Browse Articles
Discover research articles across all indexed journals
Targeting the NRG1/HER3 axis to overcome therapy resistance in head and neck squamous cell carcinoma: Insights from patient-derived xenografts.
e18056 Background: Epidermal growth factor receptor is frequently overexpressed in head and neck squamous cell carcinoma and is associated with poor clinical outcomes. Cetuximab, an approved anti-EGFR monoclonal antibody, yields modest (10–30%) and often non-durable responses due to intrinsic and acquired resistance. Compensatory signaling through other ERBB receptors, including HER3, has been proposed as a bypass mechanism. We aimed to investigate EGFR-family signaling features associated with cetuximab response and resistance using patient-derived xenografts. Methods: A characterized panel of HNSCC PDXs was established. Palpable tumors were cryopreserved and expanded for in vivo cetuximab testing and ex vivo profiling. PDX fidelity to matched patient tumors was assessed by immunohistochemistry. Molecular and proteomic characterization included next-generation sequencing (NGS), Western blotting to evaluate EGFR-family expression and heterodimer distribution. Results: All PDXs recapitulated key morphological and functional traits of the corresponding patient tumors by IHC. Integrated profiling (NGS/Western blot) identified distinct EGFR-related signatures, heterogeneous EGFR-family protein expression, and variable heterodimer patterns across models. These features paralleled differential in vivo sensitivity to cetuximab. In an HPV-negative PDX model, tumors progressing under cetuximab displayed increased expression of EGFR-family members, particularly HER2 and HER3, compared with cetuximab-responsive tumors. Conclusions: Characterized HNSCC PDXs capture clinically relevant heterogeneity and reveal EGFR-family remodeling associated with variable cetuximab response. This platform may help identify HNSCC subgroups for rational combinations incorporating emerging anti-HER3 strategies (e.g., bispecific antibodies, antibody–drug conjugates, or aptamers) to limit compensatory signaling and improve cetuximab efficacy.
Implementation of an outpatient multidisciplinary model for care of immune-related adverse events.
e13608 Background: In recognition of the growing burden of acute and chronic immune-related adverse events (irAEs) experienced by patients (pts) treated with immune checkpoint inhibitors and the need for multidisciplinary expertise, the Cancer Immunotherapy Toxicity Evaluation Program (CITE-P) was created at UCSF. Here, we evaluate the impact of CITE-P since its launch in April 2023. Methods: CITE-P is a medical oncologist-directed and nurse practitioner-led clinic within the UCSF Helen Diller Family Comprehensive Cancer Center. Pts with any irAE can be referred; pts may also self-refer. Expedited in-person and telehealth visits are offered with CITE-P providers, with expedited subspecialty consultation available by referral. Multidisciplinary care is facilitated through biweekly virtual meetings. Retrospective review of patients seen for irAEs at CITE-P was performed. Referral data were collected using the UCSF electronic medical record. Results: Between April 2023 and Dec 2025, 454 new pts were seen by CITE-P, of which 259 (57%) were women, and 194 (43%) were men. 110 (18%) pts were referred from external community or affiliate sites. The most common malignancies represented among referred pts were melanoma/skin cancers (21%), lung cancer (18%), breast cancer (11%), genitourinary cancers (11%), and GI cancers (11%). The most common reasons for referral were for endocrine irAEs (24%), GI irAEs (colitis/diarrhea, 22%), rheumatologic irAEs (14%), and hepatic irAEs (14%). Longitudinal care was important, with this new pt population generating 1531 subsequent follow up visits at UCSF. UCSF Cancer Center new pt metrics were met or exceeded for fiscal year 2025 (FY25), with 100% new pts seen within 14 calendar days from referral (goal 85%), 75% new pts seen within 7 calendar days (goal 75%), and 85% new pts seen within 5 calendar days (goal 85%). Conclusions: CITE-P creates infrastructure for pts diagnosed with acute and chronic irAEs both at UCSF and within our catchment area access to expedited specialty care. This novel multidisciplinary outpatient program facilitates timely multidisciplinary care coordination for pts with irAEs.
Staged dose escalation of adjuvant abemaciclib in high-risk HR+/HER2- early breast cancer: First safety and efficacy data from a Russian cohort.
e12539 Background: This study assessed a staged dose-escalation protocol for adjuvant abemaciclib in routine Russian clinical practice. Methods: We analyzed the outcomes of adjuvant abemaciclib administered at 150 mg once daily during the first month, followed by 150 mg twice daily from month 2 until completion of 2 years of therapy, in 64 women with HR+/HER2- breast cancer between 2022 and 2025. The age range was 28–80 years (median 49), and 48% of patients were premenopausal. All patients had high-risk recurrence criteria consistent with the monarchE trial: 65.6% had N2–3 disease, while 34.4% had N1 disease with additional high-risk features. Grade 3 histology was present in 43.7% of cases, and Ki-67 > 20% was observed in 64.1%. All patients underwent radical surgery (± radiotherapy). Neoadjuvant and adjuvant chemotherapy were administered in 62.5% and 32.9% of patients, respectively. In 4.6% of patients (≥75 years old), abemaciclib was initiated after neoadjuvant endocrine therapy and surgery. All patients received adjuvant endocrine therapy with aromatase inhibitors (with ovarian suppression for premenopausal women) as well as zoledronic acid or denosumab (100% of cases). Results: Adverse events during abemaciclib therapy were reported in 89% of patients, with diarrhea being the most common (all grades: 80%; grade 3: 7.8%). Dose reduction was required in 20% of patients, while permanent discontinuation occurred in only 2.9% (due to grade 3 diarrhea). No thromboembolic complications were observed. In one case (1.6%), interstitial lung disease of grade 1 was detected on baseline CT scan at the start of abemaciclib treatment; its manifestations resolved completely after completion of the 2-year therapy. A total of 28% of patients completed the full 2-year course of abemaciclib, while the remainder continue treatment at the time of analysis. No cases of disease progression or death were reported. All patients maintained a high quality of life and remained socially active. Conclusions: Staged escalation of adjuvant abemaciclib therapy is effective and safe, preserves a high quality of life, and reduces the incidence of severe diarrhea and treatment discontinuation in routine clinical practice.
Socioeconomic focus in neoadjuvant chemoimmunotherapy: An analysis of pathologic complete response and overall survival in clinical stage II-III NSCLC patients.
8039 Background: In 2022, CheckMate 816 supported neoadjuvant chemoimmunotherapy (CTIO) as standard treatment for clinical stage II-III non-small cell lung cancer (NSCLC). Low socioeconomic status has historically been underrepresented in clinical trials, warranting further analysis of CTIO outcomes in patients from diverse socioeconomic backgrounds. This study aims to assess the role of socioeconomic factors on pathologic complete response (pCR) and overall survival (OS) after CTIO. Methods: Data from the National Cancer Database (NCDB) was obtained for patients diagnosed with clinical stage II-III NSCLC between 2022-2023 undergoing CTIO. Complete T, N, and M stage and post-pathologic status (ypT, ypN) were obtained. OS was available for patients diagnosed in 2022. Patients receiving neoadjuvant radiotherapy or with clinical or pathologic metastatic disease were excluded. Group comparisons were based on socioeconomic factors: age (< 75 vs ≥ 75 years), sex, race (Non-Hispanic White vs Other), primary payor at diagnosis, urban/rural, percent no high-school degree quartile, and median income quartile. Primary outcomes were pCR and OS, analyzed via logistic and cox regression models, respectively. All tests were two-sided, and a p-value of < 0.05 was statistically significant. Results: 2,819 patients received CTIO from 2022-2023, with 1,134 patients diagnosed in 2022. Univariate analysis showed patients in the two lowest median income quartiles ($46,277–$57,856: OR 1.40, 95% CI 1.08-1.80, p = 0.011; < $46,277: OR 1.70, 95% CI 1.30-2.23, p < 0.001) had significantly higher odds of pCR compared with those in the highest income quartile (≥$74,063). This effect persisted in multivariate analysis ($46,277–$57,856: OR 1.59, 95% CI 1.19-2.13, p = 0.002; < $46,277: OR 2.00, 95% CI 1.41-2.83, p < 0.001). Univariate analysis showed that other race (HR 0.49, 95% CI 0.29-0.81, p = 0.006) was associated with improved OS compared to Non-Hispanic White, which persisted in multivariate cox analysis (HR 0.50, 95% CI 0.30-0.85, p = 0.010). There were no significant associations for pCR and OS with age, sex, primary payor at diagnosis, urban/rural status, or percent no high school degree quartile. Conclusions: Our findings present promising evidence of improved outcomes of neoadjuvant chemoimmunotherapy among groups facing historical marginalization, namely low-income communities and non-white race. These effects were persistent in multivariate regression models controlling for other socioeconomic variables such as age, sex, primary payor, urban/rural, and percent no high school degree quartile. In light of these findings, further studies with diverse patient populations are warranted to examine the benefit of neoadjuvant chemoimmunotherapy on patients with NSCLC.
Genomic biomarkers of primary resistance to anti-EGFR monoclonal antibodies (mAbs) by comprehensive genomic profiling (CGP) in <i>EGFR</i> -amplified (ampl) advanced gastroesophageal adenocarcinoma (aGEA) and correlative analysis from a single-arm study with panitumumab.
4052 Background: EGFR ampl is found in up to 6% of patients with aGEA and accounts for the efficacy of anti-EGFRs in this patients’ subgroup. The AMNESIA panel with KRAS / PIK3CA / MET mutations and KRAS / EGFR / MET amplifications represented a paradigm of negative selection to trastuzumab in HER2+ aGEA. Here, we aimed to characterize the prevalence and prognostic relevance of genomic drivers of primary resistance to EGFR blockade in EGFR -ampl aGEA. Methods: Patients with EGFR -ampl aGEA were retrieved from 3 CGP screening sources, i.e. the ARMANI phase 3 trial, an observational cohort established at the Fondazione IRCCS Istituto Nazionale dei Tumori (INT) of Milan and 11 patients with EGFR ISH positive aGEA treated with panitumumab as ≥2L from the 117/15 INT screening platform (thereafter Panitumumab study). CGP was performed by means of FoundationOne CDx next-generation sequencing (NGS). AMNESIA-EGFR panel grouped genomic alterations with clinical and biological rationale as driver of primary resistance to anti-EGFR mAbs, i.e. EGFR rearrangements, FGFR2 / HER2 / MET / RAS co-ampl, RAS / MEK1 / PIK3CA ex20 mut, AKT1/2 mut and PTEN loss. We evaluated prevalence of AMNESIA-EGFR alterations in the ARMANI and observational cohort. Then, we explored the prognostic impact of AMNESIA-EGFR panel and lack of EGFR ampl by NGS in the Panitumumab study. Results: EGFR- ampl by NGS was found in 3/130 (2.3%) and 7/128 (5.5%) pts in the ARMANI and observational cohort. EGFR ampl was confirmed by NGS in 8/11 pts (73%) in the panitumumab cohort. Among patients with EGFR -ampl tumors by NGS, AMNESIA-EGFR alterations were found in 9/18 (50%) pts, including: KRAS ampl (16.7%), EGFR rearrangement (11.1%), PTEN loss (11.1%), FGFR2 co-ampl (5.6%), MET co-ampl (5.6%) and MEK1 mut (5.6%). AMNESIA-EGFR panel alterations were mutually exclusive, except for one case with concurrent MET co-ampl and MEK1 mutation. In the Panitumumab study, disease control rate (DCR) was 18.2% including a partial response and a stable disease. Median progression-free survival (PFS) and overall survival (OS) were 2.0 months (95%CI, 1.8-NA) and 5.3 months (95%CI, 3.38-NA). 7/11 pts had tumors with AMNESIA-EGFR alterations or lacked EGFR ampl by NGS. AMNESIA-EGFR+ or lack of EGFR ampl were associated with inferior DCR (0% vs 50%), PFS (median PFS 2.0 vs 3.8 months; HR 3.17 [95% CI, 0.64-NA] and OS (median OS 5.3 vs 6.4 months; HR 1.80 [95%CI, 0.45–7.14]). Conclusions: Genomic drivers of primary resistance to anti-EGFR mAbs are common in EGFR -ampl aGEA. A negative selection paradigm based on CGP may optimize outcomes with anti-EGFRs. Innovative drugs that may bypass resistance mechanisms to mAbs, such as bispecific antibodies, antibody-drug conjugates and bispecific T-cell engagers, are awaited.
Potential effects of TGF-β inhibition on immune resistance by targeting immunosuppressive microenvironment in advanced gastric cancer (AGC): Multi-omics post-hoc analysis of the K-Umbrella-06 trial.
2612 Background: TGF-β signaling promotes immune exclusion by driving fibrosis and hindering T-cell infiltration. We performed multi-omics post-hoc analyses of K-Umbrella-06 to identify mechanisms and predictive biomarkers for TGF-β/PD-L1 dual blockade in HER2-negative AGC. Methods: K-Umbrella-06 (NCT04835896) was an investigator-initiated, single-arm, phase Ib/II study enrolling HER2-negative AGC pts who had progressed on 1st-line treatment. Pts received bintrafusp alfa (TGF-β trap/anti–PD-L1) and weekly paclitaxel. Pretreatment H&E whole-slide images (WSIs) were analyzed with an AI-powered WSI analyzer to quantify fibroblast and endothelial cell (EC) densities and immune phenotypes. A separate cohort treated with nivolumab + paclitaxel (n=26) served as a control. Integration of baseline tissue transcriptomics and serial ctDNA sequencing (baseline, 1 st RECIST assessment, and progression) was performed to identify predictive biomarkers and resistance mechanisms. Results: At a median follow-up of 46 months in 30 enrolled patients, the mPFS and mOS were 3.8 and 8.9 months, respectively; notably, 5 patients achieved durable responses with PFS exceeding 3 years. AI-WSI analysis revealed that high fibroblast density (≥median) was a significant predictor of superior outcomes (mPFS: 4.3 vs. 2.0 months, HR 0.29, P=0.007; mOS: 20.4 vs. 5.8 months, HR 0.28, P=0.012). Conversely, patients with higher intratumoral EC density had shorter mPFS (2.0 vs. 5.9 months, HR 2.29, P=0.058) and mOS (4.0 vs. 8.9 months, HR 1.61, P=0.285). Notably, patients with the immune-excluded phenotype achieved a higher ORR (60.0% vs. 18.2%) and prolonged survival compared to inflamed/desert types. These biomarkers were not predictive in the nivolumab + paclitaxel cohort, suggesting a TGF-β specific effect. Transcriptomic profiling of responders showed enrichment in TGF-β signaling (normalized enrichment score [NES] 2.87, P<0.001) and SMAD2/3 activity (NES 2.99, P<0.001), alongside increased naive CD8+ T cells and inflamed EC cells. Conversely, non-responders exhibited higher M2 macrophage and abundant angiogenic tip cells. Serial ctDNA analysis identified emergent TGF-β pathway alterations as a potential mechanism of acquired resistance (OR 7.30, P=0.08). Conclusions: Integrated AI-WSI, transcriptomic, and longitudinal ctDNA analyses suggest that TGF-β pathway activation and an immune-excluded phenotype are associated with clinical benefit from bintrafusp alfa plus paclitaxel, and may identify a responder subset distinct from conventional PD-1/PD-L1–based therapy. These findings support further evaluation of anti–TGF-β strategies for AGC with an immunosuppressive tumor microenvironment. Clinical trial information: NCT04835896 .
Reduced oxaliplatin exposure in gastrointestinal cancers: A systematic review and meta-analysis.
3592 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent dose-limiting toxicity from oxaliplatin that impairs quality of life in gastrointestinal (GI) cancer patients (pts). While strategies to limit exposure exist, their impact on survival remains debated. We evaluated whether reduced oxaliplatin exposure (ROE) maintains survival while mitigating toxicity. Methods: We conducted a systematic review and meta-analysis (PubMed, Embase, Scopus, Web of Science, EBM Reviews) of studies comparing ROE vs standard-duration oxaliplatin-based chemotherapy in GI cancers. ROE was defined as planned limitation of oxaliplatin exposure, including shortened duration (3-4 months), maintenance-based de-escalation, or stop-and-go strategies. Primary endpoints were disease-free survival (DFS) in curative settings, progression-free survival (PFS) in palliative settings, and overall survival (OS). Secondary endpoints included grade ≥3 CIPN and grade ≥3 adverse events (AEs). Random-effects models used Hartung-Knapp-Sidik-Jonkman correction. Heterogeneity was assessed via I² and Cochran’s Q. Results: 24 studies, comprising 15 randomized controlled trials (RCTs) and 9 retrospective cohorts, were included (N = 30,404 pts; ROE: 13,348; control: 17,056). Settings included adjuvant colorectal cancer (CRC; n = 14), metastatic CRC (mCRC; n = 5), gastric cancer (GC) (adjuvant n = 1, metastatic n = 3), and metastatic pancreatic cancer (PDAC) (n = 1). ROE strategies included shortened duration (n = 14), maintenance (n = 8), and stop-and-go (n = 2). In adjuvant CRC, ROE did not compromise DFS (HR 1.07; 95% CI, 0.98-1.16; p = 0.12; I² = 21.7%), including in high-risk subgroups (HR 1.14; 95% CI, 0.93-1.40; p = 0.14; I² = 38.9%); OS was also not different between groups (HR 1.00; 95% CI, 0.94-1.07; p = 0.89; I² = 0%), including high-risk pts (HR 1.01; 95% CI, 0.93-1.10; p = 0.68; I² = 0%). In mCRC, ROE showed no detriment to PFS (HR 1.11; 95% CI, 0.99-1.25; p = 0.07; I² = 0%) or OS (HR 1.06; 95% CI, 0.92-1.23; p = 0.33; I² = 0%). Similarly, in metastatic gastric cancer, PFS (HR 0.82; 95% CI, 0.34-1.99; p = 0.44; I² = 77.3%) and OS (HR 0.90; 95% CI, 0.67-1.21; p = 0.26; I² = 0%) were comparable. Findings remained concordant after restricting the analysis to only RCTs. Pooled analysis was not feasible for PDAC and adjuvant GC studies, but individual study findings were consistent with the above. ROE significantly reduced the risk of grade ≥3 CIPN (OR 0.32; 95% CI, 0.20-0.53; p < 0.001; I² = 80.6%) and overall grade ≥3 AEs (OR 0.65; 95% CI, 0.50-0.86; p = 0.01; I² = 59.9%). Conclusions: Across GI malignancies, ROE was not associated with inferior DFS, PFS, or OS and was associated with lower rates of severe neurotoxicity and high-grade AEs. These findings support planned limitation of oxaliplatin exposure as a strategy to improve the therapeutic index of oxaliplatin-based chemotherapy across disease settings.
Temporal and demographic trends in hypertension-associated breast cancer mortality in the United States: A CDC WONDER analysis (1999–2020).
e13097 Background: Hypertension is the most common comorbidity among breast cancer survivors and is independently associated with higher breast cancer specific mortality. However, population-level trends and disparities when both conditions co-occur remain poorly described. This study examined temporal trends, demographic disparities, and geographic variation in hypertension-associated breast cancer mortality in the U.S. Methods: Mortality data were obtained from the CDC WONDER Multiple Cause of Death database from 1999–2020. Deaths were included when both breast cancer (ICD-10 C50) and hypertensive disease (ICD-10 I10–I15) were listed as contributing causes among adults aged ≥55 years. Age-adjusted mortality rates (AAMRs) per 100,000 populations were calculated using the 2000 U.S. standard population. Temporal trends were assessed using Joinpoint regression to estimate annual percent change (APC) and average annual percent change (AAPC). Analyses were stratified by age, sex, race/ethnicity, urbanization level, census region, and U.S. state. Results: From 1999–2020, 107,759 deaths were attributed to breast cancer in the U.S., with AAMRs rising from 3.8 to 8.8 per 100,000. Joinpoint regression identified rapid increase 1999–2001 (APC 20.4%, 95% CI 9.77–30.0; p < 0.001), moderate rise 2001–2007 (APC 1.88%, 95% CI 0.04–4.52; p = 0.046), slight decline 2007–2018 (APC −0.59%, 95% CI −4.01–−0.05), and sharp increase 2018–2020 (APC 14.6%, 95% CI 7.7–19.9). Mortality was highest in adults ≥85 years (47 per 100,000 in 2020). Ages 55–64 showed rapid rise 1999–2003 (APC 12.5%, 95% CI 6.17–27.8; p < 0.01), stability 2003–2018, and sharp increase 2018–2020 (APC 20.8%, 95% CI 8.47–30.2; p < 0.001). Females had higher mortality than males (15.1 vs. 0.2), with male rates stable (APC 0.92%, 95% CI −0.72–2.86; p = 0.22). Female rates rose steeply 1999–2001 (APC 26.8%), moderately 2001–2008 (APC 1.92%), and sharply 2018–2020 (APC 15.5%). Non-Hispanic (NH) Black individuals had the highest AAMRs (13.8), NH Asian/Pacific Islander the lowest (4.7). NH White rates rose 1999–2001 (APC 26.8%), stable 2001–2018, then rose 2018–2020 (APC 12.8%). NH American Indian/Alaska Native rates rose steadily (APC 2.48%). States with age-adjusted mortality rates above the 90th percentile included District of Columbia (12.2), Nebraska (11.2), Mississippi (11.1), Oklahoma (11.1), and Ohio (10.6). Nonmetro (10.0) and micropolitan (9.6) areas had higher mortality. Large central metros rose rapidly 1999–2001 (APC 20.8%), modestly through 2010, declined 2010–2018, and rose again 2018–2020 (APC 12.6%). Conclusions: Hypertension-associated breast cancer mortality has risen over the past two decades, especially among older women, NH Black populations, and residents of rural or high-burden states which underscore the need for targeted public health interventions to reduce disparities.
Evaluating squalene epoxidase association with cholesterol-dependent AKT activation and prognosis in gallbladder cancer.
e16297 Background: Gallbladder cancer (GBC) is a highly aggressive biliary tract tumor with limited therapeutic options and poor prognosis. Metabolic reprogramming, particularly cholesterol metabolism, has emerged as a critical driver of tumor progression. Squalene epoxidase (SQLE), a rate-limiting enzyme in cholesterol biosynthesis, has been implicated in multiple cancers; however, its role and underlying mechanisms in GBC remain largely unclear. Methods: \We analyzed SQLE expression in human GBC tissues and paired adjacent para-tumor tissues using quantitative PCR, western blotting and immunohistochemistry, and evaluated its association with clinicopathological features and patient survival. Kaplan–Meier survival analysis was performed to determine the prognostic significance of SQLE. Stable SQLE knockdown and overexpression cell lines were established, and functional assays including proliferation, migration, and apoptosis assays were conducted in GBC cell lines, as well as SQLE inhibitor treated groups. Cholesterol quantification, Filipin staining were performed to elucidate the mechanistic role of SQLE in cholesterol-mediated AKT activation. In vivo tumorigenicity and therapeutic response were evaluated using a subcutaneous xenograft model in nude mice. Results: SQLE was significantly upregulated in GBC tissues compared with adjacent para-tumor tissues and was positively correlated with advanced TNM stage. High SQLE expression was associated with significantly shorter overall survival. Functional studies demonstrated that knocking down or inhibiting SQLE markedly suppressed GBC cell proliferation, migration, and invasion, while inducing apoptosis, and overexpressing SQLE had the opposite results. Mechanistically, SQLE inhibition reduced intracellular cholesterol levels and attenuated downstream AKT signaling. In vivo, targeting SQLE significantly inhibited tumor growth in subcutaneous xenograft model in nude mice. Conclusions: Our findings identify SQLE as a critical regulator of cholesterol-dependent AKT activation and a potent oncogenic driver in GBC. Targeting SQLE represents a promising therapeutic strategy and prognostic biomarker for patients with gallbladder cancer.
<i>CBFB</i> mutations as a predictive biomarker of endocrine therapy benefit in hormone receptor–positive (HR+) breast cancer: Discovery and validation in 3,799 patients.
1089 Background: Endocrine therapy (ET) is the mainstay approach for treating HR+ breast cancer, yet resistance frequently limits efficacy. Identifying reliable genomic biomarkers to predict superior treatment response remains an unmet clinical need. Methods: We performed unbiased genomic analysis of HR+ patients from the MSK-CHORD cohort (n=2,058), stratified by disease stage (metastatic vs. non-metastatic). Outcomes included progression-free survival (PFS), recurrence-free survival (RFS), and overall survival (OS). FDR-corrected Cox models were used for gene-level discovery. A chemotherapy-treated subset of the MSK-CHORD cohort served as a control to assess treatment specificity. Findings were externally validated in the independent METABRIC cohort (n=1,741). Results: Beyond known resistance biomarkers (ESR1, TP53, RB1), loss-of-function mutations in CBFB emerged as a significant predictor of ET benefit. CBFB mutations were present in 6.7% of metastatic breast cancer (MBC; n=80) and 6.3% of non-MBC (n=54). In MBC patients, CBFB mutations were associated with significantly longer PFS (HR=0.44; p=0.0002); in the adjuvant setting, RFS was similarly improved (HR=0.48; p=0.009). OS was prolonged in both settings (HR=0.49 and 0.50; p<0.05 for both). CBFB mutations were enriched in lobular histology (OR=2.3; p<0.0001); however, multivariable Cox regression confirmed CBFB as an independent predictor after adjusting for histology (HR=0.46; p=0.0003). To provide biological validation, we analyzed RUNX1, the obligate functional partner of CBFB in the CBF transcription complex. Combined CBFB/RUNX1 mutations (n=122, 10.2% in MBC; n=82, 9.5% in non-MBC) demonstrated consistent predictive benefit (HR=0.48 and 0.56; p<0.0001 and p=0.007, respectively). Notably, the survival benefit associated with CBFB or CBF-complex mutations was absent in chemotherapy-treated controls, confirming treatment-specific predictive value rather than general prognostic effect. In the METABRIC validation cohort, CBFB mutations (5.9%; 103/1,741) independently predicted longer relapse-free survival (HR=0.59; p=0.005) and OS (HR=0.52; p<0.0001). Gene expression analysis revealed that CBFB mutations were associated with significantly lower APOBEC gene family expression (p<0.001), suggesting a mechanistic link between CBF-complex loss and reduced APOBEC-mediated mutagenesis, an established driver of endocrine resistance. Conclusions: We identify CBF-complex (CBFB/RUNX1) mutations as a novel genomic biomarker of ET benefit in HR+ breast cancer, independent of disease stage and histology, and validated across two large cohorts. These findings highlight a subset of patients with exceptional outcomes and provide a potential mechanistic link between CBF alterations and APOBEC-mediated resistance.
Immunotherapy combined with chemotherapy versus chemotherapy alone in advanced pancreatic ductal adenocarcinoma: A real-world retrospective cohort study.
e16437 Background: Conventional chemotherapy remains the first-line standard for advanced pancreatic ductal adenocarcinoma (PDAC), while the benefit of combining immunotherapy with chemotherapy remains controversial. This retrospective study aimed to evaluate the efficacy, safety, and potential predictive biomarkers of first-line immuno-chemotherapy in advanced PDAC. Methods: We analyzed clinical data from 203 patients with advanced PDAC treated at the First Affiliated Hospital of Sun Yat-sen University. Patients were categorized into two groups: the chemotherapy-alone group (CT, n = 114) receiving nab-paclitaxel plus gemcitabine (AG) or (m)FOLFIRINOX, and the immuno-chemotherapy group (ICT, n = 89) receiving the same two chemotherapy regimens combined with PD-1/PD-L1 inhibitors. Comprehensive analysis included survival statistics, multivariable Cox regression, and exploratory biomarker assessments. Results: Patients in the ICT group had a significantly longer median overall survival (OS) than those in the CT group (19.2 vs. 14.3 months, Hazard Ratio [HR] = 0.62, p = 0.011). The 12-month progression-free survival (PFS) showed a significantly longer restricted mean survival time (RMST) in the ICT group compared with the CT group (RMST 0-12 = 8.61 vs. 7.13 months; difference = 1.48 months, 95% CI 0.36-2.60, p = 0.010). The disease control rate was significantly higher in the ICT group (86.5% vs. 63.2%, p < 0.001), while the overall response rate had no significant difference (16.8% vs. 15.8%, p = 0.839). No significant differences were observed in the incidence or severity of treatment-related adverse events (AEs) between the two groups. All immune-related AEs in the ICT group were mild to moderate (Grade 1-2). Biomarker exploration in a genomic subset (n = 67) identified TP53 mutation status as a significant modifier of treatment benefit, with TP53-mutant patients deriving substantial survival advantage from ICT (interaction HR = 0.19, p = 0.018). Conclusions: Compared to chemotherapy alone, first-line immuno-chemotherapy is associated with a significant improvement in overall survival in advanced PDAC, and may offer an early survival advantage. TP53 mutation may serve as a predictive biomarker for efficacy benefit from immune-chemotherapy, which supports the potential for future patient stratification strategies.
Ribozymes for RNA‐Catalyzed RNA Methylation and Labeling
ABSTRACT RNA is a cornerstone of life, executing diverse essential functions. A key determinant of RNA's functional versatility lies in natural nucleoside modifications, which greatly expand the chemical diversity and are vital for regulating the stability, folding, and function of RNA structures involved in cellular processes. Artificially introduced RNA modifications such as reactive handles, affinity tags or fluorescent reporters, are key to enable RNA isolation, imaging and tracking, in order to unravel the important regulatory roles of RNAs in any organism. Covalent RNA labeling methods are particularly desirable for downstream applications. RNA catalysts, so‐called ribozymes, have gained increasing attention as tools for the site‐directed installation of various functionalities, such as clickable tags, fluorophores, or methyl groups. Thereby, ribozymes can create both, artificially as well as naturally modified RNAs of interest. This review provides a collection of currently available ribozymes for the covalent modification of RNA that were obtained by in vitro selection using suitable cofactors. We discuss self‐modifying catalysts for RNA tagging and fluorescent labeling, as well as ribozymes for RNA‐modification in an intermolecular setup. Finally, we introduce the growing collection of methyltransferase ribozymes for site‐specific installation of natural methylated nucleosides and provide an outlook on open questions and future developments of the research field.
Spiro‐Fluorene Locked Multi‐Resonance Emitters Enabling High‐Performance Pure‐Green OLEDs With CIEy Coordinate of 0.77
ABSTRACT Pure‐green organic emitters compliant with the Broadcast Television 2020 (BT.2020) green standard are critical for ultra‐high‐definition (UHD) organic light‐emitting diodes (OLEDs). Herein, we propose a simple yet effective spiro‐fluorene locking strategy to develop two pure‐green multi‐resonance thermally activated delayed fluorescence (MR‐TADF) emitters, namely DBN‐MS and DBN‐TMS. The introduction of the spiro‐fluorene units not only extend π‐conjugation to redshift emission to 512–513 nm but also enhance molecular planarity and rigidity, suppressing vibrational relaxation and enabling ultra‐narrow full‐width at half‐maximum (FWHM = 16 nm) in toluene. Notably, DBN‐MS maintains stable emission profile ( λ em = 518–520 nm, FWHM = 19–20 nm) across a broad doping concentration range (1‐10 wt%), effectively mitigating spectral broadening and aggregation‐caused quenching. Non‐sensitized OLEDs exhibit a maximum external quantum efficiency (EQE) of 35.5%, low efficiency roll‐off with an EQE value of 26.9% at 1000 cd m −2 , and remarkable operational stability with lifetime (LT 90 ) of 167 h in a stable device structure. More importantly, the state‐of‐the‐art CIEy coordinates of 0.76–0.77 are demonstrated over 1–10 wt% broad doping range, representing the first bottom‐emitting green OLED with a CIEy value reaching 0.77, and the closest to the BT.2020 green standard reported to date.
Unravelling the Secret of Sulfur Confinement and High Sulfur Utilization in Hybrid Sulfur‐Carbons
ABSTRACT Understanding sulfur confinement and chemical transformation in hybrid sulfur‐carbon materials is critical for advancing metal‐sulfur batteries. Here, we investigate the structural evolution of a sulfur‐rich polymer into a hybrid sulfur‐carbon via inverse vulcanization and thermal condensation. Multiscale analyses reveal a stepwise transformation, beginning with the emergence of sulfur radicals at ∼175°C, followed by the progressive development of a carbon matrix above 300°C that stabilizes the radical species. Around 450°C, a transitional phase forms, consisting of conjugated carbon clusters covalently bonded to sulfur chains. This hybrid structure confines sulfur within pseudo‐graphitic nanodomains, effectively suppressing polysulfide dissolution and enhancing redox stability. DFT simulations show how sulfur confinement modulates Na‐S reaction energetics, while electrochemical testing confirms high sulfur utilization, delivering ∼1000 mAh and 1200 Wh , setting a new performance benchmark for room‐temperature Na─S batteries. These findings provide critical insights into the correlation between structural evolution and electrochemical performance, offering design principles for next‐generation sulfur‐based electrodes.
Effect of menopausal status on cognitive function and sleep in breast cancer survivors.
e12709 Background: The majority (70-80%) of invasive breast cancers (BC) express estrogen receptors, making endocrine therapy a cornerstone of most BC treatments. However, this therapy can induce menopause or hypoestrogenism in premenopausal women, and is associated with numerous negative symptoms (e.g., sleep problems). Many BC survivors also report cognitive dysfunction both during and after treatment, which is also associated with poor sleep quality, underscoring the need to examine cognitive function and sleep quality in relation to menopausal status. This study examines differences in cognitive function and sleep disturbance among BC survivors by menopausal status (1: pre/peri-menopausal, 2: naturally post-menopausal, and 3: cancer- or treatment-induced post-menopausal). Methods: This secondary, cross-sectional analysis included baseline data from 180 BC survivors from two cohorts (n = 128 stages 0-III; n = 52 stage IV). Sociodemographic information, clinical characteristics, and PROMIS Sleep Disturbance 4a assessments were collected via REDcap surveys. Administration of remote cognitive test batteries (via BrainCheck) included the Trail Making Test – Parts A and B (TMT-A, TMT-B), Digit Symbol Substitution Test (DSST), Stroop Color-Word Test, and the Immediate and Delayed Memory Tests. Analysis of covariance was conducted to assess the effect of menopausal status on the standardized cognitive test scores and sleep disturbance (t scores), covarying for years of education and age. Post hoc comparisons with Bonferroni corrections and effect sizes were also calculated. Results: Significant main effects of menopausal status were found for sleep disturbance (p = 0.012; ω² = 0.049) and TMT-A scores (p = 0.045; ω² = 0.036). Post hoc comparisons indicated that pre/peri-menopausal survivors had significantly lower sleep disturbance than naturally post-menopausal survivors (p = 0.009, Cohen’s d = 0.84). Naturally post-menopausal survivors performed worse than cancer-induced post-menopausal survivors on the TMT-A (p = 0.043, Cohen’s d = 0.51). Since Homogeneity of Variance was violated for Delayed Memory scores, nonparametric models (Kruskal-Wallis) and post hoc tests (Dunn’s) were conducted. A significant main effect for menopausal status was found (p = 0.02; rank ε² = 0.045), with pre/peri-menopausal survivors having significantly higher scores than naturally post-menopausal survivors (p = 0.022) and cancer-induced post-menopausal survivors (p = 0.022). Conclusions: After controlling for age, BC survivors who have gone through natural menopause before treatment may be more vulnerable to sleep disruption, slower processing speed, and worsened memory performance compared to pre/peri-menopausal BC survivors. Further, BC survivors who have gone through cancer- or treatment-induced menopause may be more vulnerable to worsened memory performance compared to pre/peri-menopausal BC survivors.
Patient access to precision medicine: Immune checkpoint inhibitor (ICI) usage in non-small cell lung cancer (NSCLC) and association with income levels across multiple Asian markets.
e13743 Background: Regimens containing ICIs are now considered the recommended treatment option for 1 st line (1L) advanced/metastatic NSCLC patients who are wild-type (WT) for EGFR, ALK and ROS1. However, due to their cost, some patients are unable to afford these treatment options, especially in countries where reimbursement coverage is partial or absent. This study uses real-world data to investigate the correlation between monthly household income levels (MHHI) and ICI shares in Thailand, Vietnam, Taiwan and Mainland China, and how this has evolved since 2022. Methods: Ipsos’ Oncology Monitor is a physician-reported syndicated patient record database. Between July 2021 and June 2022, 502 cancer-treating physicians (Thailand=37, Vietnam=80, Taiwan=40, China=345) were screened for specialty, role and caseload, and submitted data on 1,069 1L WT stage IIIB/IV NSCLC patients (aggregate) with known MHHI. This was compared to data collected between July 2024 and June 2025, based on data from 365 cancer-treating physicians (Thailand=27, Vietnam=84, Taiwan=53, China=201) reporting on 1,342 patients. Results: In 3 out of 4 countries, an association was observed between MHHI and the percentage of reported WT patients in each cohort receiving an ICI as part of their current 1L therapy, across both time points. In Taiwan, this association was observed in the earlier time point, but was not noted in the most recent dataset. In Mainland China, ICI uptake increased across all MHHI cohorts, but remained the highest in the highest-income segment. In Thailand and Vietnam, no progress was made in increasing access to ICIs among the lowest-income segments between July 2021 and June 2025. Conclusions: In the two South-East Asian markets included in this study, access to ICIs remains largely limited to those with higher MHHIs. While access in Mainland China has increased across all income segments and is relatively high overall, a disparity between those in the highest MMHI band and the other MMHI groups continues to exist. Only Taiwan is now displaying a relatively equal usage across all MMHI segments. More progress must be made across the region to ensure equal access to optimal treatments for all. Thailand Vietnam Taiwan Mainland China MHHI <39,999 THB MHHI 40,000 - 100,000 THB MHHI >100,000 THB MHHI <7,500,000 VND MHHI 7,500,000 - 12,000,000 VND MHHI >12,000,000 VND MHHI <40,000 NTD MHHI 40,000-100,000 NTD MHHI >100,000 NTD MHHI <7,000 CNY MHHI 7,000-9,999 CNY MHHI >10,000 CNY % of reported patients in each cohort receiving an ICI as part of their current 1L therapy for WT stage IIIB/IV NSCLC 2021-2022(n), % (20)10% (17)53% (24)79% (42)7% (109)5% (135)39% (24)21% (66)36% (20)35% (141)32% (173)36% (298)51% 2024-2025(n), % (18)6% (24)58% (33)67% (67)3% (131)2% (268)29% (42)29% (121)31% (46)33% (111)57% (133)54% (221)67%
Comparative efficacy of linvoseltamab versus teclistamab in triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM): Updated matching-adjusted indirect comparison (MAIC) with longer follow-up.
7526 Background: Linvoseltamab and teclistamab are anti-B-cell maturation antigen (BCMA)×CD3 bispecific antibodies evaluated in the LINKER-MM1 and MajesTEC-1 trials, respectively, and approved for TCE RRMM. In the absence of head-to-head trials, a previous MAIC assessed their relative efficacy at ~14-month median follow-up (mFU). We present updated results with longer follow-up for both trials. Methods: After excluding 10 patients (pts) with prior BCMA antibody–drug conjugate exposure from LINKER-MM1 to align with MajesTEC-1 eligibility, pt-level data from LINKER-MM1 (linvoseltamab 200 mg, N=107; data cut-off [DCO] July 2024; mFU 21.3 months) and aggregate data from MajesTEC-1 (N=165; DCO August 2023; mFU 30.4 months) were used. LINKER-MM1 pts were weighted to match MajesTEC-1 using prespecified prognostic factors, as described previously (Lee et al., Clin Lymphoma Myeloma Leuk 2025;25:897–909). MAICs were rerun for objective response rate (ORR), very good partial response or better (≥VGPR) rate, complete response or better (≥CR) rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS) and time to next treatment (TTNT). Treatment effects were estimated using odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs). Restricted mean survival time (RMST) was evaluated at 30 months. Results: In both unadjusted comparisons and MAICs adjusted for 6 key prognostic factors (cytogenetic risk, age, refractory status, ISS stage, ECOG score, extramedullary disease/plasmacytoma status; effective sample size 82.5), linvoseltamab showed numerically higher ORR, ≥VGPR, and ≥CR rates and significantly longer DOR, PFS, OS, and TTNT vs teclistamab (Table). Compared with prior MAICs with shorter follow-up, adjusted HRs for DOR and TTNT further decreased in favor of linvoseltamab, while other results remained stable. Conclusions: With longer follow-up, linvoseltamab continued to demonstrate comparative efficacy advantages vs teclistamab, reinforcing its potential as an effective treatment option for TCE RRMM. Outcome, linvoseltamab vs teclistamab Unadjusted Adjusted for 6 key prognostic factors OR (95% CI) OR (95% CI) ORR 1.44 (0.97–2.13) 1.50 (0.97–2.32) ≥VGPR 1.19 (0.83–1.72) 1.17 (0.79–1.74) ≥CR 1.29 (0.91–1.82) 1.21 (0.83–1.76) HR (95% CI); RMST difference, months (95% CI) HR (95% CI); RMST difference, months (95% CI) DOR 0.58 (0.36–0.96)*;3.66 (0.77–6.55)* 0.54 (0.31–0.92)*;4.06 (1.13–6.98)* PFS 0.57 (0.40–0.82)*;5.13 (2.01–8.25)* 0.55 (0.36–0.82)*;5.43 (2.04–8.81)* OS 0.68 (0.47–0.98)*;2.99 (0.22–5.75)* 0.64 (0.43–0.97)*;3.06 (0.08–6.04)* TTNT 0.42 (0.28–0.62)*;7.10 (4.27–9.94)* 0.41 (0.27–0.64)*;7.12 (4.15–10.09)* *p<0.05. OR >1, HR <1, or RMST >0 indicate better efficacy with linvoseltamab vs teclistamab.
Real-world evidence of the association between primary insomnia and early-onset hormone-related cancers.
11014 Background: Although progress has been made in reducing overall cancer incidence, early-onset cancers have continued their troublesome rise. Similarly, primary insomnia increases in incidence and prevalence each year, and with it come likelihoods of circadian disruption, immune dysregulation, and altered hormone signaling. However, real-world data characterizing the association between insomnia and early-onset hormone-associated malignancies remains limited. Methods: We sought to conduct a real-world, retrospective cohort study using the TriNetX United States Research Database, a federated network of de-identified electronic health records (EHRs) from over 70 healthcare organizations, to examine this association. Adults aged 18–50 years with primary insomnia (ICD-10: F51.01) were compared with same-aged individuals without primary insomnia using a five-year lookback period from January 25th, 2021 to January 25th 2026. Propensity score matching adjusted for demographic and clinical confounders. Incidence of early-onset cancers diagnosed within five years of the index event was assessed during follow-up. Sensitivity analyses required a ≥ 1-year lag between insomnia diagnosis and cancer onset. Results: 413,116 patients ages 18-50 were identified as having primary insomnia, whereas 18,437,709 patients ages 18-50 were identified as not having primary insomnia. Within 1-5 years of primary insomnia diagnosis, patients were more likely to develop early-onset breast cancer (RR 3.155, CI 2.863-3.477, p < 0.0001), uterine cancer (RR 1.988, CI 1.532-2.580, p < 0.0001), and ovarian cancer (RR 1.573, CI 1.276-1.940, p < 0.0001). Associations with early-onset prostate cancer (RR 1.676, CI 1.096-2.564) and testicular cancer (RR 1.243, CI 1.015-1.522) did not meet thresholds for significance. Conclusions: In this large, real-world cohort study, insomnia was associated with an increased risk of early-onset hormonal cancers more commonly affecting female patients. These findings suggest that sleep disruption may represent a clinically relevant, potentially modifiable risk factor in early-onset cancer risk stratification and warrants further investigation.
AYA POWER: An innovative and sustainable virtual model for AYA oncology education.
e21014 Background: Adolescents and young adults (AYAs, ages 15–39) with cancer face care and outcome disparities due to complex care delivery and limited provider training in AYA-specific needs. Most pediatric and medical oncology training programs lack formal AYA oncology curricula, creating a critical educational gap. To address this, AYA POWER was developed, the first interdisciplinary, virtual curriculum for oncology trainees. AYA POWER provides high-yield education to build provider confidence, identify gaps in care, and improve outcomes for AYAs with cancer. Methods: Informed by prior needs assessments, AYA POWER curriculum has covered 16 sessions on priority topics including disparities, sexual/reproductive health, psychosocial care, financial toxicity, advanced cancer, clinical trials, and survivorship from August 2023-May 2025. Sessions featured 60-minute live monthly virtual lectures, discussion, recorded content, and shared resources. Participation was assessed using registration information, including demographic and website analytics data. Following each session, attendees completed surveys evaluating satisfaction with content and overall value of the program. Results: As of May 2025, AYA POWER has reached 2,135 engagements, reflecting attendance at live virtual sessions as well as views of on-demand lecture recordings. 1,042 participants joined the live lectures, representing 528 unique attendees, as some participants joined multiple lectures. A diverse group of AYA stakeholders attended, including nurses, social workers, pediatric oncology attendings, administrators, advanced practice providers, oncology fellows, researchers, patient advocates, psychologists, and medical oncology attendings and represented 15 countries. Anonymous feedback over the two seasons (216 respondents) was overwhelmingly positive. Respondents noted the relevance, practicality, and depth of the AYA POWER curriculum, highlighting its focus on under-discussed, evidence-based topics and actionable tools for AYA cancer care. Respondents emphasized the rarity and importance of AYA-specific education and expressed strong interest in expanded content, more case-based examples, additional topics, and continued programming. Conclusions: AYA POWER responds to a clear deficit in oncology training by delivering a flexible, scalable curriculum centered on the specialized needs of AYAs with cancer. Because AYA-focused education is often minimal or absent in traditional training programs, this initiative prioritizes topics that are frequently overlooked. Broad participation from a global, interdisciplinary audience demonstrates both the practicality of the virtual format and strong demand for continued learning across roles and regions.
Disparities in breast cancer screening: Insights from an adult female outpatient population in the Northeastern United States.
e13721 Background: Breast cancer (BC) is the most frequently diagnosed cancer among women globally (excluding non-melanoma skin cancer), accounting for 15.4% of cancer-related deaths. Adherence to United States Preventive Services Task Force (USPSTF) recommendations for biennial screening mammography (BSM) among women remains suboptimal. We aimed to identify barriers to BC screening and characterize healthcare disparities within the adult primary care setting of a large tertiary-care hospital in Hartford, Connecticut. Methods: We conducted a retrospective observational study using Epic (Healthy Planet) electronic medical records of women aged 40-74 years referred for BSM between October 2022 and October 2025. The primary outcome was overdue status for BSM per USPSTF guidelines. Variables associated with healthcare disparities were collected for 1,223 patients and compared by overdue status using Wilcoxon rank-sum and Fisher’s exact tests. False discovery rates were controlled using Benjamini-Hochberg q-values. Multivariable logistic regression was performed to assess associations between risk factors and overdue status. Results: Among 1,223 eligible women, 637 (52.1%) were overdue. In baseline comparisons, overdue status differed significantly by age (median 60 vs 58), race/ethnicity (Hispanic/Latino 64% vs 50.7%), preferred language (English 54.6% vs 68.6%), insurance status (Medicaid 25.1% vs 35.6%), substance use (3.4% vs 10.5%), time since last primary care physician (PCP) visit (<1 year 84.1% vs 59.8%), and personal history of BC (7.8% vs 3.5%) (all q-values <.05). In multivariable analysis, Spanish-speaking and married women were significantly less likely to be overdue, whereas higher odds were associated with Medicaid insurance, substance use, and last PCP visit >1 year ago (all p-values <.05) (Table 1). Conclusions: These findings demonstrate significant sociodemographic and clinical disparities in USPSTF-concordant BC screening, identifying actionable subgroups for targeted outreach. Time since last PCP visit showed the strongest association with overdue screening. Future studies should evaluate whether addressing these barriers improves screening equity and reduces disparities. Multivariable logistic regression for overdue status (reference: up to date). Variables Category (vs reference) OR (95% CI) P Preferred language Spanish vs English 0.47 (0.36, 0.61) <.0001 Marital status Married vs Single 0.69 (0.52, 0.90) 0.007 Insurance Medicaid vs Private 1.73 (1.25, 2.40) 0.001 Substance use Yes vs No 2.35 (1.38, 4.01) 0.002 Last PCP visit >1 year vs ≤1 year 3.94 (2.82, 5.51) <.0001 No visit vs ≤1 year 2.91 (1.87, 4.54) <.0001 OR, odds ratio; CI, confidence interval; P, p-value from Wald test for OR = 1. Note: Multivariable logistic regression was obtained using stepwise selection with entry and retention criteria of α = 0.30 and α = 0.05, respectively.