beta and suggests a potential role for denosumab in early-stage breast cancer as an immune-sensitizing agent.
Association patterns among patient-reported adverse events in advanced NSCLC: A post-hoc analysis of the CLIMEDIN randomized controlled trial.
e23271 Background: CLIMEDIN was a randomized controlled trial of digital support for patients with advanced or metastatic non-small cell lung cancer. Patients received either general adverse event (AE) information (control arm), or personalized support depending on their reported AEs (intervention arm). Given the statistically significant difference found between the AEs reported digitally by patients and those captured directly by clinicians, this post-hoc analysis aims to identify patterns of likely co-occurrence of AEs. Methods: Between March 2022 and December 2024, 188 patients submitted 7046 reports among 22 preselected AEs, captured in the CareAcross platform database. For this analysis these reports were de-identified and structured based on the specific AEs they contained. Association rule mining (apriori algorithm with support thresholds) was used to calculate the conditional probability of an AE subset (“Associated AEs”) being reported given that another subset (“Index AEs”) was reported concurrently. Results: The analysis resulted in 7846 pairs of Associated & Index AE subsets, with up to 7 AEs per subset. The conditional probability of co-occurrence (“Confidence”) ranged from 2.5% to 100%.To make the patterns clinically meaningful and practical, analyses were restricted to subsets of 1-2 AEs, resulting in 1870 combinations. Keeping the pairs with probability > = 80% resulted in 110 records (37 of which with > = 90% probability).The majority (78/110 or 71%) of Associated AEs included Fatigue.Among the AEs that are not immediately available upon clinical examination: Anorexia was correlated with combinations containing dyspnea (with any of rash, constipation, dysphagia, dysgeusia, diarrhea) as well as dysphagia & weight loss. Dysgeusia was correlated with combinations containing anorexia (with any of pruritus, diarrhea), diarrhea (with any of cough, anorexia, dry skin), stomatitis (with any of dry skin, cough) and more.The full list of associations is available upon request.The Table contains the most frequently occurring pairs of 1 or 2 AEs that do not include Fatigue. Conclusions: Analysis of Patient-Reported Outcomes can provide relevant Real World Evidence to support clinicians in completing the view of their patients’ journeys. This can be particularly applicable when information is missing, or AEs cannot be readily evaluated clinically.Data Science and Artificial Intelligence can further help derive actionable insights for clinical care and research. Clinical trial information: 05372081 . Index AEs Associated AEs Confidence (%) Peripheral Neuropathy, Chest Pain Dry Skin 94.7 Dyspnea, Rash Anorexia 93.7 Peripheral Neuropathy, Bone Pain Dry Skin 92.1 Anorexia, Pruritus Dysgeusia 88.7 Peripheral Neuropathy, Chest Pain Bone Pain 88.4 Cough, Diarrhea Dysgeusia 88.2 Weight Loss, Dysphagia Anorexia 88.1 Cough, Diarrhea Dry Skin 87.5 Dyspnea, Rash Dysgeusia, Anorexia 86.3
A phase II trial of ivonescimab for previously treated thymic carcinoma: UCLA L-11.
TPS8140 Background: Thymic carcinoma (TC) is a rare and aggressive thymic epithelial tumor (TET), accounting for approximately 20% of thymic neoplasms. TC is often more invasive and less responsive to standard therapy than other TETs, with a 5-year survival rate of 30-50% in the advanced/metastatic setting. Effective treatment remains limited following progression with platinum-based chemotherapy. Programmed Death-(Ligand) 1 (PD-(L)1) inhibition demonstrates modest activity in recurrent TC, with an objective response rate (ORR) of 19.5-22.5% with manageable toxicities [Cho, Clin Oncol . 2019; Giaccone, J Thorac Oncol. 2021]. Moreover, vascular epithelial growth factor (VEGF) inhibition with sunitinib or lenvatinib achieved ORRs of 26-38% in second line therapy and beyond (Thomas, Lancet Oncol. 2015; Sato, Lancet Oncol. 2020). Combination of lenvatinib and pembrolizumab as second line therapy and beyond has shown an ORR of 22.5%, with a median duration of response of 8.2 months (Remon, Lancet Oncol. 2025 ). Ivonescimab is a humanized bispecific monoclonal antibody targeting both PD-1 and VEGF and shows favorable safety and efficacy in non-small cell lung cancer. In light of the known benefit of VEGF and PD-(L)1 blockade in TC, this study aims to evaluate the safety and efficacy of ivonescimab in patients with previously treated TC. Methods: This study is a multi-center, open-label, single-arm Phase II trial enrolling adults with histologically or cytologically confirmed unresectable/metastatic TC whose disease has progressed following systemic therapy. Key inclusion criteria include one-prior line of treatment, ECOG performance status ≤1, and adequate organ function. Exclusion criteria include prior treatment with PD-(L)1 inhibitors, positive paraneoplastic serologies, or autoimmune disease requiring active systemic therapy. Ivonescimab is administered intravenously on D1 of a 21-day cycle until disease progression, unacceptable toxicity, withdrawal, or loss of follow up. The primary endpoints are investigator confirmed ORR via RECIST 1.1 and safety/tolerability of ivonescimab. Secondary endpoints include progression-free survival, duration of response, time to response, and overall survival. Exploratory analyses will evaluate correlation of antitumor activity with tissue and blood-based biomarkers, such as PD-L1 expression and circulating tumor DNA (ctDNA). The study uses a Simon’s two stage design: in stage 1, 15 patients will be enrolled. The study will be stopped if ≥ 5 treatment-related serious adverse events or if ≤1 patient achieves an objective response within the first three months of treatment. Otherwise, an additional 10 patients will be enrolled in stage 2. The design has 80% power with a 5% Type I error to detect an ORR of 30% over the null hypothesis of 10%. The study is currently enrolling patients. Copyright © 2026 AACR. Originally presented at AACR 2026. Reprinted with permission. Clinical trial information: NCT06980077 .
Organ-specific proteomic aging clocks (PACs) and mortality in cancer survivors.
12112 Background: Our study suggested that plasma conventional PACs can reflect, on average, accelerated aging in cancer survivors (Wang et al., JNCI 2026), but may overlook organ-specific variations. Organ-specific PACs may better predict CVD and cancer mortality in this group. Methods: We compared the associations of one conventional and 11 organ-specific PACs (Oh et al., Nature 2023) with mortality in 806 cancer survivors (aged 66-90) in the Atherosclerosis Risk in Communities (ARIC) study, 2+ yrs post-diagnosis (up to 12-yr follow-up). ARIC measured 4,712 plasma proteins by SomaScan. We computed PACs (conventional, adipose, artery, brain, heart, immune, intestine, kidney, liver, lung, muscle, pancreas) and their deviations from chronological age (age gap) after regressing PAC on age via LOWESS model. Multivariable Cox proportional hazards regression estimated hazard ratios (HRs) for mortality associated with age gap in survivors of any cancer (455 deaths: 127 CVD, 137 cancer deaths) and the most common cancers (165 breast (BrCa), 255 prostate (PrCa), and 78 colorectal cancer (CRC)). Results: In BrCa survivors, all age gaps (except intestine) were higher for those diagnosed 2-10 vs. >10 yrs before the start of follow-up. The pattern was opposite for all age gaps in CRC survivors (except heart and lung gaps). There was no specific pattern across age gaps in PrCa survivors. Further, in all cancer survivors, all age gaps, but artery and kidney, were associated with all-cause mortality (all p<0.05), with highest HRs for conventional, heart, and liver gaps (Table 1). Only heart age gap was associated with CVD mortality (HR per 1 SD=1.29, p<0.05), with no associations of any age gaps with cancer mortality. In BrCa survivors, conventional (HR=1.81) and 4 organ age gaps (brain, heart, immune, intestine; HRs = 1.45–1.68) were associated with all-cause mortality (all p<0.05). In PrCa survivors, conventional, heart, and liver age gaps were associated with all-cause mortality [all HRs=1.35, p<0.05]. In CRC survivors, conventional, heart, and immune age gaps were positively, but non-significantly, associated with all-cause mortality [HRs = 1.48–1.56], likely limited by sample size. Conclusions: Conventional and heart PACs demonstrated consistent associations with all-cause mortality beyond chronological age and lifestyle factors in total and individual cancer survivors. Heart PAC was most strongly associated with CVD mortality. Further work is needed to replicate this analysis and to test these age gaps as a predictor for mortality. Funding: NHLBI, NCI, NPCR. Age gaps and all-cause mortality in cancer survivors; ARIC (2011-23). Age gap HR (95% CI) per 1 SD Age gap HR (95% CI) per 1 SD Conventional 1.48 (1.32, 1.66) Intestine 1.13 (1.01, 1.26) Adipose 1.13 (1.00, 1.27) Liver 1.42 (1.26, 1.60) Brain 1.19 (1.05, 1.34) Lung 1.14 (1.02, 1.26) Heart 1.41 (1.26, 1.59) Muscle 1.19 (1.06, 1.33) Immune 1.24 (1.10, 1.40) Pancreas 1.33 (1.18, 1.49)
Off-target HLA matches for prediction of response in personalised cancer vaccines: A multi-trial retrospective analysis.
2653 Background: Personalized neoantigen vaccines aim to match epitopes to a patient's HLA genotype, yet many peptides bind promiscuously across multiple HLA alleles. Promiscuous binding may reflect intrinsic peptide properties, including enhanced processing efficiency and structural stability, that drive immunogenicity independent of any single HLA match. We hypothesized that peptides with broader HLA binding profiles would show higher clinical immunogenicity, even when restricted to the patient's own HLA alleles. Methods: We curated 17 neoantigen vaccine trials (174 patients) and selected five with per-epitope CD8⁺ T cell immunogenicity data for primary analysis. Across 571 neoantigen sequences (3,806 derived peptides), we predicted binding and presentation using NetMHCpan-4.2, MHCflurry 2.0, and PRIME-2.0, and estimated peptide–MHC stability with NetMHCstabpan. A reference panel of 62 common HLA class I alleles (>95% global coverage) was used to quantify incidental coverage, defined as predicted binding (IC50 <500 nM) to non-patient HLA alleles. Mixed-effects models adjusted for patient-specific binding affinity, predicted stability, mutation type, neoantigen length, and trial structure, with Bonferroni correction for 5 pre-specified hypotheses. Results: Off-target HLA binding independently predicted clinical immunogenicity. Among peptides selected for vaccination, 35.2% bound at least one non-patient HLA allele, with the most promiscuous peptides binding up to 37 alleles. After adjusting for patient-specific binding affinity and stability, peptides from immunogenic neoantigens showed greater incidental coverage than non-immunogenic peptides (mean 2.46 vs 1.80 additional HLAs; p=0.0034). This association was consistent across tumour types and prediction methods. Among immunogenic peptides, the breadth of off-target binding correlated with response magnitude (Spearman ρ=0.46, p=0.034), with the strongest effect observed in glioblastoma. High-affinity off-target matches (IC50 <50 nM) and high-stability interactions showed the most robust associations with immunogenicity. Conclusions: Promiscuous HLA binding independently predicts neoantigen immunogenicity in clinical trials, beyond binding affinity and stability to the patient’s own HLA alleles. These results point to peptide-intrinsic properties linked to MHC stability and processing that are overlooked by current selection pipelines. Explicit modelling of HLA promiscuity and stability may improve neoantigen prioritisation, particularly in low–mutation burden tumours and patients with rare HLA genotypes.
Correlation between circulating tumor DNA and radiographic disease status in soft tissue sarcoma: A Mayo Clinic experience.
e23554 Background: Radiographic imaging remains the standard of care for disease surveillance and response assessment in soft tissue sarcoma (STS). Circulating tumor DNA (ctDNA) has emerged as a potential biomarker in solid tumors; however, its feasibility and detectability in STS remain incompletely defined due to histologic heterogeneity and variable tumor DNA shedding. We evaluated ctDNA detectability and its relationship to radiographic disease status in the most common STS subtypes: undifferentiated pleomorphic sarcoma (UPS) and leiomyosarcoma (LMS). Methods: We retrospectively analyzed patients with UPS or LMS who underwent serial ctDNA testing using a personalized assay (Signatera) alongside routine radiographic surveillance between 2022 and 2025. Any detectable mean tumor molecules (MTM) >0 was considered positive. ctDNA results were paired with the closest imaging within ±30 days and assessed using radiology report–based determinations of disease status. Exploratory sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were estimated per paired assessment using radiographic progression or recurrence as the reference standard. Results: 13 patients were included (7 female, 6 male), with a median age of 62 years (range 28–75); 7 patients (54%) had LMS and 6 (46%) had UPS. A total of 59 ctDNA–imaging paired assessments were analyzed (median 4 per patient). Overall ctDNA detectability was low and histology-dependent. Baseline ctDNA was detectable in 2 of 13 patients (15%), both with LMS. During longitudinal follow-up, ctDNA remained persistently undetectable in 10 of 13 patients (77%), including all UPS patients and 4 of 7 LMS patients. Detectable ctDNA occurred almost exclusively in LMS and was often observed in association with radiographic disease progression. Across all paired assessments, 46 of 59 (78%) were concordant. Discordance included false-negative ctDNA (negative ctDNA with radiographic disease/progression; n=9) and transient ctDNA positivity without immediate radiographic progression (n=4). Where longitudinal follow-up was available, subsequent ctDNA or imaging assessments frequently demonstrated eventual alignment; lead-time analysis for transient positives was limited by sample size. Using radiographic progression as the reference standard, exploratory per-pair test characteristics demonstrated a sensitivity of approximately 64%, specificity of 88%, PPV of 80%, and NPV of 77%. Conclusions: In this real-world cohort, ctDNA detectability differed by histology and was observed predominantly in LMS. When detectable, ctDNA trends often aligned with radiographic disease progression or recurrence, supporting a potential complementary role in disease monitoring for selected patients. These findings require confirmation in larger, prospective studies.
Early results of neoadjuvant therapy with pyrotinib, subcutaneous trastuzumab, and capecitabine for HER2-positive early breast cancer from a prospective, single-arm, multicenter trial.
606 Background: Neoadjuvant therapy has become a standard approach for HER2-positive early breast cancer, improving outcomes, pCR, and survival. Prior studies show pyrotinib combined with trastuzumab and chemo is effective and safe, but mainly via intravenous routes, impacting quality of life. This trial is the first to assess a fully oral regimen—pyrotinib, SC trastuzumab, and capecitabine—in low- to intermediate-risk patients, focusing on efficacy and safety. Methods: This single-arm, multicenter phase II trial (NCT06483386) will enroll 109 treatment-naïve adults with stage I-II, T1c-2N0-1 HER2-positive EBC (IHC 3+ or IHC 2+/FISH+). From May 2024 to June 2026, patients will receive 6 cycles of neoadjuvant pyrotinib (400mg daily), SC trastuzumab (600mg q3w), and capecitabine (1000mg/m² BID, days 1-14 followed by a 7-day break). The primary endpoint is pathological complete response (pCR) rate, as defined by RECIST 1.1. Secondary endpoints include event-free survival (EFS), objective response rate (ORR), breast-conserving rate (BCR) and safety. Results: A total of 47 patients were enrolled from May 2024 to December 2025, of whom 43 underwent surgery and 43 had pathologic assessment available. The median age was 51 years (range 33-65), and 97.9% had an ECOG PS of 0. The majority of patients had stage II disease (89.4%), with T2 tumors (91.5%); 57.4% were clinically node-positive. The pCR rate among pts with evaluable pathology was 48.8% (21/43), and ORR was over 90%. The BCR was 65.1% (25/48). In biomarker-defined subgroups, total pathological complete response (tpCR) was achieved in 53.6% (15/28) of ER negative, HER2 positive patients, and in 40.0% (6/15) of ER positive, HER2 positive patients. The most common AEs were diarrhea, nausea, anorexia, and gastrointestinal dysfunction. The incidence of grade 3 diarrhea is 19.1%, and all cases are controllable with medication, confirming good safety profile. Conclusions: The fully non-intravenous neoadjuvant regimen combining pyrotinib, SC trastuzumab, and capecitabine is an efficacious and safe regimen for patients with low- to intermediate-risk HER2-positive early breast cancer. This regimen offers a more convenient and less burdensome treatment for this patient population, potentially improving quality of life and treatment adherence. Clinical trial information: NCT06483386 .
Prognostic impact of latency interval on survival in second primary malignancies after head and neck cancer: A population-based SEER study.
e18098 Background: Survivors of head and neck cancer (HNC) are at increased risk of developing second primary malignancies (SPMs), which substantially contribute to long-term mortality. However, the prognostic significance of the timing of non-synchronous SPM development remains poorly defined. We evaluated the association between latency interval and overall and cancer-specific mortality among HNC survivors with non-synchronous SPMs. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified adults diagnosed with primary squamous cell HNC who subsequently developed a non-synchronous SPM occurring ≥2 years after HNC diagnosis, a threshold chosen to minimize misclassification of synchronous disease and early recurrence. Latency intervals were categorized as 2–4 years, 5–9 years, and ≥10 years. Modified Poisson regression with robust variance was used to estimate unadjusted and adjusted relative risks (aRRs) for overall mortality and cancer-specific mortality, adjusting for age at HNC diagnosis, race/ethnicity, tumor grade, SPM histology and site, and receipt of surgery, chemotherapy, and radiation. Results: This analysis spans contemporary SEER treatment eras. Among 19,686 HNC survivors with non-synchronous SPMs, shorter latency intervals were independently associated with worse outcomes. Compared with latency ≥10 years, a latency of 2–4 years was associated with significantly higher overall mortality (aRR 1.30, 95% CI 1.26–1.33) and cancer-specific mortality (aRR 1.29, 95% CI 1.24–1.34), and a latency of 5–9 years also conferring increased risk (overall mortality aRR 1.14; cancer-specific mortality aRR 1.12). Older age, Black race (aRR 1.12), higher-grade HNC, and SPMs of the pancreas (aRR 1.66), esophagus (aRR 1.53), lung (aRR 1.39), and stomach (aRR 1.27) were significantly associated with increased overall mortality and cancer-specific mortality. Breast, prostate, melanoma, and kidney SPMs were associated with lower mortality risk. Conclusions: In this large population-based analysis, earlier development of non-synchronous SPMs following HNC was associated with a graded increase in both overall and cancer-specific mortality, independent of demographic, tumor, and treatment factors. Mortality risk is further modified by the anatomic site of the second primary malignancy, with pancreatic, esophageal, and lung cancers conferring the highest lethality, while prostate, melanoma, and breast cancers are associated with more favorable outcomes. These findings provide population-level validation of latency and SPM site as complementary markers of survivorship risk and support more individualized, risk-adapted post-treatment surveillance strategies.
Effect of hypofractionated radiotherapy plus GM-CSF on antitumor activity with PD-1/PD-L1 inhibitors in oligoprogressive advanced NSCLC: A prospective phase II study.
e20638 Background: Oligoprogressive disease during PD-1/PD-L1 therapy is a challenging acquired resistance pattern in advanced NSCLC. Radiotherapy modulates antitumor immunity, and GM-CSF may enhance systemic immune responses. We hypothesized that combining hypofractionated radiotherapy (HFRT) with GM-CSF could restore antitumor activity and extend disease control in PD-1/PD-L1–refractory oligoprogressive advanced NSCLC. Methods: This prospective, single-arm phase II trial enrolled driver gene–negative patients with advanced NSCLC who developed oligoprogressive disease following first- or second-line PD-1/PD-L1 inhibitor therapy (ChiCTR2300069974). Progressive measurable lesions were treated with HFRT, predominantly delivered as 10–15 Gy in a single fraction (25 Gy in 5 fractions when clinically indicated). PD-1/PD-L1 inhibitors were resumed the day after radiotherapy and administered every 3 weeks, combined with subcutaneous GM-CSF (200 μg, days 1–7). The primary endpoint was objective response rate (ORR). Secondary endpoints included time to next treatment (TTNT), duration of response (DOR), overall survival (OS), and safety (CTCAE v5.0). Exploratory immune profiling was performed using peripheral blood cytokines and immune cell subsets. Results: As of December 31, 2025, 33 patients were treated. Median age was 68 years (range, 39–78), and 15.2% were female. Histologic subtypes included squamous cell carcinoma (42.4%), adenocarcinoma (39.4%), and other NSCLC subtypes (18.2%). The ORR was 42.4% (14/33), including 1 complete response (3.0%) and 13 partial responses (39.4%). Median TTNT was 10.3 months (95% CI, 7.0–13.7), and median DOR among responders was 11.4 months (95% CI, 2.6–20.3). Median OS was not reached at the time of analysis. Treatment-related adverse events (TRAE) occurred in 69.7% of patients and were predominantly grade 1–2. Grade 3 TRAE were observed in two patients (6.1%), with no grade ≥4 events. Exploratory immune analyses demonstrated post-treatment increases in IFN-γ, CD8⁺ T cells, and NK cells, supporting systemic immune reinvigoration. Conclusions: In patients with oligoprogressive, PD-1/PD-L1–refractory advanced NSCLC, HFRT combined with GM-CSF and continuation of PD-1/PD-L1 blockade demonstrated a clinically meaningful efficacy signal, durable disease control, and a favorable safety profile. These findings suggest that radiotherapy-based immune modulation may represent a viable strategy to overcome acquired immune resistance and warrant further randomized validation. Clinical trial information: ChiCTR2300069974. Key efficacy and safety outcomes. Parameter Result ORR 42.4% PR, n (%) 13 (39.4%) CR, n (%) 1 (3.0%) TTNT, months (95% CI) 10.3 (7.0–13.7) DOR among responders , months (95% CI) 11.4 (2.6–20.3) Any TRAE, n (%) 23 (69.7%) Grade 1–2 TRAE, n (%) 21 (63.6%) Grade 3 TRAE, n (%) 2 (6.1%) Grade ≥4 TRAE 0
Updated results of the randomized phase 2 dose optimization study of alveltamig (ZG006), a trispecific T cell engager targeting DLL3/DLL3/CD3, as monotherapy in patients with advanced small cell lung cancer.
8109 Background: Alveltamig (ZG006) is a trispecific T cell engager (Tri-TE) targeting Delta-like ligand 3 (DLL3) and CD3, designed to bridge tumor cells and T cells by binding to two distinct DLL3 epitopes on tumor cells and CD3 on T cells, thereby mediating T cell-specific killing of DLL3-expressing tumor cells such as small cell lung cancer (SCLC). Methods: This is a multicenter, randomized, open-label, phase 2 dose-optimization study. Patients with SCLC who have failed at least two prior lines of standard therapy are randomized 1:1 to receive ZG006 at either 10 mg or 30 mg Q2W (both with a 1 mg priming dose). Based on the prior data from dose optimization in this study with an objective response rate (ORR) at 53.3% and median progression-free survival (PFS) at 7.03 months in the 10 mg group, 10 mg Q2W was selected as the recommended dose schedule for ongoing pivotal studies in advanced SCLC. Here we present the updated efficacy data with longer follow up and key subgroup analyses from this study. Results: This analysis included 60 treated patients (30 each from 10 and 30 mg group). With a median follow-up of about 13.5 months, the median duration of response (DoR) was not mature with 9-month DoR rates reaching 61.6% and 58.4% for 10 mg and 30 mg respectively. Likewise, the median OS for both groups was not reached, however, 12-month OS rates for two groups have approached 65.9% and 59.2% respectively. Based on the IRC data as of Sept 30, 2025, for the 10 mg and 30 mg groups, patients with previously treated and stable brain metastases at baseline achieved a confirmed ORR of 50.0% (4/8) and 44.4% (4/9), respectively, while patients without baseline brain metastases had an ORR of 54.5% (12/22) and 61.9% (13/21). Patients presented with baseline liver metastases achieved an ORR of 58.3% (7/12) and 46.2% (6/13), compared with 50.0% (9/18) and 64.7% (11/17) in patients without liver metastases. While 27 patients in 10 mg and 24 patients in 30 mg had previously received immune checkpoint inhibitors, a notable ORR of 55.6% (15/27) and 58.3% (14/24) was observed. Among patients with exactly two prior lines of systemic therapy, the ORRs were 50.0% (8/16) and 64.7% (11/17), whereas those who had received three or more prior lines demonstrated an ORR of 57.1% (8/14) and 46.2% (6/13) in 10 and 30 mg groups. Conclusions: With longer follow up, both ZG006 10 mg Q2W and 30 mg Q2W continued to demonstrate robust antitumor activity with a trend of longer DoR and OS in patients with relapsed or refractory SCLC. Subgroup analyses demonstrated consistent antitumor activity across key prognostic subgroups including those with baseline treated brain metastases, those with baseline liver metastases, and those who received multiple lines of prior systemic treatment. These results also support further development of ZG006 in SCLC with ongoing pivotal studies. Clinical trial information: NCT06283719 .
Temperature-controlled hand-foot cooling for prevention of chemotherapy-induced polyneuropathy (CIPN): Updated real-world data collection in 600 patients.
e24181 Background: Advancements in oncology have significantly improved overall survival rates for cancer patients, particularly those with breast cancer. Consequently, the long-term side effects of chemotherapy —still a cornerstone of cancer treatment—on patients’ quality of life (QoL) are gaining increasing attention. Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of taxanes (paclitaxel, nab-paclitaxel, docetaxel). CIPN can significantly reduce QoL and may lead to dose delays, reductions, or even treatment discontinuation. Reported incidence rates of grade 2–3 CIPN reach up to 30% - 50% taxane-based regimens, which are frequently used in breast cancer treatment. Temperature-controlled hand-foot cooling (Hilotherapy) has shown potential in preventing CIPN and is an established component of supportive care in our department. We present the results of our real-world data collection on 580 breast cancer patients who received prophylactic Hilotherapy during chemotherapy. Methods: Temperature-controlled hand-foot cooling with Hilotherm ChemoCare CIPN (Hilotherapy) was used as a standard supportive care during each neurotoxic chemotherapy session. The standard procedure involved cooling the extremities for 30 minutes before, during and 30 minutes after chemotherapy infusion. The device temperature was set to 15–17°C, resulting in a consistent skin surface temperature of 18–20°C. CIPN symptoms were assessed at each treatment cycle according to CTCAE V5.0 criteria. Patients were stratified by taxane dosing schedule (weekly vs. three-weekly). Results: To date 503 of the planned 600 patients have completed chemotherapy. During chemotherapy, a total of 455 (90,5%) developed none or mild symptoms (highest grade: grade 0 = 32,2%, grade 1 = 58,3%). Grade 2 CIPN occurred in 47 patients (9,3%), while two patients reported grade 3 symptoms (0,4%). Conclusions: Temperature-controlled hand-foot cooling (Hilotherapy) effectively prevented ≥ grade 2 CIPN in over 90% of breast cancer patients. This method is a simple, well-tolerated and easily implementable supportive care strategy. Follow-up shows the long-term sustainability.
ErbB family members as mediators of acquired resistance to immunotherapy in high-grade serous ovarian cancer.
5548 Background: Efforts to improve immunotherapy for ovarian cancer (OC) have focused on optimizing T-cell effector-based strategies such as immune checkpoint inhibitors (ICIs), bispecific T-cell engagers (BiTEs), or chimeric antigen receptor (CAR)-T cells, or combining them with other therapeutic modalities. Relatively little is known about how adaptive resistance occurs or how to improve the intrinsic susceptibility of ovarian cancer cells to T cell-mediated cytolysis. Methods: An OC organoid derived from a patient who relapsed on immunotherapy (MGH538) was generated. OVCAR3 immune-edited cell line (OVCAR3 IE ) was generated by treating OVCAR3 wild-type (OVCAR3) tumor-bearing mice with activated T-cells, anti-PD-1, and anti-CTLA4 antibodies. Peritoneal tumors were then harvested and cultured in vitro . BiTEs-resistant cell line (OVCAR3 R ) was generated by treating OVCAR3 cells with anti-MUC16 BiTEs in vitro until the cells were resistant. Comparative RNA sequencing analysis was performed on OVCAR3, OVCAR3 IE , and OVCAR3 R . Protein expression was assessed by Western blot analysis. To evaluate cytotoxicity, OVCAR3, OVCAR3 IE , and OVCAR3 R were co-cultured with MUC16-specific CAR-T cells and MUC16-directed BiTEs, alone or in combination with pharmacologic inhibitors targeting EGFR, RAS, and Bcl-xL, including a Bcl-xL degrader DT2216. Results: MGH538, OVCAR3 IE and OVCAR3 R were confirmed to be resistant to T-cell directed cytolysis compared to OVCAR3. RNA sequencing analysis revealed significant differences in the transcriptome profiles of immune-naive and immunotherapy-exposed OC cells. In particular, significant changes in the RNA expression levels of three out of four ErbB family members (EGFR (ErbB1), ErbB2 and 3) were detected. In Western blot analysis, this finding was paralleled by significant changes in the ratio of phospho-ERK to ERK, an important component of ErbB downstream signaling. In functional assays, EGFR inhibition with gefitinib significantly enhanced CAR-T cell-mediated killing in OVCAR3, OVCAR3 IE and OVCAR3 R cells. Furthermore, blocking downstream EGFR signaling with a Ras inhibitor also restored sensitivity to immunotherapy. Finally, blocking anti-apoptotic signaling with Bcl-family inhibitor navitoclax, or the Bcl-xL inhibitor DT2216 restored susceptibility to both CAR-T cell and BiTEs-mediated killing. Conclusions: Adaptive resistance to T-cell mediated cytotoxicity appears to be mediated, at least in part, by upregulation of ErbB family members and consequent downstream Ras signaling and resistance to apoptosis. While further functional in vitro and therapeutic in vivo studies are warranted to investigate the translational potential of our findings, EGFR signaling may represent a promising target for clinical combination strategies.