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Population-based analysis of cancer disparities and social determinants of health in hereditary cancer syndrome carriers: A Healthy Nevada Project study.
10616 Background: Hereditary cancer syndromes account for approximately 5-10% of all cancers, the most common being Hereditary Breast and Ovarian Cancer (HBOC) and Lynch Syndrome (LS). Despite the availability of genetic testing that can reduce cancer morbidity and mortality in carriers, significant disparities exist across various socioeconomic and racial groups. Methods: This retrospective cohort study analyzed participants from the Healthy Nevada Project (HNP) who underwent genetic testing for hereditary cancer syndromes. A study protocol was developed by the research committee prior to implementation. Participants were classified as positive or negative for HBOC syndrome (BRCA1/2 pathogenic variants) and Lynch syndrome (mismatch repair gene pathogenic variants). Race, age and ethnicity were categorized along with census tract-level social determinants of health (SDOH) measures including median household income and percent rural population. Descriptive statistics characterized the cohort by demographic and clinical variables. Associations between SDOH and cancer outcomes including diagnosis and age at diagnosis, were assessed using chi-square and logistic regression analysis to test for significance. Multivariable logistic regression models were constructed to assess independent associations between SDOH factors and cancer outcomes, adjusting for confounding variables. Results: A total of 47,737 patients were identified using the HNP database. Genetic testing occurred after cancer diagnosis in 99.6% of participants with cancer (2,542/2,552). Delays differed significantly across racial groups (p<0.001). There were no significant bivariate nor multivariate associations between HBOC and gender (p=0.63;0.61), race (p=0.52;0.70), Ethnicity (p=0.36;0.67), income (p=0.75;0.88) or rurality (p=0.52; 0.63). In multivariable logistic regression, younger age at testing was independently associated with genetic test positivity (OR 0.993 per year; 95% CI 0.988–0.999; p=0.014). Conclusions: Population-based studies examining the intersection of hereditary cancer syndromes and SDOH remain limited, particularly in diverse cohorts that reflect real-world demographics. The absence of differences in pathogenic variant prevalence across sociodemographic groups suggests that population-based genetic screening may mitigate traditional disparities in genetic yield. However, observed differences in age at testing indicate persistent inequities in timing of access, which may influence early cancer detection. In fact, delayed post-diagnosis genetic evaluation is common across all SDOH groups in this cohort. Understanding these relationships is essential for developing equitable cancer prevention and control strategies that address both genetic predisposition and the social context in which carriers live.
Reactive versus prophylactic percutaneous endoscopic gastrostomy in patients with head and neck cancer: A multicenter real-world propensity score–matched analysis.
e18130 Background: Nutritional compromise is common among patients with head and neck cancer undergoing treatment, often necessitating placement of a percutaneous endoscopic gastrostomy (PEG) tube. Whether prophylactic PEG placement confers clinical benefit compared with reactive placement after treatment initiation remains uncertain. We compared clinical outcomes associated with reactive versus prophylactic PEG placement in a large, real-world cohort. Methods: We conducted a multicenter, retrospective real-world cohort study of adults with head and neck cancer who underwent percutaneous endoscopic gastrostomy (PEG) placement. Patients were classified as receiving prophylactic PEG (prior to treatment initiation) or reactive PEG (after treatment initiation). To minimize confounding, 1:1 propensity score matching was performed using demographic characteristics, race, and major comorbidities. Covariate balance was assessed using standardized mean differences, with values <0.1 indicating adequate balance. Clinical outcomes were compared using time-to-event analyses, and results are reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Results: After propensity score matching, baseline demographic and clinical characteristics were well balanced between the prophylactic and reactive PEG cohorts. There were no significant differences in the risk of acute kidney injury (14.0% vs 13.9%; HR 1.03, 95% CI 0.91–1.17) or aspiration pneumonia (7.7% vs 6.9%; HR 1.13, 95% CI 0.95–1.34). Patients receiving reactive PEG had a significantly higher risk of 90-day hospitalization compared with those receiving prophylactic PEG (49.9% vs 41.8%; HR 1.37, 95% CI 1.28–1.46). Conversely, reactive PEG placement was associated with a lower risk of dehydration (25.3% vs 30.1%; HR 0.85, 95% CI 0.78–0.93). Conclusions: In this large, multicenter, real-world analysis, prophylactic PEG placement was associated with significantly lower 90-day hospitalization rates than reactive PEG, without increased risk of acute kidney injury or aspiration pneumonia. These findings indicate that earlier nutritional intervention may mitigate downstream healthcare utilization and underscore the importance of strategic, individualized PEG timing as part of comprehensive supportive care for patients with head and neck cancer.
Trends and disparities in colorectal cancer among adults with diabetes mellitus in the United States: A retrospective analysis, 1999-2023.
e15674 Background: Colorectal cancer (CRC), the fourth leading cause of cancer-related deaths, affects approximately 1.5 million U.S. adults and is increasingly linked to diabetes. Diabetic patients face elevated mortality due to delayed detection, higher recurrence risk, reduced five-year survival, and poorer prognosis. This study assesses recent demographic trends in CRC mortality with diabetes as a contributing factor. Methods: We analyzed mortality data from the CDC WONDER Multiple Cause-of-Death dataset, using ICD-10 Codes: C18; C19; C20, and E10-E14. Age-adjusted mortality rates (AAMR) per 1,000,000 individuals and annual percentage changes (APC) were calculated by year, gender, race or ethnicity, and location. Results: Between 1999 and 2023, 79,568 deaths occurred from colorectal cancer in diabetic adults. The AAMR declined from 16.94 in 1999 to 13.01 in 2023 (AAPC: -1.15; 95%CI: -1.44 to -0.87). Males showed a higher AAMR of 17.17 versus 9.73 in females. Non-Hispanic (NH) Black or African American individuals had the highest AAMR (19.77), followed by Hispanic or Latino (14.23), NH White (12.48), and NH Asian or Pacific islander (9.29). AAMRs in non-metropolitan (18.52) areas were higher than in Metropolitan areas (13.49). The Midwest region exhibited the highest AAMR, followed by the South, West, and Northeast regions. State-level differences recorded Oklahoma having the highest AAMR (32.81) and Massachusetts the lowest (5.16). Conclusions: Mortality related to colorectal cancer in diabetic adults has declined significantly over the past two decades, disproportionately affecting non-Hispanic Black individuals, residents of non-metropolitan areas and the Midwest region. This emphasizes the need for targeted interventions and greater clinical sensitivity to demographic disparities. Deaths and age-adjusted mortality rates (AAMRs) per 1,000,000 for colorectal cancer related mortality among diabetic adults in the United States from 1999 to 2023. Variable Deaths (n) AAMR (95% CI) Overall 79,568 13.01 (12.58 to 13.44) SEX Male 43,494 17.17 (16.42 to 17.91) Female 36,074 9.73 (9.23 to 10.23) RACE/ETHNICITY NH Blacks 11,535 19.77(18.10 to 21.45) Hispanics 6,233 14.23(12.80 to 15.65) NH White 59,929 12.48(12.02 to 12.95) NH Asians 2,199 9.29 (7.72 to 10.87)
Hematology-oncology bootcamp: Educational impact of an interactive, guideline-based “101” curriculum.
9035 Background: Hematology-oncology is a rapidly evolving field, and incoming fellows often face early gaps in foundational knowledge during the transition from internal medicine. Mastery of core principles and guideline-based care is required before complex trial interpretation, yet traditional one-way didactic models may be insufficient. To address this, we implemented a structured, longitudinal bootcamp of ASCO- and ASH-aligned sessions delivered through interactive educational formats for fellows across all training years. Methods: Bootcamp curriculum included foundational content in anticancer pharmacology, 4 core-domain “101” sessions, NCCN-based case discussions, clinical trial design, academic career development, workshop on difficult clinical conversations and Kahoot-based heme-path and board review. Content was delivered through 6 different interactive formats over the first 10 weeks of the academic year during a weekly protected half-day. Fellows completed anonymous pre- and post-bootcamp questionnaires assessing self-reported confidence on a 5-point Likert scale. Secondary outcomes included overall knowledge improvement, clinical confidence, satisfaction, and educational format preferences. Pre- and post-intervention scores were compared using Mann-Whitney test. Results: Sixteen fellows completed the pre-bootcamp survey and 13 completed the post-bootcamp survey. There was statistically significant improvements across all 4 core-domains: General Oncology and foundations (2.9 to 3.8; p < 0.01), Classical Hematology (3.0 to 3.7; p < 0.05), Hematologic Malignancies (2.8 to 3.7; p < 0.05), and Solid Tumors (2.5 to 3.4; p < 0.05). Case-based discussions and chalk-talks were the most effective formats, used in both 101 sessions and communication workshop (Table). Moderate or major improvements in overall knowledge as well as inpatient/outpatient clinical confidence were reported by 92.3% fellows. Quality meal options encouraged in-person attendance for 84.6% fellows. Overall satisfaction with the bootcamp was high, with 84.6% fellows reporting agreement or strong agreement. Conclusions: Early delivery of foundational concepts through interactive, case-based “101” curricula improves fellows’ knowledge and clinical confidence. While traditional lectures remain important for trial interpretation, incorporating interactive formats enhance confidence and satisfaction for fellows. This structured, guideline-based bootcamp represents a scalable model for fellowship training. Educational format effectiveness. Educational Format Mean Effectiveness Score (1-5) ± SD Chalk-talks 4.2 ± 0.7 Case-based scenarios 4.2 ± 0.6 Kahoot-based interactive rounds 3.9 ± 0.6 PowerPoint 3.6 ± 0.7 Group-discussions 3.3 ± 1.1 Online Modules 2.5 ± 0.8
Single-cell atlas of peripheral blood immune landscape in pMMR/MSS rectal cancer treated with neoadjuvant chemoradiotherapy and PD-1 blockade.
3562 Background: Most colorectal cancer (CRC) patients exhibit normal mismatch repair function/microsatellite stability (pMMR/MSS), presenting a poor response to immune checkpoint inhibitor monotherapy. Neoadjuvant chemoradiotherapy (nCRT) combined with PD-1 inhibitors can enhance the efficacy of immunotherapy. However, the peripheral immune dynamics underlying this combination remain poorly understood. Methods: In this study, we selected 15 patients from the CHOICE I trial (ChiCTR2100042785) who received nCRT combined with PD-1 inhibitors. A total of 55 peripheral blood mononuclear cell (PBMC) samples were collected at three critical time points: pre-treatment baseline, during radiotherapy, and during immunotherapy. All samples underwent single-cell RNA sequencing (scRNA-seq) analysis, complemented by paired TCR/BCR profiling, to comprehensively map the dynamic evolution of the peripheral immune landscape during combined therapy. Results: We analysed 223,363 high-quality single cells and classified them into 11 distinct immune phenotypes using classical marker genes, revealing treatment-related immune dynamics. TCR clonal tracking revealed divergent dynamics that CD8+ T cells exhibited high clonal persistence (Jaccard index 0.1–0.23), significantly greater in responders than non-responders, underscoring their pivotal role in antitumor immunity. In contrast, CD4+ T cells (particularly T follicular helper cells) showed minimal clonal overlap ( < 0.03), consistent with rapid turnover. Monocyte analysis uncovered fundamental differences. Monocytes from non-responders displayed enhanced yet dysfunctional antigen presentation alongside immunosuppressive features, including specific expansion of the pro-inflammatory Mono_CD14_IL1B subset characterized by high immunomodulatory molecule expression. Conversely, monocytes in responders exhibited robust type I interferon signaling. B-cell analyses revealed that responders preferentially underwent plasma-cell differentiation, whereas B cells from NR retained an antigen-presenting–like phenotype. NK-cell analysis revealed an expanded, activated cytotoxic pool in responders (featuring CD38+, KIR3DL1+ subsets), whereas non-responders showed dominance of KLRC2+ NK cells, suggesting a dysfunctional state. These efficacy-linked changes across immune populations collectively map the systemic immune landscape under combination therapy. Conclusions: This study provides a comprehensive single-cell atlas of peripheral immune remodeling during nCRT combined with PD-1 inhibitors in pMMR/MSS rectal cancer, offering crucial insights for future patient stratification and personalized combination strategies.
EORTC GUCG 2238: “Deescalate,” a pragmatic trial to revisit intermittent androgen deprivation therapy in metastatic hormone-sensitive prostate cancer in the era of new androgen receptor pathway inhibitors.
TPS5150 Background: The systemic standard of care treatment in patients with metastatic hormone-sensitive prostate cancer (mHSPC) according to international guidelines is combination therapies with androgen deprivation therapy (ADT) + androgen receptor pathway inhibitor (ARPI) +/- docetaxel. These ADT + ARPI combinations (also called maximum androgen blockade, MAB) have been shown in phase 3 randomized clinical trials to reduce the risk of death by 20-40%, delay further treatment, and improve health-related quality of life (HRQoL). Treatment usually continues until biochemical, radiological, or clinical progression, sometimes many years after treatment initiation, exposing patients to chronic side effects affecting their HRQoL. Registration trials included highly selected patients, not representative of the general population, thereby overestimating treatment adherence and effectiveness while underreporting tolerability. Several sub-analyses of the registration trials demonstrated that patients achieving a PSA ≤0.2 ng/ml have prolonged overall survival (OS). In this study, we hypothesized that patients with mHSPC treated with MAB reaching PSA ≤ 0.2 ng/ml may benefit from treatment interruption without compromising OS. Methods: The primary goal of this academic-led, open-label, pragmatic, randomized phase III study is to investigate whether intermittent MAB (iMAB) can be safely administered to mHSPC patients who reached a PSA ≤ 0.2 ng/mL at 6 to 12 months after the start of treatment (docetaxel and radiotherapy permitted as part of standard treatment), as compared to continuing MAB (cMAB). Co-primary endpoints are: 1) Feasibility: proportion of patients who do not restart their MAB within one year of interruption. 2) Efficacy: OS assuming the iMAB regimen at three years is non-inferior to continuous treatment. Secondary objectives include toxicity, HRQoL and assessing the impact on treatment resources between iMAB and cMAB. The study will randomize 1600 patients to exclude a 4% OS difference at 3 years while <30% of patients restarted MAB after one year. The study is currently active in Belgium, Croatia, Denmark, Ireland, France and Spain. The activation of the other countries (Portugal, Italy, Romania, Slovenia, Switzerland and Czech Republic) is expected by spring 2026. The study has currently recruited 109 patients (Updated January 26, 2026). Clinical trial information: NCT05974774 .
A phase 1/2 study of EP0062 (vosilasarm), a first-in-class oral selective androgen receptor modulator (SARM), in combination with standard-of-care endocrine therapy +/- targeted therapies in patients with advanced or metastatic AR+/ER+/HER2− breast cancer.
TPS1151 Background: EP0062 (vosilasarm), a first-in-class, oral, non-steroidal, Selective Androgen Receptor Modulator (SARM) acts as a potent tissue-selective AR agonist, suppressing growth and proliferation of multiple endocrine-sensitive or -resistant AR+/ER+/HER2- breast cancer (BC) cell lines and patient-derived xenograft (PDX) models. Pre-clinically, AR activation--rather than AR suppression--exerts potent antitumor activity in AR+/ER+ breast malignancies, including those resistant to endocrine therapy and CDK4/6 inhibitors. EP0062 has been shown to inhibit the growth of AR+/ER+ BC PDX models as a single agent, and in combination with palbociclib, everolimus or elacestrant. Phase 1 of this study reported promising safety and evidence of clinical benefit with EP0062 monotherapy in advanced AR+/ER+/HER2- BC. The ongoing Phase 2 cohorts described here are the first clinical evaluation of a SARM in combination with various standard of care therapies in patients that have previously received a CDK4/6 inhibitor. Methods: The Phase 2 cohorts will include up to 75 post-menopausal women, ≥ 18 years, ECOG ≤ 1, with locally advanced/metastatic, endocrine-sensitive (> 2 y adjuvant or >6 mo treatment prior to recurrence), AR+/ER+/HER2- BC, that is measurable per RECIST v1.1, or non-measurable with an evaluable bone component. AR positivity is defined as ≥ 10% AR nuclei staining by IHC. Patients may have previously received ≤ 2 lines of endocrine therapy (including CDK4/6 inhibitor), and ≤ 1 line of chemotherapy in the advanced/metastatic setting. Treatment arms are as follows: Arm 1: EP0062 + elacestrant (mandatory ESR1 mutation); Arm 2: EP0062 + exemestane + everolimus; Arm 3: EP0062 + fulvestrant + abemaciclib. A 3+3 safety run-in will confirm the combination dose for each cohort before expansion. Starting EP0062 dose was 10 mg BID. The primary objective is to evaluate safety and tolerability. Secondary objectives are to characterise the PK profile and preliminary efficacy. Biomarkers, including CA15-3, PSA, and molecular genetics are also being evaluated. Exploratory objectives are to evaluate potential biomarkers of efficacy, safety and/or PD activity. The study is currently recruiting across the three treatment arms in USA, UK, and Spain. Clinical trial information: NCT05573126 .
Age-related efficacy of antibody-drug conjugates in solid tumors: A meta-analysis.
1664 Background: Antibody–drug conjugates (ADC) have revolutionized cancer therapeutics, with various ADC improving clinical outcomes across solid tumors and several now approved as standard of care. Older adults with cancer are historically underrepresented in trials. As therapies with ADC are shifting to earlier lines of therapy, investigating whether clinical outcomes differ from those of younger patients with cancer is of interest. Methods: We searched PubMed, Embase, and the CENTRAL databases from inception through Dec 2025 for phase III randomized controlled trials (RCTs) that included adult patients with metastatic solid tumors treated with ADC and reported survival outcomes stratified by age group: elderly (>65 years) and younger (<65 years). The co-primary endpoints were progression-free survival (PFS) and overall survival (OS) across these age subgroups. Pre-specified subgroup analyses were performed according to ADC drug, target, and cancer types. Time-to-event outcomes were pooled as hazard ratios (HR) using the inverse-variance method with random-effects models. Heterogeneity was assessed using the I². PROSPERO: CRD4202612924710. Results: Of 2194 records, 17 RCTs (phase 3) met eligibility, including 9,929 patients, spanning breast (n=12), lung (n=2), urothelial (n=1), ovarian (n=1), and gastric cancer(n=1). ADCs were stratified by payloads: topoisomerase I inhibitors (TOPO1i; 65%), microtubule inhibitors (MMAE; 29%), alkylating agents (6%); and targets: TROP-2 (53%), HER2 (41%), and FRα (6%). Elderly pts treated with ADC exhibited significant improvement in PFS with a HR of 0.57 (95% CI 0.46-0.71; p < 0.01; I 2 = 62%). Similarly, younger pts exhibited longer PFS, with a HR of 0.55 (95% CI 0.45-0.67; p < 0.01; I 2 = 86%). Likewise, elderly patients exhibited significantly greater OS with a HR of 0.78 (95% CI 0.66-0.91; p < 0.01; I 2 = 41%), comparable to that observed in younger pts (HR 0.74; 95% CI 0.65-0.85; p < 0.01; I 2 = 63%). Specifically, in elderly patients with breast cancer treated with ADC (n=7,213), significant improvements were seen with an HR of 0.49 (95% CI 0.36-0.67; p < 0.01) and 0.65 (95% CI 0.48-0.87; p < 0.01; I 2 = 39%) for PFS and OS, respectively. Similar improvements in survival outcomes were seen in younger pts (HR of 0.53; 95% CI 0.42-0.67 and HR of 0.66; 95% CI 0.57-0.77, for PFS and OS, respectively. Pre-specified subgroup analyses according to ADC payloads showed no differences in pts treated with ADC plus TOPO1i (HR 0.76 and 0.70, p <0.01). Notably, ADCs with MMAE payloads were associated with benefit only in the elderly (HR 0.77, p <0.01), with no significant benefit in younger patients (HR 0.82, p =0.11). Conclusions: In this pooled analysis, including 5,111 pts treated with ADC under phase III RCTs, survival outcomes with ADC therapies were similar regardless of age. As the number of ADCs approved for the standard of care setting is expected to increase, age should not be an exclusion criteria.
Dynamic circulating tumor DNA profiling for prediction of long-term clinical benefit in pMMR locally advanced rectal cancer receiving neoadjuvant chemoradiotherapy plus sintilimab.
3590 Background: Immune checkpoint inhibitors (ICIs) targeting PD-1 have significantly improved outcomes in locally advanced rectal cancer (LARC). Circulating tumor DNA (ctDNA) has emerged as a promising biomarker for treatment response monitoring and surveillance, capable of predicting long-term clinical outcomes. However, whether ctDNA serves as a prognostic predictor in patients with proficient mismatch repair (pMMR) LARC receiving neoadjuvant chemoradiotherapy (CRT) combined with immunotherapy remains to be explored. Methods: This prospective single-arm phase II trial enrolled pMMR LARC patients (cT 3-4 N 0 M 0 and cT 1-4 N 1-2 M 0 ) with an intermediate or high immunoscore (IS B ) (NCT05450029). Treatment-naïve patients received radiotherapy (50 Gy/ 25 fractions), 6 cycles of mFOLFOX6, and 5 cycles of sintilimab, followed by total mesorectal excision (TME) 6-8 weeks post-radiotherapy. Next-generation sequencing was used to evaluate baseline tumor tissue DNA and serial ctDNA dynamic changes. Baseline (T0) maximal somatic variant allelic frequency (maxVAF) was assessed, along with its changes at the first (T1, two cycles after therapy) and second clinical evaluation (T2, four cycles after therapy). Results: Tumor somatic mutations and aligned ctDNA analyses were conducted in 43 patients. The pathologic complete response (pCR) rate was 65.2%, with an objective response rate (ORR) of 93.5%. The R0 resection rate was 97.8%. The 3-year event-free survival rate, and 3-year overall survival rate remain immature. For dynamic ctDNA analysis, 37 patients were assessed using a 950-gene panel relevant to cancer. A significant decline in maxVAF from T0 to T1 was observed in the pCR group. Among patients who reached follow-up endpoints, circulating tumor DNA analysis reveals that patients with a > 50% decline in maxVAF from T0 to T1 demonstrated longer survival outcomes and higher response rates compared to those without such decline. Conclusions: Serial ctDNA analysis demonstrates applicability in predicting treatment response to CRT combined with immunotherapy in pMMR LARC. Dynamic changes in circulating ctDNA may serve as a potential prognostic indicator in this population. Future studies should integrate ctDNA profiling of comprehensive cancer-related gene panels with large-scale clinical data to refine patient stratification and optimize therapeutic management. Clinical trial information: NCT05450029 .
Clinicopathologic features and survival outcomes of HER2-low versus HER2-negative (IHC 0) breast cancer in real-world practice.
e23417 Background: With the advent of antibody–drug conjugates, HER2-low disease emerged as a clinically relevant subgroup. Yet the prognostic implications of HER2-low versus HER2-negative (IHC 0) disease are not fully defined, with scarce evidence in Latin America. Methods: We conducted a retrospective cohort study including adult patients with HER2-negative breast cancer treated at a tertiary cancer center in Colombia between 2018-2025. Tumors were classified as HER2-low (IHC 1+ or 2+ without amplification) or HER2-negative (IHC 0) according to pathology reports. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method and comparedusing log-rank tests. Results: A total of 176 patients with HER2-negative breast cancer were included; 29 (16.5%) were HER2-low and 147 (83.5%) HER2-negative (IHC 0). Median age at diagnosis was similar between groups (59.9 vs 56.2 years; p = 0.3). Hormone receptor positivity was high in both cohorts (ER: 93.1% HER2-low vs 82.3% HER2-negative (IHC 0); p = 0.3). The distribution of molecular subtypes differed significantly between groups (p < 0.001). HER2-low tumors were more frequently classified as Luminal B HER2-negative (51.7%), whereas HER2-negative (IHC 0) were more heterogeneous (Luminal A 36.1%, Luminal B 34.7%, triple-negative 15.0%). HER2-low tumors less frequently presented with metastatic disease at diagnosis (0% vs 6.8%; p = 0.012), thus with a higher rate of curative-intent treatment. Treatment patterns were comparable between groups. After a median follow-up of approximately 52 months, there were no statistically significant differences in OS or PFS between HER2-low and HER2-negative (IHC 0) breast cancer. Median OS was 51.9 months for HER2-low and 53.2 months for HER2-negative (IHC 0) disease (p = 0.8), and median PFS was 49.8 and 49.6 months, respectively (p = 0.8). Conclusions: In this real-world cohort, differences in molecular subtype distribution and presentation at diagnosis were observed between HER2-low and HER2-negative (IHC 0) subgroups. However, no significant differences in OS or PFS were observed; survival results should be interpreted in the context of the smaller HER2-low subgroup. These findings underscore heterogeneity within HER2-negative breast cancer and the need for larger real-world studies on the prognostic and therapeutic relevance of HER2-low status, particularly in Latin America. Baseline clinicopathologic characteristics by HER2 status. Variable HER2-low (n=29) HER2-negative (IHC 0) (n=147) Age at diagnosis, median (IQR) 59.9 (48–67) 56.2 (44–68) Estrogen receptor positive, n (%) 27 (93.1%) 121 (82.3%) Ki-67 ≥30%, n (%) 10 (34.5%) 55 (40.1%) Invasive ductal carcinoma, n (%) 24 (82.8%) 108 (73.5%) Stage III–IV at diagnosis, n (%) 6 (20.7%) 32 (21.8%) Metastatic at diagnosis, n (%) 0 (0.0%) 10 (6.8%) Neoadjuvant therapy, n (%) 6 (20.7%) 34 (23.1%)
Examining the tumor microbiology and microenvironment of patients with triple-negative inflammatory breast cancer receiving KEYNOTE-522.
e12594 Background: Patients with Stage III triple negative (TN) inflammatory breast cancer (IBC) are treated based on standard-of-care practices inclusive of the Keynote 522 regimen (KN522). Outcomes, however, are inferior to what has been reported in the non-IBC setting. Patients achieving pathologic complete response (pCR) were compared to those not achieving pCR in a cohort of patients with IBC receiving KN522 to evaluate for predictors of response. Methods: RNA sequencing (RNA-seq) was performed on 26 samples from 23 patients with IBC undergoing KN522 in the neoadjuvant setting (N = 19 baseline pre-treatment, N = 7 surgical post treatment, N = 5 paired samples). BostonGene’s Breast Cancer Classifier (BCC) was utilized to determine intrinsic subtypes. Tumor microenvironment was determined by BostonGene’s Tumor Portrait assay. Results: Among patients achieving pCR in the studied cohort (N = 4), 75% (N = 3) and 25% (N = 1) patients had basal and luminal B subtype, respectively, while in the non-pCR group (N = 5), 30% (N = 3) were HER2-low. The pCR group demonstrated higher PD-L1 RNA-seq expression and a trend towards higher abundance of T cell subsets in the tumor cell microenvironment comparatively. Among non-pCR cases, deconvolution analysis revealed reduced tumor fractions following neoadjuvant systemic therapy. A shift in tumor portrait was observed in 3/5 samples, including increased fibrosis features in two cases and loss of immune component in one. These non-pCR cases showed increased angiogenesis and endothelial enrichment signatures, trending toward reduced matrix remodeling. No association was identified between immune-related adverse events (irAEs) and either pCR or BCC subtype. Conclusions: While the small sample size and molecular heterogeneity preclude our ability to draw definitive conclusions, our findings show that in TN IBC, response to neoadjuvant therapy correlated with high PD-L1 expression and T cell abundance, whereas non-responders demonstrated angiogenic and endothelial shifts. No association was observed between irAEs and pCR or BCC. These findings highlight potential biomarkers of response and progression in TN IBC; however, interpretation is limited by the small cohort size and molecular heterogeneity.
Phase 2/3 trial of pumitamig (PD-L1 × VEGF-A bsAb) plus chemotherapy versus bevacizumab plus chemotherapy in previously untreated, unresectable, or metastatic colorectal cancer (ROSETTA CRC-203).
TPS3672 Background: Microsatellite-stable/mismatch repair-proficient metastatic colorectal cancer (mCRC) demonstrated limited benefit from immune checkpoint inhibition and is treated with first-line standard chemotherapy with/without biologic agents, such as anti-VEGF or anti-EGFR therapy. Pumitamig (BNT327/BMS986545) is an investigational bispecific antibody engineered to simultaneously target both PD-L1 and VEGF-A within the tumor and tumor microenvironment, a dual mechanism intended to enhance antitumor immunity and inhibit angiogenesis. Pumitamig plus chemotherapy has shown encouraging efficacy and manageable safety in patients (pts) with solid tumors (Cheng Y, et al. J Thorac Oncol 2025;20[suppl 1]. Abstract 301P; Schmid P, et al. SABCS 2025. Abstract PS1-13-25). This phase 2/3 trial aims to investigate the safety and efficacy of pumitamig and establish if it improves clinical outcomes when added to chemotherapy versus current standard of care in pts with previously untreated mCRC. Methods: ROSETTA CRC-203 is a global, randomized, blinded phase 2/3 study. Pts aged ≥ 18 years, with ECOG PS 0-1, with previously untreated, unresectable, or mCRC, no microsatellite instability-high/mismatch repair-deficient biomarkers, no BRAF V600E mutation and measurable disease per RECIST v1.1 are eligible. Key exclusion criteria include untreated central nervous system metastases, significant cardiovascular disease, recent or active malignancy, and prior systemic therapy with checkpoint inhibitors or chemotherapy. Pts in the Phase 2 dose-optimization part of the study will be randomized 1:1:1 to receive pumitamig low or pumitamig high dose + FOLFOX (Q2W)/FOLFIRI (Q2W) or bevacizumab + FOLFOX (Q2W)/FOLFIRI (Q2W). The primary endpoint is objective response rate (ORR) by RECIST v1.1 per investigator assessment, with progression-free survival (PFS), and duration of response (DOR) as secondary endpoints. In phase 3, eligible pts will be randomized 1:1 to receive pumitamig at the recommended phase 3 dose + FOLFOX (Q2W)/FOLFIRI (Q2W)/CAPOX (Q3W) or bevacizumab + FOLFOX (Q2W)/FOLFIRI (Q2W)/CAPOX (Q3W), until disease progression or unacceptable toxicity. The primary endpoint is PFS by RECIST v1.1 per blinded independent central review. Overall survival, ORR, and DOR are secondary endpoints. Safety will be monitored throughout the study according to CTCAE v5.0. Recruitment is ongoing. ClinicalTrials.gov ID: NCT07221357. Clinical trial information: NCT07221357 .
A phase I, first-in-human study to evaluate the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activities of GenSci139 in patients with solid tumors.
TPS4638 Background: HER2 and EGFR are frequently co-expressed in solid tumors. Bispecific targeting of these receptors can produce synergistic enhancement in cell binding and internalization, potentially overcoming monotherapy resistance and maintaining efficacy in low antigen-expression settings. GenSci139 is a bispecific antibody-drug conjugate (ADC) directed against both EGFR and HER2, incorporating a cleavable linker to deliver a topoisomerase I inhibitor. In preclinical studies, GenSci139 demonstrated broad-spectrum efficacy, surpassing ENHERTU in HER2-low tumor models. It also displayed a favorable pharmacokinetic and a tolerable safety profile. These findings support further clinical evaluation of GenSci139 in urothelial carcinoma (UC), non-small cell lung cancer (NSCLC), gastric cancer (GC), triple-negative breast cancer (TNBC) and other EGFR/HER2-driven malignancies. Methods: This first-in-human, open-label study (NCT07230977) comprises a dose escalation phase with backfill (Part 1) and a dose expansion phase (Part 2). Part 1 employs an accelerated titration followed by a “3+3” design to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE). Backfill cohorts will be enrolled at selected dose levels according to predefined criteria. Part 2 will further evaluate preliminary antitumor activities in predefined cohorts. Key eligibility criteria include advanced solid tumors, measurable disease per RECIST1.1, adequate hematologic and organ function, being able to provide tumor tissues. GenSci139 is administered intravenously every 3 weeks until disease progression, unacceptable toxicity, withdrawal of consent, initiation of alternative anticancer therapy, or other discontinuation criteria are met. Primary endpoints in Part 1 include the incidence of dose-limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs). After determination of the MTD/RDE, Part 2 will evaluate the preliminary anti-tumor activity of GenSci139, with primary endpoints including objective response rate (ORR), disease control rate (DCR) and Duration of response (DoR). The study initiated in December 2025 and is currently recruiting. Clinical trial information: NCT07230977 .
Construction and clinical application of a bundled nursing care program for PICC management in patients with nasopharyngeal carcinoma.
e13612 Background: Purpose To develop a bundled nursing care program for peripherally inserted central catheter (PICC) management in patients with nasopharyngeal carcinoma (NPC) and to preliminarily evaluate its clinical effectiveness. Methods: A total of 70 patients with locally advanced NPC who underwent first-time PICC placement between October 2024 and September 2025 at a tertiary hospital were enrolled. Patients were randomly assigned to the intervention group or the control group (n = 35 per group). The control group received routine nursing care during concurrent chemoradiotherapy, whereas the intervention group received a structured bundled nursing care program in addition to routine care. Catheter-related complications, unplanned catheter removal, reinsertion rate, catheter dwell time, and incidence of insertion-site pain during catheterization were compared between the two groups. Results: The overall incidence of catheter-related complications was significantly lower in the intervention group than in the control group (17.14% vs 57.14%). The rates of unplanned catheter removal (11.43% vs 34.29%) and catheter reinsertion (5.71% vs 25.71%) were also significantly reduced in the intervention group (all P < 0.05). Median catheter dwell time was longer in the intervention group compared with the control group (115 [IQR, 106–129] days vs 108 [IQR, 94–118] days; P < 0.05). In addition, the incidence of catheter insertion-site pain during and after concurrent therapy was significantly lower in the intervention group (P < 0.05). Conclusions: Implementation of a bundled nursing care program for PICC management in patients with NPC significantly reduces catheter-related complications and unplanned catheter removal, prolongs catheter dwell time, decreases reinsertion frequency, and alleviates insertion-site pain. This approach may improve quality of life and nursing care experience for patients undergoing chemoradiotherapy.
Comparative effectiveness of adjuvant chemotherapy on survival in node-positive (N2/N3), stage III ER+/HER2− invasive lobular breast cancer (ILC) versus invasive ductal cancer (IDC).
545 Background: ILC is characterized by loss of E-cadherin expression, with distinct biological and clinical features, and is often perceived to be less sensitive to chemotherapy compared with IDC. Oncologists and pts may face a treatment dilemma regarding the benefits of adjuvant chemotherapy in pts with lower biologic risk but higher anatomic risk (N2/N3), stage III ILC. In this study, we sought to compare the benefit of adjuvant chemotherapy in pN2/N3 ILC compared with IDC. Methods: We used the National Cancer Database (NCDB) to identify adults with primary, non-metastatic, ER-positive/HER2-negative invasive breast cancer diagnosed between 2010 and 2022 who underwent upfront surgery. Patients receiving neoadjuvant systemic therapy were excluded. Analyses were limited to pathologic stage I–III disease with known nodal involvement (N2–N3) and tumor category (T1–4). Propensity score matching (1:3, caliper 0.2; using R 4.5.1) was performed to balance age, sex, race, insurance status, grade, pathologic stage, nodal category, tumor category, Charlson-Deyo comorbidity score, and year of diagnosis. Overall survival (OS) was assessed using Kaplan–Meier methods and Cox proportional hazards models used to estimate hazard ratios (SPSS v28). Results: After propensity matching, we analyzed 28,115 pts with pN2/N3 disease (ILC 9,603 and IDC 18,512). Upstaging from cN0 to pN2/3 was higher for ILC than IDC (20.3% vs 13.3%, p<0.001). ILC pts were more likely to undergo mastectomy compared to IDC (80.2% vs 71.2%, p<0.001). Receipt of adjuvant chemotherapy for pN2/N3 disease was similar between IDC and ILC (78.0% vs 78.4%, p=0.37), as was use of adjuvant radiation and endocrine therapy. Among patients receiving chemotherapy, treatment was associated with a 65% reduction in death in ILC (HR 0.35, 95% CI 0.32–0.38, p<0.001) and a 73% reduction in IDC (HR 0.27, 95% CI 0.26–0.29, p<0.001), compared with no chemotherapy. 5-year OS among chemotherapy-treated patients was lower for ILC compared with IDC (HR 1.4, 95% CI 1.33-1.49; p<0.001, Table 1). In contrast, no OS difference was observed between ILC and IDC among patients who did not receive chemotherapy (HR 1.03, 95% CI 0.96-1.11; p=0.38). Chemotherapy was associated with higher 5-year OS in both IDC (87.7% vs 58.9%) and ILC (84.3% vs 59.2%). Conclusions: Adjuvant chemotherapy was associated with a substantial improvement in 5-year OS among patients with pN2/N3 disease in both IDC and ILC. Pts with ILC and extensive nodal involvement benefit from adjuvant chemotherapy. 5-year survival of IDC and ILC. IDC (18,512) ILC (9,603) No Chemotherapy (4,078) Adjuvant Chemotherapy (14,434) No Chemotherapy (2,071) Adjuvant Chemotherapy (7,532) pN2 (18,669) 62.8% 90.1% 64.4% 87.6% pN3 (9,446) 48.3% 82.2% 51.4% 79.4% pN2/pN3 Combined (28,115) 58.9% 87.7% 59.2% 84.3% P <0.001, log rank.
Antigen presentation suppression as a hallmark of immune evasion and poor outcomes in small cell lung cancer.
8084 Background: Antigen-presenting machinery (APM) is critical for tumor immune recognition. The loss of APM promotes immune evasion and immunotherapy resistance in cancers, including small-cell lung cancer (SCLC). SCLC has a high tumor mutational burden (TMB), and it displays profound APM suppression, explaining its weak response to immune checkpoint inhibitors. We aimed to capture APM gene expression in a large real-world cohort (RWC) and prospective clinical trial datasets to address the clinical implications of APM suppression for current treatment strategies. Methods: We calculated a classical antigen-presenting MHCs (CAMs) score using a gene signature comprised of 18 genes closely associated with MHC-I expression and antigen presentation. We evaluated this score in 6,000 real-world lung cancer samples and in the transcriptomic dataset of a Phase III clinical trial evaluating the effect of chemo-immunotherapy as a first-line treatment in extensive-stage SCLC (IMpower133). Transcriptomic, genomic, and proteomic data were collected for analysis. Results: Patients with SCLC were stratified into 3 groups according to hierarchical clustering of CAM gene expression for functional enrichment, differential gene expression, response to drug, and survival analyses. CAM expression was markedly suppressed in SCLC compared to other lung cancer histologies. In SCLC, CAM-low accounted for 53% of patients, followed by CAM-intermediate (40%) and -high (7%). We found no statistical difference in TMB-high (³10 mutations/Mb) proportion across CAM groups. CAM-intermediate- and high groups had lower TP53, RB1, and PTEN mutation rates and a higher PI3K mutation rate compared to CAM-low. CAM-low tumors displayed the highest DNA damage response and neuroendocrine signature scores and the lowest RB1 expression. CAM-low tumors showed the lowest expression of cytokine and cytokine receptors involved in lymphocyte trafficking, as well as the lowest CD8⁺/Treg and M1/M2 ratios, consistent with a highly immunosuppressive context. CAM-low and intermediate groups had the lower PD-L1 expression and worse overall survival from the start of chemoimmunotherapy in the RWC. Most targetable markers, such as DLL3, were down-regulated in CAM-low tumors. We also identified high expression of novel immune targets in the CAM-low population that may inform future drug design. Conclusions: We demonstrate that in RWC and clinical trial samples, most patients with SCLC are CAM-low, exhibit immune evasion features, and have poor outcomes, as well as reduced expression of most druggable targets. Our data suggests that SCLC’s immunosuppressive microenvironment may lessen the efficacy of new-generation compounds. We highlight potential novel treatment strategies targeting defective APM tumors that may activate the immune microenvironment and augment the effect of existing immunotherapy agents.
Bipolar‐Axis Intergrowth Ferroelectrics for Efficient and Stable Photocatalytic Overall Water Splitting
ABSTRACT Ferroelectric semiconductors show huge potential in photocatalytic overall water splitting (POWS), while achieving strong polarization remains challenging. Herein, we develop bipolar‐axis intergrowth ferroelectrics Bi 7 Ti 4 NbO 21 ( i BTN) with colossal polarization intensity and favorable reaction thermodynamics for efficient and stable POWS. Compared to conventional unipolar‐axis ferroelectrics Bi 3 TiNbO 9 and Bi 4 Ti 3 O 12 with symmetric stacking of structural units, the asymmetric stacking structure simultaneously induces prodigious dipole moments superimposed along the a ‐axis (3793.53 D) and interlayer dipole moments along the c ‐axis (106.39 D) within i BTN, establishing ultra‐strong orthogonal polarization fields. Thus, i BTN achieves the lowest exciton binding energy (43.62 meV), highest density of states, ultra‐low electron effective mass (0.010 m 0 ), and exceptionally high electron‐hole effective mass ratio ( m e / m h = 400), enabling synergistic enhancement across the entire photogenerated carrier dynamics process of “generation‐separation‐transport”. Simultaneously, ferroelectric polarization optimizes surface catalysis, allowing favorable adsorption characteristics and low POWS reaction energy barrier. Consequently, i BTN exhibits state‐of‐the‐art POWS rates among pristine ferroelectric photocatalysts, with stoichiometric H 2 and O 2 evolution rates of 73.31 and 37.34 µmol·h −1 , respectively. Outdoor tests present a stable POWS activity of i BTN for 50 h in 10 days, with a solar‐to‐hydrogen efficiency reaching 0.11%, demonstrating considerable practical potential. The development of multipole‐axis intergrowth ferroelectrics unlocks a new path toward efficient POWS.
Hierarchically Engineered Multi‐Enzyme Nanoreactors for in vitro Drug Biosynthesis and Pathway Transplantation Into Cells
ABSTRACT Even though most proteins evolved to function within multi‐protein systems such as metabolic networks or signaling pathways, most technical protein applications are based on isolated proteins, for example therapeutic antibodies or industrial enzymes. Reliable methods for the stabilization, in vitro operation and intracellular delivery of multi‐protein systems could unlock new applications in green biotechnology, diagnostics, and medical therapy. We demonstrate that the entire violacein biosynthesis pathway, consisting of up to six separately purified enzymes, can be infiltrated into a hierarchically etched MIL‐101(Fe) (eMIL) metal organic framework. eMIL nanoreactors reshaped pathway dynamics and reaction flows, multiplied violacein yield in vitro and enabled pathway reuse, lyophilization and storage. Moreover, eMIL nanoreactors delivered the six‐protein system into mammalian cells, where it produced violacein from cell‐provided substrates and cofactors. These findings pave the way for the design of “smart” stimuli‐responsive multi‐enzyme nanoreactors for biotechnological and medical applications.
A phase 3 study of sacituzumab govitecan in patients with previously treated extensive-stage small cell lung cancer.
TPS8137 Background: Treatment options for extensive-stage small cell lung cancer (ES-SCLC) that has progressed after platinum-containing therapy with or without anti–programmed cell death protein (ligand) 1 (anti–PD-[L]1) therapy are limited. Despite the evolving treatment landscape for ES-SCLC, toxicities and poor clinical outcomes with the current globally approved standard of care (SOC), topotecan, highlight the unmet need for novel agents. Sacituzumab govitecan (SG), a Trop-2–directed antibody-drug conjugate, demonstrated encouraging antitumor activity and manageable safety as a second-line treatment for ES-SCLC in the phase 2, open-label TROPiCS-03 study. At a median study follow-up of 12.3 months in TROPiCS-03, the investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) was 42% and median overall survival (OS) was 13.6 months. Neutropenia (44%) and diarrhea (9%) were the most common grade ≥3 treatment-emergent adverse events (TEAEs), and no TEAEs led to discontinuation of SG; 1 treatment-related TEAE caused death. EVOKE-SCLC-04 (NCT06801834) is a randomized, phase 3, open-label, multicenter study evaluating the efficacy and safety of SG versus SOC (topotecan, lurbinectedin [in countries/regions where approved], or amrubicin [Japan only]) in patients with previously treated ES-SCLC. Methods: Key eligibility criteria for EVOKE-SCLC-04 include age ≥18 years, confirmed SCLC diagnosis, Eastern Cooperative Oncology Group performance status score of 0–1, measurable disease per RECIST v1.1, and disease progression after 1 prior line of platinum-containing therapy with or without anti–PD-(L)1 therapy. Prior tarlatamab treatment is allowed. Patients with untreated central nervous system (CNS) metastases and/or carcinomatous meningitis are excluded unless these are asymptomatic and immediate CNS-specific treatment is not required. Patients will be randomized 1:1 to either SG (10 mg/kg on Days 1 and 8) or SOC: topotecan (1.5 mg/m 2 daily on Days 1–5), lurbinectedin (3.2 mg/m 2 on Day 1), or amrubicin (40 mg/m 2 daily on Days 1–3) administered as intravenous infusion in 21-day cycles, until progressive disease (assessed by investigator review per RECIST v1.1), unacceptable toxicity, or death. Randomization will be stratified by chemotherapy-free interval (≥90 vs <90 days), CNS involvement (yes vs no), geographic region (East Asia vs non-East Asia), and prior anti–PD-(L)1 therapy (yes vs no). The primary endpoint is OS; secondary endpoints include progression-free survival, ORR, duration of response, patient-reported outcomes (time to first deterioration in shortness of breath and physical functioning), and safety/tolerability. This study is open and actively recruiting as of February 2025 and plans to enroll 695 patients from approximately 275 sites globally. Clinical trial information: NCT06801834 .
PTCy, abatacept, and short course of tacrolimus (CAST) therapy in GVHD prevention in mismatch-unrelated donors.
e18568 Background: Hematopoietic stem cell transplant (HSCT) remains a potentially curative therapy for a wide range of hematologic malignancies, but its success is complicated by the development of GVHD. Patients who undergo transplant via mismatch-unrelated donors (MMUD) have a greater risk of developing GVHD. Post-transplant cyclophosphamide (PTCy), abatacept, and short-course tacrolimus (CAST) is a novel GVHD prophylaxis regimen that demonstrates improved outcomes in haploidentical transplants. Methods: This retrospective study investigated 16 patients with a median age of 44 (range, 26-75) who underwent MMUD allo-HSCT for GVHD prophylaxis. The median follow-up of 11.98 months. Results: Fifteen patients had a single foundational HLA mismatch: 7 (47%) at HLA-A, 1 (7%) at HLA-B, 2 (13%) at HLA-C, and 5 (33%) at HLA-DRB1. One patient had mismatches at both HLA-A and HLA-B. Underlying diagnoses included AML in 5 patients (31%), ALL in 5 (31%), MDS in 4 (25%), NHL in 1 (6%), and HL in 1 (6%). The day + 120 cumulative incidences of grade 2-4 and grade 3-4 acute GVHD with death as a competing risk were 7.1% (95% CI, 0.3-31.4) and 0% (95% CI, 0.0-21.5), respectively with one patient developing grade 2 acute GVHD of the skin. One patient developed biopsy-proven grade 3 acute GVHD in the GI tract on day + 175. The 1-year cumulative incidence of moderate-to-severe chronic GVHD was 21.4% (95% CI, 7.6-47.6). Chronic GVHD manifestations included involvement of the skin (n=4), oral mucosa (n=3), liver (n=2), eyes (n=1), and genitourinary tract (n=1). The 1-year relapse rate, progression-free survival, overall survival, and GVHD- and relapse-free survival (GRFS) were 6.3% (95% CI, 0.3-28.3), 87.5% (95% CI, 64.0-97.8), 87.5% (95% CI, 64.0-97.8), and 62.5% (95% CI, 38.6-81.5), respectively. Infections were documented in 7 of 16 patients (43%; 95% CI, 23.1–66.8). These included one case of parainfluenza-associated upper respiratory tract infection, one case of cytomegalovirus viremia, and three cases of pneumonia attributable to Pseudomonas aeruginosa , Pneumocystis jirovecii , and Candida species. One patient died during hospitalization for neutropenic fever in the setting of relapsed AML. Another patient died from complications of veno-occlusive disease. Conclusions: This retrospective study demonstrates that the CAST regimen is effective in reducing the development of grades 2-4 acute GVHD after MMUD peripheral blood allo-HSCT.