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Missed by the guidelines: A meta-analysis of USPSTF lung cancer screening ineligibility among patients diagnosed with lung cancer.

10573 Background: Lung cancer (LC) screening utilizes low-dose CT recommended by the US Preventive Services Task Force (USPSTF) based on age and smoking history. However, the proportion of patients who develop LC but are ineligible for screening at diagnosis remains unclear. We performed a meta-analysis to quantify the burden of LCs missed under USPSTF 2013 and 2021 criteria and identify key reasons for ineligibility. Methods: We systematically searched PubMed, Embase, and Scopus to identify studies reporting USPSTF screening eligibility among adults diagnosed with primary LC who ever smoked. Data were pooled using random-effects models. Primary outcomes included pooled proportions (PP) of LC cases ineligible for USPSTF screening using 2013 and 2021 criteria. Secondary analyses evaluated reasons for ineligibility, including age, smoking pack-years (yrs), and quit-yrs. Statistical significance is defined as p <0.05. Heterogeneity was assessed using the I² statistic. Results: Eight studies comprising 12,487 LC cases utilized the USPSTF 2013 criteria. The PP of screening-ineligible cases was 57.6% (95% CI, 48.94%-66.2%; I²=97.3%). Under USPSTF 2021 criteria, 11 studies including 20,313 cases were analyzed, yielding a pooled ineligible proportion of 40.9% (95% CI, 31.9%-50.5%; I²=98.8%). In reason-specific analyses, insufficient smoking exposure (pack-yrs) was the primary cause of ineligibility using both criteria, accounting for 68.2% (2013) and 59.3% (2021) of ineligible cases. Age-based exclusions declined from 34.7% under USPSTF 2013 to 31.8% under USPSTF 2021. Quit-year restrictions contributed to ineligibility under both criteria (25.8% in 2013; 49.6% in 2021), reflecting a greater proportional contribution among remaining ineligible cases under the 2021 criteria. Categories of ineligibility were not mutually exclusive. Conclusions: More than half of LCs were ineligible for screening under USPSTF 2013 criteria, and over 40% remain ineligible under current guidelines. Smoking pack-year thresholds remain the primary reason for ineligibility to screen and thereby miss a cancer diagnosis. These findings highlight limitations of current criteria and support the development of alternative risk-based screening strategies. Lung cancer screening ineligibility under USPSTF 2013 and 2021 criteria. Pooled Proportion (95% CI) I² (%) USPSTF 2013 Criteria Overall Ineligibility 57.6% (48.4-66.2) 97 Age-based exclusion (<55 or >80 yrs) 34.7% (28.2-41.8) 70 Insufficient pack-yrs (<30) 68.2% (54.6-79.2) 93 Quit-year exclusion (>15 yrs) 25.8% (10.8-49.8) 97 USPSTF 2021 Criteria Overall Ineligibility 40.9% (31.9-50.5) 98 Age-based exclusion (<50 or >80) 31.8% (18.4-49.0) 96 Insufficient pack-yrs (<20) 59.3% (45.6-71.6) 89 Quit-year exclusion (>15 yrs) 49.6% (37.1-62.0) 94

Modern concepts of endometrial squamous cell carcinoma.

e17626 Background: Endometrial cancer is the leading oncogynecological malignancy, with a concerning trend of shifting age incidence and worsening prognosis. Over 75% of endometrial carcinomas are represented by estrogen-dependent endometrioid adenocarcinoma (EAC). The remaining 20% comprise more aggressive rare tumors, including squamous cell carcinoma of the endometrium (SCCE). Morphologically, EAC with squamous metaplasia (found in 15% of cases) is distinguished from pure SCCE (reported in about 2%). The etiology and pathogenesis of these carcinomas are insufficiently understood. This study aimed to define the pathomorphological features of EAC with squamous metaplasia and SCCE by analyzing the association between immunohistochemical and virological factors. Methods: The study was conducted on retrospective material from 90 patients (aged 32–89 years) with verified diagnoses of EAC, EAC with squamous metaplasia, and SCCE. All patients received standard treatment. Morphological structure, expression of p16 and pRb markers, and detection of high-risk HPV DNA (types 16 and 18) were analyzed in resected tumor tissues. Comparative and statistical analysis was performed using the Mann-Whitney U test. Results: All patients with SCCE were in deep menopause; the tumor developed against a background of atrophic endometrium and was accompanied by diffuse adenomyosis in 82% of cases. SCCE was characterized by low differentiation grade (G3) in 75% of patients, whereas G3 was found in only 38% of EAC with squamous metaplasia. Markers p16 and pRb demonstrated signs of progression from EAC to SCCE. The median p16 expression level was 1.7-fold higher in squamous metaplasia (p=0.059) and 2.3-fold higher in SCCE (p=0.020) compared to pure EAC. The median pRb levels showed almost no differences in the carcinoma groups; however, in the SCCE group, a sharp 2.3-fold decrease in pRb expression was observed (p=0.041). Altered p16 and pRb expression is closely linked to the E6 protein, which determines the malignant phenotype of HPV infection. HPV was detected in 46.7% of EAC cases, 52.9% of EAC with squamous metaplasia, and 78.5% of SCCE cases. Typing analysis revealed that HPV type 18 was more frequent in EAC with squamous metaplasia (66.7%), whereas HPV type 16 predominated in SCCE (82%). Furthermore, the level of the E6 protein in tissue with a squamous component was 37.4 times higher than in intact (tumor-free) endometrium. Conclusions: The obtained data reveal the potential role of p16, pRb markers, and HPV in the etiology of endometrial squamous cell carcinoma and open prospects for targeted therapy.

Efficacy and safety of AKT inhibitor NTQ1062 combined with fulvestrant in patients with HR-positive/HER2-negative metastatic breast cancer：a proof-of-concept, multicenter, open-label, nonrandomized, phase Ib/II study.

e13043 Background: NTQ1062 is an oral, potent, and pan-AKT small-molecule inhibitor with favorable pharmacokinetic properties. This phase Ib/II study (NCT06172322) was designed to assess the efficacy and safety of the NTQ1062 in combination with fulvestrant in patients with hormone receptor-positive (HR + ), human epidermal growth factor receptor 2-negative (HER2 - ) metastatic breast cancer (mBC) and to establish the optimal biological dose (OBD) of NTQ1062 for subsequent phase III development. Methods: Eligible patients were women with a histologically confirmed HR + /HER2 - mBC who had experienced disease progression on prior endocrine therapy. Patients were stratified into three dose cohorts: NTQ1062 400 mg or 500 mg once daily (qd), 200 mg twice daily (b.i.d.). Treatment cycles consisted of 21 days of continuous NTQ1062 administration followed by a 7-day rest period, in combination with standard-dose fulvestrant administered per clinical practice guidelines. The primary endpoints were safety and determination of the OBD. Secondary endpoints included objective response rate (ORR), progression-free survival (PFS) and biomarker analysis. Results: As of the data cutoff (Nov 26, 2025), 56 patients were enrolled to receive study treatment. The cohorts were as follows: 15 patients in 400 mg (qd) cohort, 16 in 500 mg (qd) cohort, and 25 in 200 mg (b.i.d.) cohort. Among the patients, 62.5% had previously received a CDK4/6 inhibitor. Visceral metastases were present in 47 patients (83.9%). A total of 25 patients (44.6%) in the overall population harbored confirmed PIK3CA/AKT1/PTEN alterations. Confirmed partial response (PR) was achieved in 14 patients, resulting in an overall ORR of 25.0% (95% CI, 14.4-38.4), with the 200 mg (b.i.d.) cohort showing a higher response rate (36.0%). In all patients, the median PFS (mPFS) was 6.7 months (95% CI, 3.7-11.1), with 7.4 (95% CI, 3.7-NA) months in the 200 mg (b.i.d.) groups. The most common grade 3 TRAEs (incidence ≥5%) were diarrhea (12.5%, 7/56), maculopapular rash (7.1%, 4/56), and hyperglycemia (7.1%, 4/56). Treatment-related serious adverse events (SAEs) were reported in 5 patients (8.9%), all requiring hospitalization. Conclusions: NTQ1062 combined with fulvestrant demonstrated a favorable and manageable safety profile and encouraging clinical activity in patients with HR + /HER2 - mBC who had progressed on prior endocrine therapy. Based on superior efficacy and a more favorable tolerability profile observed across dose levels, 200 mg (b.i.d.) was determined to be the OBD of NTQ1062 for the combination with fulvestrant. Clinical trial information: NCT06172322 .

Optimal timing of endocrine therapy interruption for pregnancy in young women with hormone receptor–positive early breast cancer.

627 Background: The POSITIVE trial showed that temporary interruption of adjuvant endocrine therapy (ET) after 18–30 months to attempt pregnancy did not increase short-term recurrence risk in young women with hormone receptor–positive (HR+) breast cancer (BC). However, whether this effect varies by baseline recurrence risk and the timing of interruption remains uncertain. Methods: Using the French National Health Data System (SNDS), we emulated two target trials among women aged ≤42 years with early-stage HR+ BC diagnosed between 2011 and 2020. Trial 1 emulated the POSITIVE design, comparing ET interruption at 18–30 months with uninterrupted ET for ≥24 months. Trial 2 compared nine ET-interruption windows (6-month intervals) with uninterrupted ET for ≥24 or ≥60 months. The primary endpoint was the 5-year risk of BC events. Analyses used a clone–censor–weight approach with marginal structural models. Results: In Trial 1 (n = 10,835), ET interruption at 18–30 months was associated with a 5-year BC event risk of 17.2%, compared with 16.0% for uninterrupted ET ≥24 months (risk difference, 1.2 percentage points; 95% CI, −0.7 to 3.1). Risk varied by baseline recurrence risk: interruption had minimal impact in low- or intermediate-risk women (risk difference, −0.6 percentage points; 95% CI, −2.7 to 1.6) but increased risk in high-risk women (risk difference, 5.8 percentage points; 95% CI, 1.8 to 10.0). In Trial 2 (n = 22,916), earlier ET interruption was associated with higher 5-year BC risk, which decreased with longer prior ET duration. Compared with uninterrupted ET ≥24 months, interruption at 6–12 months increased risk by 8.3 percentage points, whereas interruption at 24–30 months increased risk by 2.7 percentage points. Low- or intermediate-risk women showed comparable risk when interruption occurred at 24–30 months, whereas high-risk women required ≥36–42 months of ET to achieve similar safety. Among pregnancy-seeking women, 64% conceived, and 47% resumed ET. Conclusions: The oncologic impact of temporary ET interruption depends on baseline recurrence risk and prior ET duration. Interruption after 24 months appears safe for low- or intermediate-risk women, whereas high-risk patients may benefit from delaying interruption to at least 36 months. These findings support a risk-adapted approach to fertility counseling.

Ethnic distribution and clinical impact of serum tumor marker abnormalities in metastatic breast cancer patients.

e13007 Background: Serum tumor markers (STMs) - CA15-3, CA27-29 and CEA - are commonly used for surveillance and metastatic breast cancer (mBC) treatment monitoring. The ethnic distribution and prognostic impact of each STM are poorly understood. Methods: This research was a multi-center retrospective study including records of patients with confirmed mBC and ≥2 values for each STM. Median and maximum (max) values of STMs for each patient were analyzed. Mann-Whitney (M-W) and Kruskal-Wallis tests, as well as Spearman correlations, comprised statistical analyses; significant findings were declared at p < 0.05. Results: The study included 237 patients: 9.3% Hispanic (H), 91.6% > 50 years old, 57.2% and 37.6% with history of alcohol and tobacco use, respectively. All STMs were consistently lower in H compared to non-H (Table 1) and were not associated with alcohol/tobacco use, specific mBC histology/subtype or TP53 mutation. Higher median CA15-3 and CA27-29, but not median CEA, statistically correlated with longer time from diagnosis to new metastatic deposit (p = 0.003 and 0.016, respectively). All median and max STM values directly correlated with an increasing number of metastatic sites (p≤0.003) and lines of chemotherapy (p≤0.045). Only CEAmax was negatively correlated with higher number of HER2 therapies (p = 0.042). No STM was correlated with time from diagnosis to mBC-related death in H and non-H patients. Conclusions: STMs remain helpful mBC monitoring tools as the degree of their elevation correlated with increasing number of metastatic sites and lines of chemotherapy, while CA 15-3 and CA27-29 elevation positively correlated with time to first progression. However, STMs lack prognostic information and showed no statistically significant differences by race, alcohol/tobacco use or specific mBC histology/subtype. To our knowledge, this study is the first to suggest ethnic variability in STMs. Reasons for lower STM values in Hispanics will need to be elucidated in larger studies. STM Medians and maximums with interquartile ranges (IQRs) by ethnicity. Ethnicity CA 15-3 median (U/ml) CA 15-3 max (U/ml) CA 27-29 median (U/ml) CA 27-29 max (U/ml) CEA median (ng/ml) CEA max (ng/ml) Non-Hispanic 30.50 (19.00-86.5) 101.00 (32.00-464.00) 55.0 (33.50-134.25) 152.00 (58.00-527.25) 4.30 (1.90-9.45) 9.50 (3.20-47.70) Hispanic 16.00 (11.75-45.50) 35.00 (17.00-94.00) 33.50 (20.12-82.75) 64.50 (26.50-147.50) 2.85 (2.00-4.25) 3.85 (2.65-13.17) P-value (M-W) 0.009* 0.014* 0.022* 0.011* 0.415 0.065

Integrated imaging cytology profiling system for rapid point-of-care molecular diagnosis of leptomeningeal metastasis in breast cancer.

3073 Background: Leptomeningeal metastasis (LM) from breast cancer has a poor prognosis (median survival ~4 months). Early and accurate diagnosis and phenotyping enable timely therapeutic intervention, particularly with emerging targeted agents such as antibody–drug conjugates (ADCs), to improve clinical outcomes. Yet, MRI and CSF cytology often lack sensitivity. We developed iSCOPE, an integrated imaging cytology platform that rapidly enriches and detects tumor cells in CSF via single-cell immunomolecular profiling. Methods: Breast cancer patients with neurological symptoms and/or suspicion for LM were enrolled in the study (IRB: KNUCH 2020-08-015). CSF (5–10 mL) was obtained by lumbar puncture for iSCOPE testing, and the rest was for conventional cytology examination. iSCOPE (integrated single-cell on-chip point-of-care evaluation) enriches large epithelial cells from unprocessed CSF at single-cell capture sites in a microfluidic chip while smaller blood cells pass through. Captured cells are then immunolabeled with QUAD markers (a four-marker combination overexpressed in breast cancer), as well as HER2 and ER/PR, for phenotyping. Automatic quantitative fluorescence imaging using a miniaturized imager reports the total cells, QUAD-positive cells, and their phenotypes in 1 hour. iSCOPE was validated using FNA cytology samples and then applied to CSF samples. Results were compared with conventional CSF cytology. Results: In the validation study using FNA cytology samples, iSCOPE demonstrated excellent breast cancer detection accuracy based on QUAD-positive cell counts (area under the curve/AUC = 0.995), and receptor phenotyping showed concordance with clinical pathology (AUC > 0.9). In CSF testing, iSCOPE correctly discriminated between LM ( n = 7) and control CSF samples from patients with normal pressure hydrocephalus ( n = 5). In serially collected CSF testing due to inconclusive diagnoses, iSCOPE detected LM in two cases, a few months earlier than conventional cytology when a suspicious finding was initially made (Table 1). Conclusions: This study demonstrates the clinical feasibility of iSCOPE for CSF-based diagnosis of LM in breast cancer. iSCOPE addresses current challenges in cytology analysis by incorporating a microfluidic chip to enrich for scant, suspicious cells and by using immunomolecular profiling to detect tumor cells. The CSF study results highlight the potential clinical use of iSCOPE for detecting LM in a point-of-care setting. CSF analysis for LM diagnosis. ID Primary subtype LM diagnosis (MRI) LM diagnosis (Cytology) LM diagnosis (iSCOPE) S1 TNBC 2/8/2025 2/10/2025 2/10/2025 S2 HR+ HER2- Negative 2/18/2025 Suspicious S3 HR+ HER2- 4/2/2025 3/31/2025 8/14/2024 S4 HR+ HER2- 2/28/2025 (suspicious) 8/28/2025 2/17/2025 S5 TNBC 12/26/2025(suspicious) Negative Negative

Implementing clinical-scale multiscale spatial transcriptomics: Tumor architecture profiling in SCRUM-Japan MONSTAR-SCREEN-3.

3132 Background: Spatial interactions between tumor cells and the tumor microenvironment (TME) influence disease progression, yet current diagnostic profiling lacks spatial resolution. A clinically implementable framework enabling cross-cancer spatial characterization using pretreatment clinical specimens is needed. SCRUM-Japan MONSTAR-SCREEN-3 (MONSTAR3) is an ongoing prospective clinical screening platform enrolling over 3,200 patients with solid tumors, integrating clinical annotation with multi-omic. We report an intermediate analysis validating the feasibility of extracting reproducible spatial phenotypes from pretreatment specimens at clinical scale. Methods: Spatial transcriptomics (Xenium 5K) was performed on 331 pretreatment FFPE tumor specimens from 309 patients representing ≥15 solid cancer types enrolled in MONSTAR3. Specimens obtained at diagnosis or prior to systemic therapy included unresectable advanced and curative-intent settings. Analyses examined spatial organization of tumor–immune interactions at the TME level, cancer cell functional states, neighborhoods, and tertiary lymphoid structures. Spatial features were systematically compared across cancer types and disease settings without treatment outcomes. Results: We generated a spatial atlas comprising approximately 20 million cells with high-confidence annotation across over 15 cancer types, representing one of the largest clinically annotated pan-cancer spatial transcriptomic resources to date. The atlas captures tumor-microenvironment organization, cancer-intrinsic functional heterogeneity, conserved cellular niches, and specialized immune structures including tertiary lymphoid structures with defined maturation states. Spatial tumor architecture varies substantially across cancer types despite similar cellular composition, underscoring value of spatially-resolved profiling beyond conventional cell-type quantification. Analysis across disease stages revealed that advanced tumors exhibit higher spatial compartmentalization of cancer functional states, with immunogenic and proliferative cancer populations showing consistent spatial separation across cancer types. Pan-cancer niche analysis identified conserved cellular neighborhoods, a subset of which showed stage-specific enrichment or prognostic associations. We also performed detailed spatial characterization of tertiary lymphoid structures, which demonstrated association with immunotherapy response in an independent cohort. Conclusions: We present a large-scale pan-cancer spatial atlas integrated within a nationwide precision oncology framework. This resource enables systematic investigation of spatial tumor biology and nominates spatially-defined features as candidate biomarkers for patient stratification and therapeutic response studies.

ADAPT-T-DXd: Multi-institutional real-world study of dose-adapted trastuzumab deruxtecan in HER2-positive and HER2-low metastatic breast cancer.

1106 Background: Trastuzumab deruxtecan (T-DXd) has demonstrated substantial efficacy in HER2-positive and HER2-low metastatic breast cancer (MBC) at a standard dose of 5.4 mg/kg in the DESTINY trials. But high treatment cost remains a major barrier to access in low/middle-income countries. We evaluated the clinical activity and safety of dose-adapted T-DXd in a multi-institutional real-world Indian cohort, where dose modification was primarily driven by financial constraints. Methods: This retrospective analysis included 63 patients with HER2+ or HER2-low MBC treated with dose-adapted T-DXd across multiple Indian centers. Dose-adapted T-DXd refers to the administration of T-DXd at doses lower than the standard 5.4 mg/kg dose in DESTINY trials. Dose selection was based on affordability. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints were progression-free survival (PFS), duration of response (DoR), and safety. An evaluable cohort (n = 53) was defined as patients receiving ≥2 cycles of therapy. DoR measured from treatment initiation to radiologic progression or last drug exposure. Results: The median age was 57 years; 42.9% had hormone receptor–positive disease. HER2 subtypes included HER2 3+ (63.5%), HER2 2+/ISH+ (11.1%), and HER2-low (22.2%). Patients had received a median of three prior lines of therapy. The median administered dose of trastuzumab deruxtecan was 3.7 mg/kg, corresponding to 68% of the standard dose. At a median follow-up of 8.3 months, the objective response rate (ORR) was 58.7% (95% CI, 46–71%) in the full cohort and 66.0% (95% CI, 53–79%) in the evaluable cohort. The highest ORR was observed in HER2 3+ disease (76.5%). Median progression-free survival was 5.3 months (95% CI, 4.2–6.4) in the full cohort and 7.1 months (95% CI, 5.8–8.4) in the evaluable cohort. Median duration of response was 8.3 months, with 40–45% of responses ongoing at data cutoff. Grade ≥3 neutropenia occurred in 9.0% of patients, and interstitial lung disease occurred in 7.0%; no grade 5 pulmonary events were observed. Dose reductions due to toxicity were uncommon. Conclusions: Dose-adapted trastuzumab deruxtecan demonstrated clinically meaningful activity with a manageable safety profile in patients with HER2-positive and HER2-low metastatic breast cancer in a real-world setting. The shorter median PFS likely reflects reduced dose intensity, limited follow-up and real-world heterogeneity, rather than loss of intrinsic drug activity. These findings support further prospective evaluation of dose-adapted strategies to improve treatment accessibility in resource-limited settings.

Single-cell analysis of plasma cell–centered inflammatory–immunosuppressive niches and response to daratumumab in primary light-chain amyloidosis.

7553 Background: Primary light-chain amyloidosis (pAL) is a plasma cell disease in which clonal plasma cells produce misfolded immunoglobulin light chains that lead to progressive organ dysfunction. Daratumumab (Dara), an anti-CD38 monoclonal antibody, is the backbone of first-line regimens for pAL; however, ~10–30% of treated patients fail to achieve ≥VGPR. Currently, there remains an unmet need to delineate the immune microenvironmental mechanisms underlying Dara resistance in pAL to enable the identification of predictive biomarkers and therapeutic targets, particularly for patients who lack prognostic cytogenetic markers such as 1q21 gain. Methods: We profiled 630,111 single cells obtained from a prospective observational cohort of 30 patients treated with a frontline Dara–bortezomib–dexamethasone regimen, including 11 paired samples collected pre-treatment and post-treatment. Overall, 37.0% of patients showed suboptimal responses (≤PR) before cycle 6 or initiation of next-line therapy. Plasma cells enriched with CD138⁺ magnetic beads and whole bone marrow were profiled with single-cell RNA-seq. Results: At cohort baseline, 93.3% of the patients were Mayo 2004 stage I–IIIa, 46.7% harbored the t(11;14) translocation, and 20.0% had 1q21 gain. Suboptimal responders showed two plasma cell-centered immune processes already upregulated at baseline: (i) an inflammatory axis with elevated PTGES2/PTGES3 (PGE₂)–EP2/EP4 (BH-adjusted Wilcoxon p < 0.05) signaling between plasma cells and myeloid, NK, and T cells, possibly driven by upstream PTGS2-expressing myeloid-derived suppressor cell-like CD38⁻ CD14⁺ monocytes that expanded during treatment; and (ii) an immunosuppressive axis in which non-classical MHC class I on plasma cells increased inhibitory interactions mainly with NK and T cells (including HLA-E–KLRK1, HLA-G–LILRB1, and HLA-F–LILRB1) (BH-adjusted Wilcoxon p < 0.05). Compared with patients with 1q21 gain, patients with t(11;14) were associated with higher non-classical MHC class I and PTGES3-dependent prostaglandin signaling and lower PTGES2-dependent prostaglandin signaling. Possibly driven by this microenvironment, myeloid cells downregulated phagocytosis and endocytosis, NK cells showed impaired effector functions, and T cells upregulated exhaustion, accompanied by an enhanced interferon response in suboptimal versus good responders (BH-adjusted Wilcoxon p < 0.05). Conclusions: This single-cell cohort revealed a baseline inflammatory–immunosuppressive niche in pAL that underpins suboptimal hematologic responses to Dara, characterized by up-regulated non-classical MHC class I and prostaglandin signaling between plasma cells and immune cells and associated with impaired immune effector functions during Dara treatment.

Comparative effectiveness in <i>MET</i> ex14 NSCLC: Outcomes from a propensity score–based analysis of 8 pooled real-world datasets (the TOGETHER study).

e20749 Background: MET ex14 skipping alterations in non-small cell lung cancer (NSCLC), recognized as important drivers of tumorigenesis, present in 3-4% of cases and are associated with poor prognosis. While case series suggest worse real-world outcomes in patients with MET ex14 skipping alterations compared to the broader NSCLC population, there is limited comparative effectiveness evidence on these outcomes for standard treatments prior to the first regulatory approvals of targeted therapy with selective MET receptor tyrosine kinase inhibitors (MET TKIs). Methods: Patient-level data from eight international real-world datasets of MET ex14 skipping NSCLC patients covering the period from 2010 to 2022 were pooled, applying inclusion/exclusion criteria consistent with the tepotinib MET TKI VISION trial. Propensity score (PS) weighting (based on clinical input) was applied to perform comparisons of real-world progression-free survival (PFS) and overall survival (OS) in four treatment classes: chemotherapy (CT), immunotherapy monotherapy (IO), IO plus chemotherapy (IO+CT), and an unapproved TKI (crizotinib). Results: Ultimately, 406 patients, treated across 661 lines of therapy, were incorporated into the analyses. Median PFS was, in months (95% CI): CT 4.8 (3.9–7.3), IO 5.7 (3.2, 10.7), IO+CT 4.9 (3.6, not evaluable), crizotinib 7.4 (4.7, 11.6). Median OS ranged from 11.9 months (8.4, 19.7) for crizotinib, to 18.4 months (11.0, 32.9) for IO. However, OS estimates are confounded by the effects of subsequent treatments and susceptible to immortal time bias due to the retrospective nature of data. Results were consistent across sensitivity analyses, including stratification by treatment line, disease subtype, and bootstrapping by sequential exclusion of datasets. Conclusions: Pooled real-world datasets of traditional therapies for MET ex14 skipping NSCLC demonstrated limited effectiveness. Median PFS was similar across treatment classes. IO (whether alone, or in combination with CT) did not demonstrate its clinical advantage in PFS or OS outcomes generally seen in the wider NSCLC population, while crizotinib did not outperform chemotherapy. These uniformly poor outcomes illustrate the need for further targeted treatment options in MET ex14 skipping alterations NSCLC. Confounding of OS, in part due to the use of subsequent therapies forms an important limitation of the analyses.

Facility-level differences in treatment patterns and outcomes among patients aged ≥ 75 years with follicular lymphoma: A National Cancer Database analysis.

e19064 Background: Follicular lymphoma (FL) is one of the most common indolent non-Hodgkin lymphomas, typically affecting older adults (1). Patients aged ≥75 years are underrepresented in clinical trials, and there are limited data evaluating whether survival differs by treatment setting. Using the National Cancer Database (NCDB), we examined differences in treatment patterns and overall survival among elderly patients with FL treated at Academic Cancer Programs (ACP) versus Community Cancer Programs (CCP). Methods: We conducted a retrospective cohort study of patients aged ≥75 years diagnosed with FL between 2004 and 2022. Patients were stratified by treatment facility type: ACP and CCP. Demographic, socioeconomic, clinical, and survival data were compared between patients treated at ACP and CCP. Kaplan-Meier analysis and Cox proportional hazards models were used to estimate overall survival (OS), adjusting for age, race/ethnicity, insurance status, Charlson-Deyo comorbidity score, and distance from the treating facility. Results: A total of 38,443 patients were identified, with 18,197 (47%) treated at ACP and 20,246 (53%) at CCP. Median age was 80 years in both groups with comparable sex distribution. Most patients were non-Hispanic (~91–92%), with Hispanics comprising &lt;5% in each cohort. Patients treated at ACP were more likely to reside in metropolitan areas, have higher income, and education levels, and travel longer distances for care (8.9 vs. 7.5 miles, p&lt;0.001). Medicare was the primary payor in both settings. Comorbidity burden was low, with &gt;70% of patients having a Charlson-Deyo score of 0 in both cohorts. Overall, 42% had early-stage disease (I–II) and 47% had advanced-stage disease (III–IV) across both settings. Treatment was administered to 49% of patients at ACP and 48% at CCP, with earlier initiation of treatment at CCP (23 vs 26 days; p&lt;0.001). Median OS was slightly longer for patients treated at ACP compared with CCP (5.66 vs. 5.11 years, p &lt; 0.001). Kaplan–Meier–estimated OS at 2, 5, and 10 years favored ACPs (75.3% vs 72.3%, 54.0% vs 50.6%, and 26.7% vs 24.2%). Conclusions: Our study revealed small but statistically significant survival advantages for elderly patients aged ≥75 years with FL treated at ACP. Despite comparable stage at diagnosis, comorbidity burden, and treatment receipt, patients treated at ACP demonstrated slightly longer OS, suggesting that specialized expertise, research-driven protocols, and comprehensive supportive care may contribute to better outcomes in this population. Prospective studies are warranted to validate these findings and identify interventions to improve equity in community settings. 1. Yar Cheema IBCL-1257: Mapping the Gaps: Understanding Survival Disparities in Follicular Lymphoma Across Socioeconomic Demographics (2000–2021). Clinical Lymphoma, Myeloma and Leukemia.

A review on doped quantum dots of Ag/CdTe: Synthesis, characterization and applications

Evaluation of the safety and efficacy of TRC003 in metastatic triple-negative breast cancer: A prospective, open-label, multicenter, single-arm exploratory clinical trial.

TPS1161 Background: TRC003 (also named 225 Ac-TR2205) is a novel molecule of targeted alpha therapy (TAT) designed to deliver alpha-particle radiation to cancer cells expressing prostate-specific membrane antigen (PSMA). Compared to beta-particles, alpha-particles have a shorter path length and higher linear energy transfer, resulting in more frequent double-strand DNA breaks and potentially superior antitumor efficacy. In an ongoing pilot study, TRC003 has demonstrated a favorable safety profile and promising activity in patients with prostate cancer. Notably, PSMA expression has been reported in up to 60% of breast cancer neovasculature, with the highest rates observed in triple-negative breast cancer (TNBC). A head-to-head study found valuable insights into the expression of PSMA in TNBC and underscore the potential clinical significance of PSMA PET/CT in enhancing both diagnostic and therapeutic approaches for TNBC. This study aims to investigate the preliminary safety and efficacy of 225 Ac-TRC003 in patients with metastatic TNBC (mTNBC). Methods: This is a prospective, open-label, multicenter, single-arm study in accordance with ICH GCP guidelines at two centers. The primary objective is to evaluate the safety and tolerability of TRC003. Secondary endpoints include Objective Response Rate (ORR), Disease Control Rate (DCR), Duration of Response (DoR), Time to Progression (TTP), progression-free survival (PFS) and overall survival (OS). Key eligibility criteria include: 1) age ≥18 years; 2) histologically confirmed mTNBC with documented progression after ≥2 prior lines of systemic therapy (including at least 1 line for metastatic disease); 3) presence of PSMA-positive lesions on imaging, without FDG-positive &amp; PSMA-negative target lesions; 4) at least one measurable lesion per Response Evaluation Criteria in Solid Tumors version (RECIST) 1.1; 5) Eastern Cooperative Oncology Group performance status of ≤ 1; and 6) adequate bone marrow, renal, and hepatic function. Fifteen eligible participants will be enrolled to receive 7.40 MBq (200 μCi) (±10%) of TRC003 by intravenous infusion every 8 weeks (±1 week), for up to 8 cycles if clinical benefit is observed. Treatment will continue until disease progression, unacceptable toxicity, or consent withdrawal, meeting any study withdrawal criterion, whichever occurs first. Tumor assessments (contrast-enhanced CT/MRI and bone scan) will be performed every 8 weeks until disease progression is confirmed per RECIST 1.1. Clinical trial information: MR-37-25-039070.

From rinse to result: Feasibility of genotyping core biopsy supernatant in lung cancer.

e20051 Background: Non-small cell lung cancer (NSCLC) patients require molecular testing, even in early stage, to inform the optimal approach to their disease. Diagnosis can be made using core needle biopsy (CNB); however, tissue samples can be insufficient for molecular testing, and plasma-based detection can be falsely negative. CNB cell-free DNA (cfDNA) isolated from supernatant may offer an alternate rapid diagnostic sample. Methods: In this prospective single-arm study, stage I-III non-squamous NSCLC patients undergoing diagnostic evaluation at the University Health Network (Toronto, Canada) were enrolled, with a planned accrual of 100 patients. Next-generation sequencing (NGS) was performed on CNB supernatant (TruSight Oncology 500), or CNB pellet genomic DNA if insufficient cfDNA (TSO500), CNB tissue (Oncomine Comprehensive Assay v3), and plasma cfDNA NGS (TSO500). Turnaround time (TAT) was calculated from biopsy date NGS test request to the molecular result date. Sensitivity was calculated in patients with tier 1 variants in tissue NGS. Results: As of Nov. 2025, 29 patients were enrolled with median age 74 years, 62% female, and 81% had stage I-II disease. 19 patients had tier 1 variants in tumour tissue, and available CNB results. Sensitivity and alterations are shown in Table 1. TAT was similar between supernatant and tissue biopsy. Conclusions: Overall, CNB supernatant had high sensitivity compared to tissue biopsy. Plasma NGS testing had low sensitivity in patients with early-stage disease. Similar TAT is likely influenced by sample batching. Further study is required to examine workflow to accelerate molecular results using CNB supernatant. Tier 1 variant sensitivity with tissue biopsy. Sample Sensitivity Alterations Tissue N/A see below CNB totalCNB pelletCNB supernatant 19/19 (100%)13/13 (100%)6/6 (100%) EGFR exon 21 L858R (n=4) EGFR exon 19 del (n=5) EGFR exon 20 ins (n=1) EGFR G719C (n=1) ALK (n=2) ROS1 (n=1) MET exon 14 skipping (n=3) KRAS (n=2) Plasma 0/9 (0%) N/A N/A = not applicable.

Clinical trial in progress: Phase I/II study of tebentafusp in combination with liver-directed therapies for the treatment of metastatic uveal melanoma.

TPS9596 Background: Uveal melanoma (UM) has a high rate of metastasis, most commonly to the liver. Tebentafusp-tebn (Tebe) is a first-in class immune-mobilizing monoclonal T cell receptor against cancer (ImmTAC) that gained regulatory approval after it showed significantly improved overall survival (OS) compared to single-agent investigator’s choice in a pivotal randomized phase III trial. For patients with oligometastatic liver disease, liver-directed therapies (LDT) such as hepatic immunoembolization (IE) and chemoembolization (CE) have been used with success. LDT and Tebe may have therapeutic limitations when administered independently, but combining the two approaches is a potentially beneficial strategy that could provide both short-term hepatic disease control and long-term systemic disease control. Methods: This is an investigator-initiated, multicenter, open-label phase I/randomized phase II trial to assess the safety and clinical efficacy of Tebe in combination with LDT in HLA-A*02:01 positive patients with metastatic UM [NCT06626516]. In Part 1 of the study, we will investigate the safety and efficacy of Tebe + IE in patients with low to moderate hepatic disease burden (M1a or M1b disease with largest tumor ≤ 5 cm, AND &lt; 50% liver involvement). In Part 2, we will investigate the safety and efficacy of Tebe + CE in patients with bulky hepatic disease (M1b disease with largest tumor &gt; 5cm, M1c disease, or &gt;50% liver involvement). Patients must be 18 years or older, HLA-A*02:01 with metastatic UM in the liver. Extra-hepatic disease is allowed. Patients must be treatment naïve in the metastatic setting for Part 1 and must have no more than two prior lines of treatment (systemic or liver directed) for Part 2. Patients will receive Tebe at the approved step-up dosing regimen (20 mcg IV on C1D1, 30 mcg IV on C1D8, then 68 mcg on C1D15 and weekly thereafter). Patients in Part 1 will receive IE with GM-CSF 1500mcg every 4 weeks (starting at week 5) for the first four treatments and then 4 weeks as maintenance if clinically indicated. Part 1 has a phase I safety lead-in (Part 1A), followed by a phase II trial (Part 1B) where patients are randomized 2:1 to receive Tebe + IE or Tebe alone. Patients in Part 2 will receive CE with BCNU 300mg every 4 weeks for a total of 2 (unilobar disease) or 4 (bilobar disease) treatments followed by weekly Tebe. Eighteen patients, 52 patients, and 39 patients will be enrolled in Part 1A, Part 1B, and Part 2, respectively (total 109 patients). Primary endpoints for Part 1A is safety lead-in and 6-month progression-free survival (PFS), 6-month PFS for Part 1B, and 6-month PFS for Part 2. Secondary endpoints include overall response rate, liver-specific PFS, OS, and toxicity. Enrollment for Part 1A began in October 2025 at Thomas Jefferson University Hospital. Clinical trial information: NCT06626516 .

STELLA: A dose expansion of the ATR kinase inhibitor alnodesertib (ART0380) administered orally in combination with low-dose irinotecan to patients with advanced or metastatic CRC and PDAC.

TPS3184 Background: Replication stress (RS) creates cancer cell vulnerability to which the critical DNA damage response kinase, ATR (Ataxia-Telangiectasia and Rad3-related) responds. ATR senses the stress, halts the cell cycle, and promotes DNA repair to allow proliferation. Alnodesertib is an ATR inhibitor developed to prevent cancer cells from successfully repairing RS and proliferating further. In earlier stages of alnodesertib development, preclinical and translational research demonstrated that tumor cells experience three combined biological insults: irinotecan-induced RS, endogenous RS via ataxia-telangiectasia mutated (ATM) loss, and RS rescue prevention by ATR inhibition. Data from the dose escalation and initial dose expansion cohorts of this trial in a tumor agnostic population showed encouraging results in ATM-negative cancers (confirmed Overall Response Rate of 50% in 20 patients with ATM negative cancers and responses across 8 cancer types including complete responses, Ulahannan et al, AACR 2025). Tumor-specific dose expansion cohorts are now enrolling, including colorectal cancer (CRC) and pancreas ductal adenocarcinoma (PDAC). Methods: Two tumor-specific cohorts are now open, each enrolling approximately 50 patients (pts): ATM-negative CRC and ATM-negative PDAC. Pts will receive the recommended dose of alnodesertib 200mg orally on days 1-3 and 8-10 combined with low-dose irinotecan 60mg/m 2 IV on days 1 and 8, of each 21-day cycle. Tumor tissue is prescreened by immunohistochemistry for ATM protein loss (H score 0) for enrollment eligibility. Pts with CRC must have received a maximum of 2 prior chemotherapies excluding prior trifluridine/tipiracil, fruquintinib, or regorafenib, and pts with PDAC must have received a maximum of 1 prior chemotherapy for advanced disease. Prior targeted agents are allowed and do not count as prior lines of therapy. Key objectives include safety, tolerability, and preliminary efficacy. Clinical trial information: NCT04657068 .

Tissue-specific programming of CD8 effector T cells in immune checkpoint inhibitor-associated vitiligo and anti-tumor immunity in melanoma.

e21503 Background: Immune checkpoint inhibitor (ICI) therapy targeting PD-1 and CTLA-4 (e.g., ipilimumab-nivolumab) has revolutionized treatment of advanced melanoma. While there are few reliable predictors of response, ICI-associated vitiligo is a common immune-related adverse event in melanoma and is associated with favorable clinical outcomes. Understanding the immunological correlates of ICI-associated vitiligo may therefore provide crucial insights into the mechanisms underlying durable response to melanoma immunotherapy. Methods: We performed single-cell multiomic profiling (gene expression, CITE-seq, T cell receptor [TCR] sequencing) of matched primary tumor, lymph node metastasis, and vitiligo skin from a metastatic melanoma patient who both achieved durable response to ipilimumab-nivolumab and developed vitiligo. To contextualize these findings, we integrated ~57,000 T cells from publicly available single-cell datasets encompassing ICI-treated melanoma, autoimmune vitiligo, and healthy skin. Results: Across tissues and datasets, we identified six CD4⁺ and eight CD8⁺ T cell states conserved across conditions, though exhibiting tissue-specific abundance shifts. CD8⁺ T cell populations revealed the most pronounced differences, most notably demonstrating enrichment within vitiligo skin of a distinct MHC II-expressing CD8⁺ effector population with high expression of GZMA , GZMK , and GZMH , along with activation-associated programs suggesting recent TCR engagement and a non-terminal inflammatory effector state. Additional cytotoxic CD8⁺ subsets with checkpoint-associated and tissue-resident memory-like features were seen across tumor and skin, whereas CD4⁺ T cell states demonstrated more modest tissue-specific variation. In contrast, transcriptionally related CD8⁺ T cells within tumor exhibited characteristics suggesting functional limitation within the suppressive tumor microenvironment. Through leveraging paired single-cell TCR sequencing from the same patient, ongoing analyses are evaluating the clonal relationships between vitiligo- and tumor-infiltrating T cells to determine whether shared TCRs adopt divergent transcriptional programs across tissues. Conclusions: Our data support a framework whereby ICI-associated vitiligo reflects tissue-specific effector-state programming of melanoma-reactive CD8⁺ T cells, providing mechanistic insight into the link between treatment-induced autoimmunity and effective anti-tumor immunity.

Impact assessment of implementing evidence-based de-escalation strategies in early breast cancer management in South Africa.

e12744 Background: In South Africa, where oncology resources are limited, adopting evidence-based radiation and chemotherapy de-escalation strategies may reduce patient toxicity and enhance resource efficiency. The applicability and impact of these strategies, validated in high-income countries as non-inferior in low-risk breast cancer patients, remain unknown in South Africa. Methods: We conducted a retrospective analysis of the South Africa Breast Cancer &amp; HIV Outcomes (SABCHO) cohort drawn from five public hospitals in Gauteng and KwaZulu-Natal provinces. Patients were aged ≥18 years with stage I–III breast cancer diagnosed and treated between 2015 and 2019. Radiation de-escalation eligibility was based on CALGB 9343 and PRIME II trials, adjusted for the life expectancy in South Africa. Chemotherapy de-escalation eligibility was based on TAILORx and RXPONDER trials utilizing calculated Magee recurrence scores (MRS) in lieu of Oncotype (eligible if MRS &lt; 18 or &lt; 25 with mitosis score = 1). We assessed the prevalence of de-escalation eligibility, treatment receipt patterns, and compared overall survival (OS) by treatment receipt using Cox proportional hazard models and Kaplan-Meier curves. Results: Among 2,369 patients, 210 (8.6%) were eligible for radiation de-escalation and 440 (18.6%) for chemotherapy de-escalation. Of these, 26.3% received adjuvant radiation and 45.2% received chemotherapy. OS stratified by receipt of treatment did not differ significantly in either group. 5-year median OS was 94.5 months and 93.3 months in patients who received radiation and those who did not, respectively (HR 1.42, 95% CI 0.82-2.43). Median OS was 96.8 months and 98.4 months in patients who received and did not receive chemotherapy, respectively (HR 0.93, 95% CI 0.60-1.42). Conclusions: Many patients receiving adjuvant radiation and chemotherapy in this South African cohort may have been appropriate for treatment de-escalation, highlighting an opportunity to mitigate toxicity and reallocate scarce resources without reducing survival. Prospective research into the clinical impact of de-escalation strategies in South Africa is warranted. Sociodemographic and clinical characteristics of early breast cancer patients in SABCHO cohort. Characteristic Overall (N = 2369) Age, years (median [IQR]) 54.0 [44.0 – 65.0] Race Asian/Indian 190 (8.0%) Black 1915 (80.8%) Mixed 107 (4.5%) White 159 (6.7%) HIV status Positive 470 (19.8%) Overall Stage Stage I 445 (18.8%) Stage II 1225 (51.7%) Stage III 699 (29.5%) Tumor stage T0 170 (7.2%) T1 502 (21.2%) T2 933 (39.4%) T3 312 (13.2%) T4 91 (3.8%) Other/Unknown 361 (15.2%) Nodal stage N0 914 (38.6%) N1 808 (34.1%) N2 212 (8.9%) Tumor size, mm 30.0 [21.7 – 45.0] Hormone receptor (HR) Positive 1749 (73.8%) Negative 620 (26.2%) HER2 status Negative 1627 (68.7%) Positive 611 (25.8%) Unknown 131 (5.5%) Histology IDC 2061 (87.0%) ILC 92 (3.9%) Other 213 (9.0%)

Trends in liver metastases at diagnosis among young adults with colorectal cancer: A SEER-based analysis, 2010–2022.

e15543 Background: Early-onset colorectal cancer (CRC) is increasing in incidence among young adults, yet contemporary trends in metastatic presentation remain incompletely defined. We evaluated temporal changes in liver metastases at diagnosis among young adults with CRC in the United States. Methods: Using the SEER database, we identified patients aged 25–49 years diagnosed with CRC from 2010–2022. The primary outcome was presence of liver metastases at diagnosis. Multivariable logistic regression assessed the association between year of diagnosis and liver metastases, adjusting for age group, sex, and race/ethnicity. Year was analyzed as a continuous variable and by period (2010–2012, 2013–2016, 2016–2019, 2019–2022). Effect modification by sex and race/ethnicity was assessed using interaction terms. Results: Among 48,210 patients with newly diagnosed CRC identified, 8,778 (18.2%) had liver metastases at diagnosis while 39,432 (81.8%) did not. In adjusted analyses, more recent year of diagnosis was associated with lower odds of liver metastases (adjusted odds ratio [aOR] per year, 0.99; 95% CI, 0.98–0.99; p &lt; 0.001). When year of diagnosis was grouped into four time periods (2010–2012, 2013–2016, 2016–2019, and 2019–2022), there were no meaningful differences in the odds of liver metastases at diagnosis for patients diagnosed between 2013–2016 or 2016–2019 compared with 2010–2012. In contrast, patients diagnosed in 2019–2022 had significantly lower odds of liver metastases at diagnosis (aOR 0.87; p &lt; 0.001), indicating that the decline was concentrated in the most recent era. Temporal trends did not differ by sex (interaction p = 0.39) and were consistent across racial and ethnic groups. Conclusions: The prevalence of liver metastases at diagnosis among young adults with CRC has modestly but significantly declined over the past decade, driven primarily by improvements since 2019. These findings suggest potential stage migration related to earlier detection or evolving diagnostic practices in early-onset CRC and have important implications for screening strategies and outcomes in this growing population. Annual proportion of young adults (aged 25–49 years) presenting with liver metastases at the time of colorectal cancer diagnosis in SEER, 2010–2022. Year N total N with liver mets at diagnosis (%) with liver mets at diagnosis 2010 3085 565 18.3 2011 3139 613 19.5 2012 3126 579 18.5 2013 3099 628 20.3 2014 3392 620 18.3 2015 3597 654 18.2 2016 3673 692 18.8 2017 3864 724 18.7 2018 3805 703 18.5 2019 4065 756 18.6 2020 3986 730 18.3 2021 4482 762 17.0 2022 4897 752 15.4

CAPELA: A phase II multicenter open-label randomized study of capecitabine in combination with elacestrant versus capecitabine alone in advanced estrogen receptor (ER)–positive breast cancer (TBCRC 070).

TPS1156 Background: Endocrine therapy (ET) in combination with targeted treatments can effectively treat metastatic ER-positive (ER+) breast cancer (BC); however, nearly all patients ultimately progress on these therapies, eventually requiring treatment with chemotherapy. Current standard of care, based on older data, is to discontinue ET when starting chemotherapy. Many of these studies used tamoxifen, which has partial agonist activity, in combination with chemotherapy. Newer estrogen-targeting agents, e.g. oral selective ER degraders (SERDs), function as ER antagonists. Preclinical work investigating the combination of SERD and chemotherapy has demonstrated an additive effect of the agents in ER wildtype tumors and a synergistic effect in tumors with ESR1 mutation ( ESR1m ); this synergy was attenuated with P53 silencing. Methods: CAPELA, an investigator-initiated, multicenter, open-label randomized phase II study, is designed to assess the safety and efficacy of capecitabine monotherapy vs. capecitabine + elacestrant in patients with advanced/unresectable ER+ HER2- BC. Eligible patients will have progressed on a CDK4/6 inhibitor and had no prior treatment with chemotherapy for metastatic disease. At least 50% of enrolled patients are required to have ESR1m tumors. Patients will be randomized 1:1 to receive capecitabine 1000mg/m 2 PO BID days 1-14 of a 21-day cycle +/- the oral SERD elacestrant 345 mg PO daily. Randomization will be stratified by prior lines of ET in the metastatic setting (1 vs. &gt;1), visceral disease (yes/no), TP53 mutation status, and ESR1m status. Patients with tumors with an ESR1m who are randomized to the monotherapy arm will have the option to crossover to elacestrant monotherapy at the time of progression to evaluate benefit of concurrent vs. sequential use of these agents. The primary endpoint is hierarchical assessment of median progression free survival (mPFS) in 1) the ESR1m population and if positive 2) the intention to treat (ITT) population. Secondary endpoints include safety/tolerability, median overall survival (OS), objective response rate, median time to second progression, clinical benefit rate, and patient reported outcomes in the ESR1m and ITT populations. PFS and OS in the ESR1m not detected population will also be evaluated. Exploratory correlative studies on collected plasma, serum, and archival tissue will also be conducted. The study will enroll 297 patients over an estimated 3 years. The trial will open at 10 sites through the Translational Breast Cancer Research Consortium (TBCRC). Clinical trial information: NCT07222215 .