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Popliteal node metastasis in infra-popliteal melanoma: Arcane or mundane?

e21594 Background: Infra-popliteal melanoma constitutes a major percentage of cutaneous melanoma among women. The primary lymphatic drainage of is to the groin with incidence between 20 to 30%. The popliteal basin harbingers metastases in 1.5 - 10%. Popliteal metastasis though recognized as early as 1980 by lymphoscintigraphy studies, has still not seen the light of guidelines. The principles of sentinel node biopsy remain the same for both basins. Non-recognition of popliteal metastases can result in potential understaging. We aimed to quantify the popliteal node metastasis, compare clinicopathologic factors and analyze oncologic outcomes of popliteal node metastasis in infra-popliteal melanoma. Methods: A descriptive study of all patients with infra-popliteal melanoma treated at our Institute between January 2010 and December 2024 treated with curative intent with wide excision of lesion/residue or scar with sentinel lymph node biopsy of inguinal and popliteal basins. Results: Among 80 patients the prevalence of occult popliteal metastases in our cohort was 15% with male-to-female ratio 2:1 and mean age of 65 years, common among patients with T4b (100%), and hindfoot (87.5%) melanoma. A third had isolated popliteal involvement in the absence of inguinal node involvement. For every 3 patients with positive popliteal scintigram, 1 patient had histology proven metastasis. There were no popliteal metastases beyond the sentinel nodes. Inguinal node metastases occurred in 31 patients (38.75%) 84% clinically occult. Three (11.5%) patients had inguinal metastases beyond sentinel nodes mirroring MLST 2. The median follow-up duration was 81 months and the OS of pN+ patients was 30 months (95% CI 24 to 37 months) and that of pN- patients which was 108 months (95% CI 32 to 184 months). The median OS among patients with isolated popliteal metastasis (n = 4) was 18 months (95% CI 0 – 60 months) while that of patients with isolated inguinal metastasis (n = 22) was 30 months (95% CI 23 to 37 months). The dual node positive cohort (n = 8) had a median OS of 15 months (95% CI 0-44 months). The log-rank test did show a significant difference in between overall survival of 3 subgroups (p = 0.000). Conclusions: While the traditional nodes metastases in cutaneous melanoma is common (with an incidence of 38.75% highest recorded in our cohort), so is the true popliteal metastases (15% incidence). Interval nodes are not a rare manifestation of disease, but rather an event in the natural history with finite possibility and solid anatomical pathways with decussation, and isolation probably with an aggressive biology. Multiple case series and retrospective reports of popliteal metastasis in infra-popliteal melanoma advocate the sentinel node biopsy of traditional as well as occult nodes. Identifying occult nodal metastases in cutaneous melanoma is crucial now, more than ever, in the era of effective adjuvants (targeted therapy, immunotherapy).

Real-world clinicopathologic features and outcomes of gastric, esophageal, and gastroesophageal junction cancers: A single-center cohort study.

e16057 Background: Upper gastrointestinal cancers encompass biologically and clinically distinct entities with evolving management paradigms. Despite shared anatomic boundaries, gastric, esophageal, and gastroesophageal junction (GEJ) cancers differ in histology, metastatic behavior, and treatment strategies. Real-world data on presentation, treatment, and outcomes remain limited. We evaluated clinicopathologic characteristics and survival outcomes among patients (pts) with gastric, esophageal, and GEJ cancers treated at a tertiary referral center. Methods: We conducted a retrospective review of pts diagnosed with cancer at the American University of Beirut Medical Center between 2016 and 2024. Patients who verbally consented to be part of the oncology database, presenting with gastric, esophageal, or GEJ cancers and complete clinical data were included. Descriptive statistics were used to summarize clinicopathologic characteristics. Results: A total of 1,118 pts diagnosed with GI cancers were reviewed among whom 212 pts (159 gastric, 25 esophageal, 28 GEJ) were included. Baseline demographic and clinicopathologic characteristics are summarized in Table 1. Advanced-stage disease was common across tumor types, with the highest burden of stage IV disease observed in gastric cancers. Histologic distribution differed by tumor location, with adenocarcinoma predominating in gastric and GEJ tumors, whereas esophageal cancers exhibited greater histologic heterogeneity. The most frequent metastatic sites were liver (20%) and peritoneum (18%), followed by bone (4%) and lung (1%). Surgical resection and first-line chemotherapy utilization varied by tumor type, with surgery performed most frequently in GEJ cancers. First-line systemic therapy was administered to 69%, 92%, and 89% of pts with gastric, esophageal, and GEJ cancers, respectively. Survival outcomes differed across groups, with the highest survival observed in gastric cancer and the lowest in esophageal cancer. The 1-, 2-, and 5-year overall survival rates were 97%, 89%, and 74%, respectively. Conclusions: Despite shared anatomic proximity, gastric, esophageal, and GEJ cancers demonstrated distinct patterns of presentation, histology, treatment, and survival in this real-world cohort. These findings underscore the clinical heterogeneity of upper gastrointestinal malignancies and support tumor-specific risk stratification and management approaches. Baseline characteristics and outcomes by tumor type. Variable Gastric (n=159) Esophageal (n=25) GEJ (n=28) Age (years) 66 (25-89) 58 (35-77) 64 (33-81) Mean BMI (kg/m²) 23.3 22.2 23.1 Female, n (%) 75 (47%) 9 (36%) 6 (21%) Stage IV, n (%) 99 (62%) 12 (48%) 14 (50%) Histology, n (%)AdenocarcinomaSquamous cell carcinoma 132 (83%)- 10 (40%)9 (36%) 25 (89%)3 (11%)

The red blood cell proteome and interactome identify a Band 3-BLVRB axis regulating hypoxic metabolic adaptation

Red blood cells (RBCs) are transcriptionally silent yet dynamically remodel metabolism in response to oxygen tension. Using ultra-pure human RBCs, we generated the deepest contamination-free proteome to date (3,775 proteins) and mapped the oxygen-dependent interactome. These datasets reveal an oxygen-responsive metabolon centered on the Band 3 (SLC4A1) N-terminus. We identify biliverdin reductase B (BLVRB) as a previously unrecognized Band 3 interactor that dissociates under hypoxia, coincident with increased Band 3-deoxyhemoglobin contacts. This reversible assembly functions as an oxygen-sensitive switch coordinating redox and glycolytic remodeling. Humanized mice lacking Band 3 N-terminal segments exhibit impaired oxygen-dependent regulation of BLVRB binding to band 3, impaired hypoxic activation of glycolysis, reduced 2,3-bisphosphoglycerate synthesis, and diminished exercise tolerance, demonstrating physiological relevance. Population-scale cis-pQTLs for SLC4A1 and BLVRB suggest functions beyond canonical heme catabolism. Mechanistically, biochemical analyses in vitro suggest that hemoglobin β (HBB), Band 3, and BLVRB can undergo S-nitrosation and may participate in trans-nitrosation reactions with the glycolytic enzyme GAPDH, whose modification at C152 inhibits enzymatic activity in vitro. Collectively, these findings define a Band 3-BLVRB axis that integrates oxygen-dependent protein interactions with thiol-based redox chemistry, providing a framework for understanding how an anucleate cell achieves metabolic adaptability through reversible protein-protein interactions and post-translational modification. These findings suggest that perturbation of the Band 3-BLVRB axis may influence oxygen delivery and metabolic flexibility during hypoxic stress, with potential relevance to high-altitude adaptation, exercise physiology, and cardiopulmonary disease.

Chitosan–zinc oxide nanocomposite as an efficient carrier for ciprofloxacin with enhanced antibacterial activity

Smartphone camera takes users’ pulse passively during device use

Intraoperative indocyanine green fluorescence angiography to reduce anastomotic leak after esophagectomy for esophageal cancer: A systematic review and meta-analysis.

e16097 Background: Anastomotic leak remains one of the most serious complications following esophagectomy for esophageal cancer, contributing to prolonged hospitalization, morbidity, and mortality. Intraoperative indocyanine green (ICG) fluorescence angiography has been introduced to objectively assess conduit perfusion and potentially reduce leak rates; however, its clinical benefit remains uncertain. This systematic review and meta-analysis aimed to evaluate the effectiveness and safety of ICG fluorescence angiography during esophagectomy. Methods: A comprehensive systematic search of major electronic databases was conducted to identify comparative studies evaluating ICG fluorescence angiography versus standard assessment during esophagectomy for esophageal cancer. Pooled risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI) were calculated using random-effects models. Results: Eleven studies encompassing 1,069 patients were included, with 524 patients in the ICG group and 545 in the control group. The mean age was 65.2 ± 8.22 years in the ICG group and 63.6 ± 9.26 years in the control group, with male predominance across studies. Use of ICG fluorescence angiography was associated with a lower risk of anastomotic leak compared with conventional assessment, although this reduction did not reach statistical significance (RR 0.58, 95% CI 0.25–1.34). No significant differences were observed in operative time (MD −0.14 minutes, 95% CI −0.30 to 0.01), hospital length of stay (MD −0.16 days, 95% CI −0.36 to 0.05), 90-day mortality (RR 1.06, 95% CI 0.26–4.35), or overall postoperative complications (RR 0.88, 95% CI 0.70–1.12). Conclusions: Intraoperative ICG fluorescence angiography appears to be a safe adjunct during esophagectomy and may offer a clinically meaningful reduction in anastomotic leak rates, although current evidence does not demonstrate statistically significant benefits in key postoperative outcomes. These findings suggest that ICG-guided perfusion assessment holds promise but should complement, rather than replace, surgical judgment. Well-designed randomized trials with standardized protocols are needed to clarify its true impact and define which patients are most likely to benefit.

Longitudinal tumor-informed ctDNA monitoring and clinical outcomes in advanced urothelial carcinoma treated with enfortumab vedotin ± pembrolizumab.

4569 Background: Enfortumab vedotin plus pembrolizumab (EV±P) is standard-of-care for patients (pts) with locally advanced/metastatic urothelial carcinoma (la/mUC), although not all pts experience durable benefit. Tumor-informed circulating tumor DNA (ctDNA) assays enable a personalized, real-time assessment of disease kinetics, and early ctDNA dynamics (<12 weeks) have been linked to EV±P radiographic response and survival outcomes. However, the prognostic relevance of ctDNA dynamics relative to durable clinical benefit is not well defined. Methods: We conducted a multicenter, retrospective real-world analysis of pts with la/mUC who received ≥1 cycle of EV±P and ≥1 commercial plasma ctDNA test using a clinically validated, personalized, tumor-informed assay (Signatera, Natera, Inc.). Associations between ctDNA features and progression-free survival (PFS) and overall survival (OS) were evaluated using Cox proportional hazards models. Results: A total of 110 pts with 545 plasma samples were analyzed. All pts had ≥1 ctDNA test (median: 4 tests/pt) immediately prior to and/or after EV±P initiation, with median time between serial ctDNA collections of 7.3 (IQR: 5.4-12.0) weeks. In this cohort, 69% (76/110) of pts had ≥1 ctDNA test (355 total) beyond 12 weeks post-EV±P initiation. Among these 76 pts, 31.5% (24/76) were persistently ctDNA negative (≥2 consecutively negative samples with no positives), while 65.8% (50/76) were anytime ctDNA-positive. Time-varying covariate analysis incorporating all serial results after 12-weeks reaffirmed that ctDNA-positivity was associated with worse PFS and OS (PFS: HR: 36.8, p<0.005; OS: HR: 17.7, p=0.01). Serial ctDNA negativity within 4-24 weeks (i.e. ≥2 consecutively negative samples with no positives) was strongly associated with durable OS/PFS beyond 24 weeks (PFS: HR=0.05, 95% CI: 0.01-0.42, p=0.005; OS: HR=0.046, 95% CI: 0.0004-0.33 [Firth], p=0.0002). Furthermore, single-timepoint ctDNA positivity evaluated at 12–24 weeks (HR: 11.8; 95% CI: 2.72–51.60; p=0.001) and >24 weeks (HR: 6.8; 95% CI: 2.5–18.6; p=0.0002) was strongly associated with inferior PFS. Findings were similar for OS (12-24wk: HR: 7.2, 95% CI: 1.7-31.3; p=0.008; >24wk: HR=3.8, CI: 1.2-12.3; p=0.03). Conclusions: Longitudinal ctDNA dynamics are strongly prognostic in pts with la/mUC treated with EV±P, even when assessed beyond 12 weeks from treatment start. Sustained ctDNA negativity further identifies pts with durable clinical benefit. These findings support ctDNA as a potentially complementary biomarker to standard imaging in this clinical context.

Real-world outcomes of urothelial bladder cancer (UBC): A retrospective multicenter analysis from Peru.

e23433 Background: Urothelial bladder cancer (UBC) outcomes in Latin America remain poorly characterized. Although incidence rates are lower than in Western countries, the disease is frequently diagnosed at advanced, muscle-invasive stages, and management is often affected by delayed diagnosis and limited access to specialized care. Real-world data describing survival outcomes and treatment patterns in Latin America (LATAM) are scarce. This study assessed real-world outcomes in a multicenter cohort of UBC patients from Peru. Methods: We conducted a retrospective multicenter cohort study including Peruvian patients with UBC treated at 6 institutions from 2015-2025. Recurrence- free survival (RFS, assessed among patients undergoing definitive surgery until first recurrence) and overall survival (OS) were analyzed by the Kaplan-Meier method and compared with log-rank test. A level of p < 0.05 was considered significant. Cox proportional hazards models were used for univariable and multivariable analyses. Results: 215 patients were included; median age was 71 years and 72% were male. Clinical stage distribution was as follows: stage I 19%, stage II 16%, stage III 46%, stage IVA 4%, and stage IVB 15%. Smoking history was documented in 8% of patients. 72% were muscle invasive bladder cancer (MIBC). Regarding medical treatment, neoadjuvant chemotherapy was administered to 10.7% of patients. Surgery was performed in 40.0% (n = 84), 5 recurrences (6%) were documented. Median follow-up for RFS was 23 months (1–80). 1-, 3- and 5-year RFS rates were 95%, 88%, and 88%, respectively. With a median follow-up of 18 months, 1-, 3- and 5-year OS rates were 62%, 39%, and 30%, respectively (median OS of 21 months). OS differed significantly according to multiple clinical characteristics, including histologic grade (p = 0.016), TNM classification (p < 0.001) and receipt of surgery (p < 0.001). In multivariable analysis, compared with stage I-II, stages III (HR 4.31, 2.25-8.24, p < 0.001) and IVB (HR 4.26, 2.07-8.77, p < 0.001) were the strongest predictors of mortality. OS was longer among patients who underwent surgery (median 42 vs 12 months, p = 0.001). No significant OS differences were observed according to neoadjuvant chemotherapy use, likely reflecting the limited number of treated patients. Conclusions: This study provides valuable real-world data on outcomes in patients with urothelial bladder cancer treated at multiple centers in Peru. Clinical stage at diagnosis was the primary determinant of overall survival; a high proportion presented with advanced stage (III-IV), likely contributing to short OS. The low utilization of neoadjuvant chemotherapy underscores important gaps between guideline recommendations and real-world practice, highlighting areas of unmet need and opportunities to improve access to curative-intent treatment in resource-limited settings.

Post-treatment pathway profiling and platinum resistance in high-grade serous ovarian cancer: Discovery and external validation study.

e17602 Background: High-grade serous ovarian cancer (HGSOC) shows initial platinum sensitivity in >70% of patients, but most resist within 18 months. Current baseline biomarkers (CA-125, BRCA) provide limited predictive power. We hypothesized that residual pathway activation in post-treatment samples predicts resistance better than pre-treatment measurements, as chemotherapy selects resistant clones. Methods: Discovery: We analyzed paired treatment-naïve and post-neoadjuvant (NACT) scRNA-seq data from 11 patients (GSE165897), scoring DDR, PI3K, and VEGF pathways against platinum-free interval (PFI). Validation: We analyzed copy number (CN) signatures from 47 paired diagnosis-relapse samples (BriTROC-1), testing if relapse features outperformed diagnosis features. Statistics included Spearman, ROC with bootstrap 95% CIs, and Wilcoxon tests. Results: Discovery: Post-treatment DDR score showed strong inverse correlation with PFI (ρ=-0.711, p=0.014); pre-treatment did not (ρ=-0.182, p=0.592). Post-treatment PI3K achieved AUC=0.750 (p=0.020) for resistance classification. Pathway deltas showed no correlation, indicating absolute post-treatment state predicts resistance. High post-treatment DDR patients had significantly shorter PFI (median 65 vs 393 days, p=0.012). Validation: CN signature 7 at relapse achieved AUROC=0.874 (95% CI: 0.750-0.974, p=0.035), outperforming diagnosis (AUROC=0.694). This +0.180 improvement confirmed the serial profiling hypothesis across modalities. Conclusions: Post-treatment features predict resistance across independent cohorts and modalities. Key insight: Absolute post-treatment molecular state—not baseline or change—is the predictive signal. Strongest signals (DDR, CN signature 7) align with known mechanisms (DNA repair, CCNE1). This approach could enable prediction months before radiographic progression, complementing CA-125 kinetics. Larger prospective studies are needed despite consistent findings.

Initial results from NEXUS-01, a phase 1 study of LY4052031, an antibody-drug conjugate targeting Nectin-4, in participants with advanced or metastatic urothelial carcinoma.

4508 Background: Enfortumab vedotin plus pembrolizumab (EVP) is the current first-line standard of care for locally advanced / metastatic urothelial carcinoma (mUC). However, subsequent treatment options are limited, representing an urgent and growing unmet need. Preclinical data suggest that EV resistance may be payload mediated and consequently Nectin-4 remains a viable target for alternative therapies. LY4052031 is a next generation anti-Nectin-4 ADC, comprising a humanized IgG1 antibody conjugated to Camp98, a novel topoisomerase I inhibitor, via a cleavable peptide linker with homogeneous drug antibody ratio of 8. Here, we report the initial clinical data from the phase 1 dose escalation cohort of NEXUS-01 (NCT06465069). Methods: Adults with locally advanced / mUC or other selected solid tumors were eligible. Participants (pts) must have received or were ineligible for available standard therapies, and have ECOG PS 0-1. Dose escalation utilized a Bayesian optimal interval design. Key endpoints were safety, PK, and antitumor activity of LY4052031 per RECIST v1.1. Results: As of 25 Nov 2025, 70 pts (47 mUC, 23 non-UC) received LY4052031 doses ranging from 0.6-5.4 mg/kg IV Q3W. Median age was 66 years (range, 31-82); 60% had ECOG PS 1. Among pts with mUC, 70% (33/47) had prior EV (6% [2/33] had discontinued EV due to treatment-related toxicity). LY4052031, total antibody, and Camp98 exhibited mostly linear, dose-proportional PK, except at 4.8-5.4 mg/kg for payload. The most common treatment-emergent AEs (TEAEs) were nausea (43%), alopecia (39%), fatigue (37%), decreased appetite (29%), constipation, diarrhea, dysgeusia, mucositis, vomiting (27% each), and anemia (24%). The most common grade ≥3 TEAE was anemia (13%). Low activity scores (AS) for CYP2D6, the metabolic clearance pathway for Camp98, were associated with increased dose-limiting toxicity at higher dose levels. Thus, the study was amended to require CYP2D6 genotyping prior to treatment with dedicated dose finding in pts with low AS ( < 0.5). Response was assessed in efficacy evaluable pts, defined as all treated pts who had at least 1 post-baseline response assessment or who discontinued prior to the first post-baseline response assessment. In 21 efficacy evaluable mUC pts (AS ≥0.5) treated with 2.4-4.8 mg/kg, ORR was 48% (10/21) and DCR was 81% (17/21) with 1 CR, 9 PR, and 7 SD. Among those who had prior EV (8 EV and 7 EV/P), ORR was 40% (6/15) and DCR was 80% (12/15) with 1 CR, 5 PR, and 6 SD; in the EV naïve pts, ORR was 67% (4/6) and DCR was 83% (5/6) with 4 PR and 1 SD. Median follow-up was 7 months (95% CI, 2.79-NE); median DoR was 7 months (95% CI, 2.7-NE). Conclusions: LY4052031 demonstrated promising clinical activity at multiple dose levels, including in EV pre-treated mUC. CYP2D6 AS specific dose optimization is ongoing and updated results will be presented. Clinical trial information: NCT06465069 .

A first-in-human phase 1a study of LP-184, a tumor site–activated novel alkylating agent, in patients with advanced solid tumors.

e15156 Background: Conventional alkylating agents are limited by systemic toxicities and lack of selectivity. LP-184 is a novel acylfulvene pro-drug that alkylates DNA only after being metabolized by the intracellular enzyme prostaglandin reductase1 (PTGR1), which is highly expressed in many solid tumors. In preclinical studies, LP-184 exhibited up to 12-fold enhanced anti-tumor activity in tumors with compromised DNA damage repair (DDR), such as BRCA and ATM mutations. LP-184 is being developed to target solid tumors with high PTGR1 expression and DDR deficiency. Methods: The dose escalation Phase 1a study (NCT05933265) enrolled patients with relapsed or refractory advanced solid tumors. The primary objective was to evaluate the safety and tolerability of LP-184. A Bayesian optimal interval design with a 30% target toxicity rate was used to define the maximum tolerated dose (MTD). Patients received LP-184 IV over 30 minutes on days 1 and 8 of each 21-day cycle until disease progression or intolerability. PTGR1 expression was quantified by RT-qPCR using archival tissue. Gene alterations were obtained when available from patients’ most recent pre-enrollment genetic reports. Results: 63 patients were treated across 12 dose cohorts, with dose levels (DL) ranging from 0.01 to 0.61 mg/kg. Dose limiting toxicities (DLTs) occurred in 3 patients, including one case of grade 3 platelet count decrease progressing to grade 4 at 0.49 mg/kg (DL11; DLT rate = 20%) and two cases at 0.61 mg/kg (DL12; DLT rate = 40%) consisting of grade 3 alanine aminotransferase increase and acute liver injury. Dose delays due to treatment-related adverse events (TRAEs) were reported in 15 (24%) patients. Dose reduction due to TRAEs were reported in 2 patients (3%), both treated at DL11. Drug discontinuation due to TRAEs occurred in 4 patients (6%), including one each at DL07, DL08, DL11, and DL12. The most common TRAEs (≥20%) were nausea (52%), vomiting (46%), fatigue (21%), and platelet count decrease (21%). Grade ≥3 TRAEs that occurred in more than two patients included platelet count decrease (n = 6, 10%) and anemia (n = 3, 5%). The best observed response was stable disease, which occurred in 40% of evaluable patients. Durable disease control (≥ 1 year) was observed in 3 patients with DDR mutations of known interest. LP-184 had an apparent elimination half-life of ~20 minutes and achieved the projected therapeutic concentration at DL07. PTGR1 was quantifiable in 94% of assayed samples, supporting the feasibility of assessing associations between PTGR1 expression and clinical benefit in future studies. Conclusions: LP-184 demonstrates a manageable safety profile with encouraging antitumor efficacy in tumors harboring key DDR alterations. The MTD is 0.49 mg/kg IV administered on days 1 and 8 every 21 days. Clinical trial information: NCT05933265 .

Trends in female breast cancer incidence and mortality in adolescents and young adults in Sub-Saharan Africa from 1990 to 2023.

e22585 Background: Breast cancer (BC) among adolescent and young adults (AYA), defined as individuals aged 15 to 39 years, is a growing public health concern globally. Sub-Saharan Africa (SSA) has a predominantly young population, yet temporal and regional trends in BC incidence and mortality among AYA women remain poorly characterized. This study analyzes trends in AYA BC incidence and mortality rates in SSA from 1990 to 2023 to guide strategic cancer control planning efforts. Methods: Data on BC incidence and mortality among AYA women in 46 SSA countries were extracted from the 2023 Global Burden of Disease database, representing the most recent available country-level estimates. Age-standardized rates are reported per 100,000 population. Temporal trends in incidence and mortality rates by country and region (Eastern, Western, Central, and Southern) were assessed by calculating estimated annual percentage change (EAPC) with 95% uncertainty intervals (UI). Results: There were an estimated 59,462 new cases of BC among AYA women in SSA in 2023, with an age-standardized incidence rate (ASIR) of 24 (95% UI: 16–32). The incidence of AYA BC increased significantly from 1990 to 2023, with an EAPC of 2.3% (95% UI: 1.8–2.7). All four regions had statistically significant increases in incidence, with the highest in Southern SSA (EAPC: 4.0%, 95% UI: 3.8–4.3) and the lowest in Eastern SSA (EAPC: 1.5%, 95% UI: 1.0–2.1). Thirty-eight of 46 countries had statistically significant increases in AYA BC. São Tomé and Príncipe, Zimbabwe, Cape Verde, and South Africa had the largest increases in incidence, while Central African Republic had the lowest. Four countries (Mozambique, Rwanda, Madagascar, and Tanzania) experienced decreasing incidence between 1990 and 2023. In 2023, there were 24,252 deaths from AYA BC in SSA, with an age-standardized mortality rate (ASMR) of 9.7 (95% UI: 6.7–13). Côte d'Ivoire had the highest ASMR (18, 95% UI: 11–26). Central SSA had the highest ASMR (15, 95% UI: 9.2–21), while Southern SSA had the lowest (5.1, 95% UI: 3.5–6.9) in 2023. The overall ASMR increased by 1.6% (95% UI: 1.2–2.1) from 1990 to 2023. Thirty-five of 46 countries had increased ASMR, 5 countries had decreased ASMR, and 6 countries had no statistically significant change in ASMR. Conclusions: The rising burden of AYA BC in SSA is particularly concerning given the region’s high BC mortality rates. Regional variations in the incidence and mortality of AYA BC were also observed, underscoring the need for further cancer epidemiology research dedicated to SSA. These findings may inform cancer policy, public health interventions, and resource allocation, highlighting the needs of the AYA population. Future studies should explore modifiable risk factors contributing to the rising incidence of AYA BC in SSA and health systems efforts to improve access to care for patients in the region.

Lung cancer screening practices among head and neck cancer survivors in U.S. veterans: A pilot survey.

e23148 Background: Survivors of head and neck (HNC) cancers constitute a uniquely high-risk population for second primary lung cancers (SPLC). Despite SPLC being a leading cause of mortality in HNC survivors, most major screening trials excluded these patients, creating a critical evidence gap. Methods: We conducted a national, cross-sectional survey of Veterans Affairs (VA) medical centers participating in the VA Lung Precision Oncology Program (LPOP). The survey was developed with input from the LPOP Lung Cancer Screening Outcomes Workgroup and assessed site-level practices, policies, and infrastructure for lung cancer screening (LCS) among HNC survivors. One representative from each center completed the survey. The survey was created using VA REDCap and distributed electronically across the LPOP network. Results: In total, 42 out of 115 sites (21 centers, 24 hub sites, and 91 spoke sites) initiated the survey, and 26 submitted complete responses. Most participating sites were high-complexity facilities (77%) and Commission on Cancer-accredited (62%). While 69% of centers reported awareness of guidelines addressing LCS for HNC survivors, nearly 90% indicated that their site lacked formal guidance or were unsure if guidance existed. Although 92% would consider enrolling HNC survivors in LCS programs, timing of likely enrollment varied: 31% after completion of curative treatment, 23% on a case-by-case basis, 19% two to three years post-treatment if no recurrence, 15% would not consider HNC history, and 3% more than five years post-treatment. Notably, 42% of centers reported routinely performing additional surveillance imaging after curative HNC treatment, and 19% perceived that communication barriers among multidisciplinary teams contributed to LCS being overlooked. Regarding survivorship resources, 34% of centers lacked a formal HNC survivorship clinic, and 50% were unsure. Only 23% agreed that current guidelines adequately address imaging surveillance for HNC survivors, and 15% agreed that guidelines sufficiently define LCS eligibility. Conclusions: Substantial variation exists in LCS practices for HNC survivors across VA medical centers, with inconsistent enrollment timing, frequent additional surveillance imaging, limited site-specific guidance, and gaps in survivorship infrastructure. These findings highlight the need for standardized, evidence-based approaches to address LCS in this high-risk population.

Integrating clinicopathologic factors and immune repertoire sequencing to optimize decision-making in neoadjuvant chemoimmunotherapy for HNSCC: A pooled analysis.

e18065 Background: Neoadjuvant chemoimmunotherapy (NACIT) improves survival in locally advanced head and neck squamous cell carcinoma (HNSCC), but optimal patient selection and treatment decisions remain challenging. Clinicopathologic factors combined with Immune repertoire sequencing (IRS), which can directly reflect the activation of the adaptive immune system and its capacity for tumor recognition, are promising to identify prognostic factors guiding clinical decision at different stages and explore underlying mechanisms. Methods: Patients with locally advanced oral or oropharyngeal carcinoma across 3 studies treated with tislelizumab, albumin-bound paclitaxel, and cisplatin were included. Clinicopathologic factors labeled with baseline, preoperative, and postoperative timepoints, integrated with whole exome sequencing (WES) mutation features and IRS data quantifying indexes (d50, inverse Simpson, clonal proportion) as well as clonotypes, were analyzed. Key endpoints were overall survival (OS), event-free survival (EFS), and major pathological response (MPR). Multivariate logistic regression and Cox proportional hazards models identified independent prognostic factors, while correlation analyses explored associations between immune repertoire indices and clinical characteristics. Results: A total of 101 patients were included with a median follow-up of 38 months, ranging from 2 to 55 months. Pathological assessment revealed 51 (50.5%) cases of MPR and 32 (31.7%) cases of pCR. The 3-year OS and EFS rates were 69.4% and 60.1%, respectively. Clinically, performance status (PS) was found as a robust independent baseline predictor across all endpoints and timepoints. De-escalated share similar prognosis with radical surgery but initial surgical margin significantly affected survival. Biologically, the IRS model based on specific T-cell and B-cell clonotypes demonstrated high predictive accuracy for prognostic prediction. High immune repertoire diversity and clonality were significantly correlated with better PS and primary tumor. WES data showed limited prognostic utility in this cohort. Conclusions: Clinically, performance status can reflect antitumor immune activity, while compromised initial surgical margins warn against excessive de-escalation surgery. Biologically, B-cell clonotypes are critical for predicting NACIT response, and the correlation between higher immune diversity and better physical status as well as primary tumor supports immunotherapy in advance and strategies focused on rejuvenating systemic immunity.

Surgical de-escalation of implant-based breast reconstruction (IBBR) after mastectomy for breast cancer treatment or prevention: The international randomized phase III PREPEC trial (OPBC-02).

504 Background: The optimal positioning of implants following skin- (SSM) or nipple-sparing mastectomy (NSM) for breast cancer treatment or prevention is unclear. Pre-pectoral IBBR obviates the need to dissect the major pectoral muscle but provides less soft tissue coverage of the implant. The PREPEC trial hypothesized pre-pectoral IBBR would result in improved long-term quality of life (QoL) compared to sub-pectoral IBBR. Methods: OPBC-02/PREPEC (NCT04293146) was a pragmatic, international, randomized, phase III superiority trial. Women ≥18 years undergoing SSM or NSM for treatment or prevention of breast cancer were randomized (1:1) to pre-pectoral or sub-pectoral IBBR. Surgery otherwise followed standards of care. The primary endpoint was patient-reported physical well-being chest as assessed by BREAST-Q 24 mo after surgery (prespecified MID 4 points; SD 13). 372 pts provided 80% power (two-sided t-test α = 0.05). Multiple imputation was implemented for missing scores across all timepoints (day 10; 1, 6, 12, 18, 24 mo). The IBBR assignment difference at 24 mo was estimated by linear mixed modeling, adjusted for baseline score, stratification factors, pre-selected covariates, and random center effect. Loss or replacement of expander or implant for any reason within 24 mo was the primary safety endpoint. Results: From July 2020 to February 2023, 383 pts were randomized at 26 OPBC centers in 10 countries. The full analysis set comprised 380 pts (191 randomized to pre-pectoral, 189 to sub-pectoral IBBR). Surgery was unilateral in 72.9% of pts and NSM in 58.4%. The setting was therapeutic in 77.9% of pts, therapeutic and preventive in 15.5%, and preventive in 6.6%. BREAST-Q completion was 83-95% across 6 post-baseline timepoints. Pre-pectoral IBBR significantly improved physical well-being at 24 mo compared to sub-pectoral IBBR (least-square means 79.2 [95%CI 75.5-82.8] vs 74.3 [70.7-78.0], respectively). The mean difference of 4.8 (95%CI 1.0-8.7; p = 0.01) surpassed the predefined threshold for a clinically meaningful difference. The effect was robust in sensitivity analyses, and consistent in subgroup analyses. Loss or replacement of expander or implant for any reason within 24 mo occurred in 68 pts, 21.1% vs 14.5% after pre-pectoral and sub-pectoral IBBR, respectively. The covariate-adjusted model estimated 5.7% (95%CI -2.4% - 13.8%) more implant loss with pre-pectoral IBBR. At least one complication occurred in 54.1% vs 55.9% of pts, respectively. Early complications were more frequent after pre-pectoral IBBR (crude estimated increase range 3-5%); late complications were more frequent after sub-pectoral IBBR. Conclusions: Pre-pectoral IBBR significantly and relevantly improved long-term QoL at the cost of a higher risk of loss or replacement of expander or implant compared to sub-pectoral IBBR. Clinical trial information: NCT04293146 .

Real-world evidence on the influence of node positivity and advanced clinical stage on response and survival after CROSS regimen in esophageal/GEJ cancer.

e16103 Background: The CROSS regimen (weekly carboplatin/paclitaxel with concurrent radiation) improves outcomes in resectable esophageal and gastroesophageal junction (GEJ) cancer, but real-world performance across the full spectrum of clinical stage--including patients with cT4, cN2-3, or limited metastatic (cM1) disease--remains unclear. Methods: We performed a retrospective cohort study of all patients treated with CROSS-based neoadjuvant chemoradiotherapy from 2012–2022 at a regional cancer center. Patients were stratified into three prespecified groups based on initial clinical staging: Group 1: cT1-3N0M0, Group 2: cT1-3N1M0, and Group 3: cT4 and/or cN2–3 and/or oligometastatic cM1. Outcomes included overall survival (OS), progression-free survival (PFS), surgical resection, and pathologic complete response (pCR). Survival was estimated using Kaplan-Meier methods and compared using log-rank testing; multivariable Cox models adjusted for age, sex, and ECOG performance status. Results: Among 138 patients, 68 (49%) were in Group 1, 54 (39%) in Group 2, and 16 (12%) in Group 3. Surgical resection rates decreased with advancing clinical burden: 70.6% in Group 1, 57.4% in Group 2, and 25.0% in Group 3 (p=0.004). pCR rates were 13.2%, 7.4%, and 0%, respectively (p=0.26). Median PFS was 34 months, 13 months, and 6 months for Groups 1-3, respectively (global log-rank p=0.001). Median OS was 46 months, 19 months, and 17 months, with a nonsignificant trend across groups (p=0.09). Conclusions: In this real world cohort, higher clinical disease burden--including cT4 tumors, bulky nodal involvement, or limited metastatic disease--was associated with sharply reduced resection rates, absence of pCR, and significantly inferior PFS following CROSS neoadjuvant chemoradiotherapy. Survival outcomes for Group 3 patients were poor and overlapped substantially with those of cN1 disease, suggesting that CROSS alone is inadequate for node-positive presentations. These findings support the need for intensified or systemic-dominant perioperative strategies for patients with advanced locoregional or oligometastatic esophageal cancer.

Detecting <i>MTAP</i> loss in liquid biopsies from patients with clinically advanced colorectal cancer (CRC).

3553 Background: Homozygous loss of the MTAP gene ( MTAP loss) is an emerging biomarker guiding investigational use of PRMT5 and MAT2A inhibitors in a wide variety of tumor types, including CRC. Detecting copy number changes, including homozygous losses, in solid tumors is often challenging and requires robust assay and analytic pipeline especially when the amount of extracted DNA is small. In clinically advanced CRC, small endoscopic and needle-based biopsies are often used for diagnosis, imposing significant limitations on immunohistochemistry (IHC) and comprehensive genomic profiling (CGP) required for treatment selection and clinical trial enrollment. We assessed whether liquid biopsy (LBx) CGP could provide treatment-relevant information on MTAP loss compared to tissue biopsy (TBx) CGP for patients with CRC. Methods: Hybrid capture-based CGP was performed on 46,173 clinically advanced CRC (stage III, IV) TBx cases using the FoundationOne CDx assay and on 9,049 LBx cases using the FoundationOneLiquid CDx assay. Tumor fraction (TF) for each LBx sample was determined using assessments of aneuploidy and variant allele frequencies, as previously described. Results: MTAP loss was detected in 498 (1.08%) TBx cases. For LBx, detection of MTAP loss increased with higher TF, with detections observed only at TF ≥5% (Table 1). With TF ≥5%, the frequency of MTAP loss detection was comparable to or exceeds that observed with TBx. Regarding complete vs partial MTAP exon loss, TBx and LBx showed similar patterns, with complete loss of all 8 MTAP exons observed in 85.7% of TBx cases and 84.5%-89.8% in LBx cases, increasing in higher TF levels. Conclusions: LBx emerges as a promising tool for detecting MTAP loss in clinically advanced CRC, with MTAP loss detection rates approaching those of TBx when LBx TF is ≥5%, while detection is limited at lower TF levels. Incorporation of LBx for MTAP loss detection may expand patient access to biomarker-driven clinical trials involving PRMT5 and MAT2A inhibitors for patients with clinically advanced CRC when sufficient tissue for tissue-based CGP is not feasible. MTAP loss detected by TBx and LBx in clinically advanced CRC. Cohort (cumulative)* MTAP no loss MTAP loss MTAP loss frequency TBx (n=46173) 45675 498 1.08% LBx TF ≥0% (100% of LBx, n=9049) 9002 47 0.52% LBx TF ≥1.0% (62.7% of LBx) 5624 47 0.83% LBx TF ≥5.0% (48.7% of LBx) 4359 47 1.07% LBx TF ≥10.0% (41.5% of LBx) 3712 46 1.22% LBx TF ≥20.0% (31.5% of LBx) 2812 38 1.33% LBx TF ≥30% (24.8% of LBx) 2214 29 1.29% *TF thresholds represent cumulative subsets of the LBx cohort.

Patterns and determinants of radiotherapy treatment default in a rural cancer centre: A retrospective observational study.

11175 Background: Radiotherapy requires uninterrupted daily treatment over several weeks, making treatment adherence challenging, particularly in rural and resource-limited settings. Treatment default adversely affects outcomes and reflects underlying socioeconomic, access-related and clinical barriers. There is limited real-world data from rural India evaluating the magnitude and determinants of treatment default. This study aimed to determine the radiotherapy default rate and identify the associated factors. Methods: This retrospective observational study included patients enrolled for definitive, adjuvant, and palliative radiotherapy over a 2 year period at a rural tertiary cancer centre. Radiotherapy default was defined as missing 3 or more consecutive fractions after initiation of treatment or failure to complete the planned prescribed dose. Descriptive statistics were used to summarise patient demographics, socioeconomic characteristics and clinical variables. The radiotherapy default rate was expressed as a percentage. Associations between radiotherapy default and categorical variables were analysed using Chi-square or Fisher’s exact test, as appropriate. Variables significant on univariate analysis were included in a multivariate logistic regression model to identify independent predictors of radiotherapy default. A p-value &lt; 0.05 was considered statistically significant. Results: Among 2755 patients enrolled for radiotherapy during the study period, 363 patients defaulted, resulting in an overall default rate of ~13.2%. Higher default rates were significantly associated with longer daily travel distance, financial constraints, lower educational status, inadequate family support, poor baseline general condition, treatment related toxicities, diet-related difficulties- particularly among head and neck cancer patients (p &lt; 0.05). On multivariate logistic regression analysis, long travel distance, financial constraints, poor general condition, inadequate family support and diet-related difficulties remained independent predictors of radiotherapy default. Conclusions: Radiotherapy default remains a clinically significant challenge in rural practice and is driven by a combination of socioeconomic, access-related and clinical factors. Long travel distance, financial constraints, inadequate family support, poor general condition and diet-related difficulties independently contribute to treatment default. Early identification of high-risk patients and targeted interventions—including patient and caregiver counselling, nutritional optimisation, financial and travel assistance, symptom control, and multidisciplinary supportive care—have the potential to reduce radiotherapy default rates and improve treatment completion in resource-limited settings.

The mitochondrial apoptosis profile in meningiomas and gliomas: Comparing the effects of patient sex, tumor histology, and grade.

e14063 Background: Gliomas and meningiomas are the most common malignant (primary) and benign brain tumors, respectively. Mitochondrial dysfunction plays an important role in the pathogenesis of neoplasms across all locations. This study aimed to investigate the features of key apoptosis marker levels in the mitochondria (Mx) of brain tumor cells. Methods: The study included 18 patients with supratentorial brain tumors: gliomas (n=12, comprising LGG G2 (17%, n=3) and HGG G3 (50%, n=9)) and meningiomas (n=6). All patients underwent cytoreductive tumor resection. Progression within the first year was observed in all glioblastoma patients and one patient with G3 astrocytoma. The mean patient age was 52.91 ± 12.03 years, with 56% male and 44% female. Mitochondria were isolated using standard differential centrifugation with an Avanti J-E high-speed refrigerated centrifuge (Beckman Coulter, USA). The mitochondrial fractions were analyzed by enzyme-linked immunosorbent assay (ELISA) for cytochrome C (Bioscience, Austria), AIF and Bcl-2 (Cloud-Clone Corp., China), and calcium (Ca²⁺) (Abris, Russia) content. Statistical analysis followed standard guidelines for medical research. Results: AIF content in glioma Mx did not differ from that in meningioma Mx for patients of either sex. Only in males was Ca²⁺ content in meningioma Mx 4.3-fold lower than in females with meningiomas (p=0.0001) and males with gliomas (p=0.0011). The Bcl-2 level in glioma Mx was lower than in meningioma Mx by 5.6-fold in males (p=0.00001) and 5.8-fold in females (p=0.00001). Bcl-2 levels in meningioma Mx did not differ between sexes, whereas Bcl-2 content in glioma Mx was 1.5-fold lower in males than in females (p=0.025). The most notable findings were related to cytochrome C content. In meningioma Mx, the lowest values were characteristic of females, being 2.0-fold lower (p=0.0016) than in males with meningiomas. Conversely, in glioma Mx, the lowest values were in males, being 1.8-fold lower (p=0.0093) than in females with gliomas. Consequently, cytochrome C content in glioma Mx was 1.7-fold lower in males (p=0.0102) and 2.2-fold higher in females (p=0.0025) compared to patients of the corresponding sex with meningiomas. Conclusions: The mitochondrial apoptosis profile in brain tumors is not consistently linked to histological type, tumor grade, or malignancy. Patient sex appears to be a more significant factor, particularly regarding cytochrome C content.

Phase II study of T-Bren (BL-M07D1) monotherapy or in combination with pertuzumab in patients with treatment-naïve HER2-positive unresectable locally advanced or metastatic (LA/M) breast cancer.

1049 Background: T-Bren is a HER2-directed antibody-drug conjugate (ADC) consisting of an anti-HER2 monoclonal antibody linked to a potent topoisomerase I inhibitor (Ed-04). In phase I study, T-Bren demonstrated encouraging antitumor activity with a manageable safety profile in patients (pts) with HER2-positive unresectable LA/M breast cancer (BC) who had failed standard treatments. Results of safety and efficacy from a phase II study assessing T-Bren monotherapy or in combination with pertuzumab in treatment-naïve HER2-positive unresectable LA/M BC are presented. Methods: Treatment-naïve pts with HER2-positive (IHC3+, or IHC2+/ISH+) unresectable LA/M BC were treated with T-Bren monotherapy at 4.4mg/kg Q3W (cohort A) or T-Bren 4.4mg/kg Q3W in combination with pertuzumab (cohort B). Primary endpoints were ORR and RP2D for combination treatment. Results: As of Nov 30, 2025, a total of 83 pts were enrolled and treated in cohort A (n = 43) and cohort B (n = 40). All pts were included in the analysis (see table below). The median follow-up was 10.6 months. In cohort A, ORR was 93.0%, confirmed ORR (cORR) was 86.0%. In cohort B, ORR and cORR were 87.5%. Median PFS have not reached in either cohort. The landmark PFS rate at 12-months was 79.1% in cohort A and 90.8% in cohort B. The most common grade 3 and above hematologic TRAEs in both cohorts were neutropenia (51.8%), anemia (37.3%), leukopenia (36.1%), and thrombocytopenia (26.5%); the most frequent grade 3 and above non-hematologic TRAEs were weight decreased (7.2%), hypokalemia (6.0%), and nausea (6.0%). Grade 3 and above TRAEs were able to be effectively managed with standard supportive measure including dose reductions, as demonstrated by the TRAE leading to discontinuation rate of 4.8%. No treatment related death or ILD was reported. Conclusions: T-Bren as monotherapy or in combination with pertuzumab has demonstrated a promising antitumor activity and a manageable safety profile in pts with treatment-naïve HER2-positive unresectable LA/M BC. Phase III study assessing T-Bren in treatment-naïve HER2-positive unresectable LA/M BC is in preparation. Clinical trial information: NCT06445400 . Cohort A: T-Bren 4.4 mg/kg D1Q3W (N=43) Cohort B: T-Bren 4.4 mg/kg D1Q3W+ pertuzumab D1Q3W (N=40) Total (N=83) ORR, % (95% CI) 93.0 (80.9, 98.5) 87.5 (73.2, 95.8) 90.4 (81.9, 95.7) cORR, % (95% CI) 86.0 (72.1, 94.7) 87.5 (73.2, 95.8) 86.7 (77.5, 93.2) DCR, % (95% CI) 100 (91.8, 100) 97.5 (86.8, 99.9) 98.8 (93.5, 100) 12-mo PFS rate, % (95% CI) 79.1 (32.9, 95.2) 90.8 (74.1, 97.0) 89.9 (77.8, 95.6) 12-mo OS rate, % (95% CI) 100 (100, 100) 95.0 (81.5, 98.7) 97.4 (89.9, 99.3)