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Adjuvant trastuzumab with or without pertuzumab after pathologic complete response to neoadjuvant HER2-targeted therapy and chemotherapy in HER2-positive breast cancer: A retrospective cohort study.

e12503 Background: Neoadjuvant dual HER2 blockade with trastuzumab (T) and pertuzumab (P) has been shown to improve rates of pathologic complete response (pCR). While current guidelines support one year of adjuvant trastuzumab, the incremental benefit of continuing dual HER2 blockade (T+P) in patients who achieve pCR remains uncertain. Given concerns regarding potential overtreatment, added toxicity, and cost, our study compared the survival outcomes in patients with pCR treated with adjuvant T+P versus T alone. Methods: We performed a single-center retrospective cohort study of patients with HER2-positive invasive breast cancer who achieved pCR after neoadjuvant dual anti-HER2 therapy and chemotherapy followed by definitive surgery and subsequently received adjuvant anti-HER2 therapy for a total of one year. Patients received adjuvant T alone or T+P, per treating physician preference. Outcomes included recurrence-free survival (RFS) and distant recurrence-free survival (DRFS), defined from date of surgery to recurrence or death; patients without events were censored at last follow-up. Associations with baseline functional status and comorbidity burden (ECOG performance status [PS], Charlson comorbidity index [CCI]) were evaluated using univariate Cox proportional hazards modeling. Results: A total of 128 patients who achieved pCR after neoadjuvant treatment were included; 109 received adjuvant T and 19 received T+P. Median age at diagnosis was 53.5 years. The groups did not differ significantly by race, sex, or baseline performance status (mean CCI of 1.57 vs 1.32). Patients receiving T+P had a higher prevalence of cN1 involvement at diagnosis. At a median follow-up of 9.28 years, 5-year RFS was 94% (95% CI, 89–98) with T and 95% (95% CI, 85–100) with T+P; 5-year DRFS was similarly high in both groups. On univariate analysis, CCI >2 was associated with worse RFS (HR 3.44, 95% CI, 1.15-10.2). Five-year overall survival was high across cohorts, with no statistically significant difference by adjuvant regimen (96% vs 100% for T and T+P), including among patients with higher comorbidity burden. Using Lexidrug-based pricing estimates, addition of pertuzumab increased estimated drug cost by ~$590 per cycle (~$6,500 over 11 cycles) compared with trastuzumab alone. Conclusions: Among patients with HER2-positive breast cancer achieving pCR following neoadjuvant dual HER2-targeted therapy and chemotherapy, long-term recurrence outcomes were excellent and were comparable between adjuvant trastuzumab alone versus continued dual HER2 blockade. These findings suggest the absolute benefit of adjuvant pertuzumab may be limited in this population who achieved a pCR and support further prospective evaluation of risk-adapted de-escalation strategies to minimize overtreatment and cost.

An exploratory, single-center, single-arm trial of R-ISV-FOLactis in situ vaccination for advanced soft tissue sarcoma.

2592 Background: Advanced soft tissue sarcomas (STSs) have limited treatment options and exhibit low responsiveness to immunotherapy, largely due to an immunosuppressive tumor microenvironment (TME). In situ vaccination (ISV) represents a promising strategy to convert immunologically “cold” tumors into “hot” ones. FOLactis, a food-grade probiotic Lactococcus lactis engineered to express a fusion protein of Fms-like tyrosine kinase 3 ligand (Flt3L) and OX40 ligand (OX40L), has shown antitumor immune activity in preclinical models. This study investigates the synergistic antitumor effect and safety of intratumoral FOLactis in combination with hypofractionated radiotherapy and anti-PD-1 therapy in clinical settings. Methods: In this investigator-initiated, single-arm trial, patients with advanced STS who had failed standard therapies received intratumoral injections of FOLactis combined with hypofractionated radiotherapy and PD-1 blockade. Primary endpoints included safety and efficacy, secondary endpoints encompassed abscopal responses and mechanistic exploration of treatment efficacy. Results: Between July 2022 to July 2025, 16 advanced STS patients were enrolled. The R-ISV-FOLactis regimen was well-tolerated, with grade 3 adverse events occurring in 37.5% of patients. Injected lesions showed a best objective response rate (ORR) of 56.25% and a disease control rate (DCR) of 100%. Median progression-free survival (mPFS) for all lesions was 6.3 months, while mPFS for injected lesions was not reached. Abscopal responses were observed in 56.25% of patients. Immunological analyses revealed increased frequencies of peripheral memory CD8⁺ T cells, PD-1⁺ CD8⁺ T cells, and dendritic cells (DCs), alongside decreased regulatory T cells (Tregs) and tissue-resident CD103⁺CD4⁺ T cells in responders, indicating systemic immune activation. Furthermore, reshaped TME with reduced fibroblasts and increased immune cell infiltration were associated with enhanced antitumor immunity. Moreover, significant increase of CD8⁺ T cell density in regions distal to neutrophil clusters, along with elevated 4−Cresol Sulfate levels suggesting neutrophil modulation. Conclusions: R-ISV-FOLactis exhibited a favorable safety profile and encouraging efficacy against both local and distant tumors. The treatment induced systemic immune activation and metabolic remodeling, supporting its further development as a novel ISV strategy for advanced STSs. Clinical trial information: ChiCTR2200060660.

Validation of a treatment-based algorithm to infer biomarker status in real-world data.

e23019 Background: Real-world (RW) precision oncology studies require accurate identification of actionable biomarkers, yet structured electronic health record (EHR) biomarker fields are often inconsistently captured. Treatment exposure can serve as a proxy for biomarker positivity when restricted to biomarker-defined therapies, but the validity of this approach in RW data is not well characterized. NTRK gene fusions and BRAF V600E mutations are clinically actionable biomarkers with tissue-agnostic targeted therapy approvals, offering complementary contexts to assess treatment-based inference. This study developed and validated treatment-based inference algorithms for NTRK fusion–positive and BRAF V600E–mutated metastatic solid tumor patients (pts) and assessed the incremental contribution of treatment-based inference (ICTBI) beyond structured biomarker fields in community oncology. Methods: Using structured RW data from the US Oncology Network iKnowMed EHR database, analyses were conducted separately for NTRK fusion and BRAF V600E using algorithm-specific validation cohorts (VCs; pts with interpretable structured biomarker results) and application cohorts (ACs; pts receiving biomarker-restricted targeted therapies). The study period spanned biomarker-specific FDA approval dates through 12/31/2025. Qualifying therapies included larotrectinib or entrectinib for NTRK fusion and dabrafenib + trametinib for BRAF V600E. Within VCs, algorithm-inferred biomarker status was assigned based solely on qualifying therapy exposure, with structured biomarker fields masked. Inferred status was compared with documented biomarker results to estimate positive predictive value (PPV), sensitivity, and specificity. Within ACs, ICTBI was calculated as the proportion of biomarker-positive pts identified exclusively through treatment exposure. Results: In the NTRK fusion VC (n = 34,765), treatment-based inference demonstrated high specificity (99.98%) and PPV (84.31%) with low sensitivity (7.68%), consistent with biomarker rarity and limited treatment exposure. In the NTRK AC (n = 90), 52% of biomarker-positive pts were identified exclusively through treatment-based inference, indicating substantial ICTBI. In the BRAF V600E VC (n = 6,021), treatment-based inference showed very high PPV (98.99%) and specificity (99.92%) with moderate sensitivity (39.42%), reflecting broader targeted therapy uptake. In the BRAF V600E AC (n = 643), 44% of biomarker-positive pts were identified exclusively via treatment-based inference. Conclusions: Treatment-based inference demonstrated high validity and meaningfully improved identification of biomarker-positive pts. Incorporating this approach has the potential to enhance RW cohort completeness, improve the feasibility of biomarker-driven studies, and support more robust evaluation of precision oncology therapies in community practice.

Pilot study of HB-200 in patients with HPV16+ head and neck squamous cell carcinoma and detectable TTMV-HPVDNA after definitive therapy.

e18038 Background: Approximately 10-15% of patients with HPV16+ HNSCC develop recurrent, incurable disease after definitive therapy. NavDx is a tumor tissue-modified viral (TTMV) HPV DNA assay that can detect minimal residual disease (MRD) in peripheral blood prior to clinical or radiographic recurrence, with a positive predictive value of approximately 95%. MRD represents a novel clinical setting in patients with HPV16+ HNSCC and allows identification of a high-risk subset of patients for early intervention. HB-200 is an arenavirus-based therapeutic vaccine, consisting of alternating HB-202 and HB-201, designed to elicit a T-cell response against the HPV16 E6 and E7 oncoproteins. We conducted a pilot study to evaluate the feasibility of treating patients with MRD-positive HPV16+ HNSCC using HB-200. Methods: Patients with histologically proven HPV16+ HNSCC who completed definitive therapy without evidence of clinical or radiographic disease, but with detectable NavDx, were enrolled. Patients received 2 cycles of HB-200 (42-day Cycle: HB-202 1x10^7 RCV FFU on D1, HB-201 5x10^6 RCV FFU on D22). Peripheral blood for NavDx and E6/E7 ELISPOT was collected at pre-, on-, and post-treatment time points. Imaging was performed pre-treatment and after two cycles of HB-200. The primary endpoint was feasibility, as defined by identification and enrollment of patients with HNSCC HPV16+ MRD and completion of HB-200 treatment. Secondary endpoints included safety, NavDx kinetics, and disease-free survival (DFS). Results: Five patients were enrolled. See Table 1 for clinical annotation and NavDx time points. Patient #2 discontinued early due to pathologic confirmation of recurrent disease after 1 cycle. Patients #1 and #5 remain disease free (NED) by imaging and exam after treatment. Patient #1 remained NavDx-negative and NED for >12 months. Median DFS for the cohort was 110 days (23-455). All patients had detectable increases in E6/E7-specific antigen T-cells by ELISPOT; 4/5 patients had a >8-fold increase in E6 and 3/5 patients had a >8-fold increase in E7 antigen specific T-cells after one cycle of HB-200. These levels declined but persisted at 2-3 fold above baseline after treatment completion. All patients completed therapy with no grade > 3 adverse events. Conclusions: HB-200 therapy can clear TTMV-HPV DNA detected by NavDx in a subset of patients with HPV16+ HNSCC MRD and induces E6/E7 antigen specific T-cells. Treatment of MRD is feasible and further study is warranted to establish the therapeutic standard. Clinical trial information: NCT06373380 . Patient #1 Patient #2 Patient #3 Patient #4 Patient #5 Age/Sex 68 y/o M 67 y/o M 59 y/o M 60 y/o M 67 y/o M Baseline NavDx 70 4 35 4 4 On Treatment NavDx 5 NA 35 Negative Indeterminate End of Treatment NavDx Negative NA 185 6 4 Current Status NED NED after 3 cycles of anti-PD1 monotherapy Active disease receiving chemotherapy + anti-PD1 Active disease receiving chemo-radiation NED

Phase 3 randomized trial to evaluate the impact of anselamimab on all-cause mortality in κ light-chain amyloidosis.

7501 Background: AL amyloidosis is a plasma cell dyscrasia (PCD) characterized by κ or λ Ig light chain amyloid fibrils that deposit in vital organs. Anselamimab is an investigational mAb designed to complement anti-PCD therapy through accelerated removal of amyloid fibrils. Cardiac Amyloid Reaching for Extended Survival (CARES) studies (NCT04512235 and NCT04504825) investigated the efficacy and safety of anselamimab compared with placebo, in addition to anti-PCD therapy. Methods: Alongside anti-PCD therapy with CyBorD (daratumumab was permitted) newly diagnosed patients with European modification of Mayo stage IIIa or IIIb AL amyloidosis were randomized 2:1 to receive anselamimab (1000 mg/m 2 ) or placebo (normal saline) IV every 7 days for 4 weeks followed by every 14 days for the remainder of the blinded study (18 months after the last participant enrolled). The primary endpoint was a hierarchical combination of time to all-cause mortality (ACM) and frequency of adjudicated cardiovascular hospitalizations (CVH) using the Finkelstein-Schoenfeld test and win-ratio in the combined study population. Subgroup analysis by involved κ or λ free light chain (iFLC) was prespecified. Results: 271 patients were randomized to receive anselamimab and 135 placebo. Baseline characteristics were similar between treatment arms. The median duration of treatment was 21.4 months and 21.1 in the anselamimab and placebo arms, respectively. Daratumumab was used in 79.3% and 83.7% of the anselamimab and placebo arms, respectively. Results of the primary efficacy analyses are shown in the table. Anselamimab-treated patients with κ iFLC had a 62% reduction in ACM (HR = 0.38; 95% CI, 0.17, 0.86; nominal P = 0.012) and a 71% reduction in risk for CVH (estimated CVH rate ratio = 0.29; 95% CI, 0.10, 0.87; nominal P = 0.028). Patients with λ iFLC had a 10% reduction in risk for CVH; none in ACM. Safety data were comparable between both treatment arms. In anselamimab-treated patients, safety findings were similar between κ subgroup and full population. Conclusions: Anselamimab, a κ light chain–directed anti-fibril monoclonal antibody used alongside standard of care chemotherapy, offers a first-in-class, new therapeutic option for patients with newly diagnosed κ AL amyloidosis. Clinical trial information: NCT04512235 and NCT04504825 . Summary of primary efficacy endpoints. Endpoint Overall κ Isotype λ Isotype Anselamimab (N=271) Placebo (N=135) P -value Anselamimab (N=48) Placebo (N=24) P -value Anselamimab (N=219) Placebo (N=109) P -value ACM and CVH win ratio (95% CI) 1.1 (0.8, 1.5) 0.332 2.06 (0.98, 4.31) 0.100 0.9 (0.6, 1.3) 0.848 ACM n (%) 90 (33.2) 52 (38.5) 15 (31.3) 14 (58.3) 73 (33.3) 37 (33.9) HR (95% CI) 0.8 (0.6, 1.1) 0.290 0.38 (0.2, 0.9) 0.012 1.0 (0.7, 1.5) 0.647 CVH Frequency/year (95% CI) 0.6 (0.4, 0.8) 0.9 (0.6, 1.4) 0.145 0.41 (0.2, 0.8) 1.4 (0.6, 3.4) 0.028 0.7 (0.4, 1.0) 0.8 (0.4, 1.3) 0.664 Incidence risk ratio (95% CI) 0.7 (0.4, 1.2) 0.29 (0.1, 0.9) 0.9 (0.5, 1.7)

In vivo CAR T-cell engineering in B-cell malignancies: A systematic review of emerging clinical and translational evidence.

e14512 Background: Autologous ex vivo CAR T-cell therapies have transformed outcomes in relapsed/refractory (R/R) B-cell malignancies, producing durable remissions in diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBCL), and multiple myeloma (MM), but remain limited by leukapheresis needs, protracted manufacturing times, lymphodepleting chemotherapy, and high cost. In vivo CAR T can overcome these barriers by delivering CAR-encoding payloads directly to endogenous T cells via lipid nanoparticles (LNPs), lentiviral vectors, or fusogenic viral particles, enabling CAR T-cell generation inside the patient. Methods: We performed a literature search of peer-reviewed publications, conference proceedings (ASH, ASCO, EHA), and registered clinical trials (2018–2025) evaluating in vivo CAR T. Identified platforms included KLN-1010 (in vivo anti-BCMA CAR), INT2104 (CD20 CAR), Umoja CD22 CAR, Capstan CD8-targeted LNP CD19 CAR, and Orna circular RNA CD19 CAR systems. Endpoints included CAR expression, B-cell aplasia, MRD negativity, objective response rate (ORR), CRS, ICANS, and CAR persistence. Results: First-in-human in vivo CAR T trial (KLN-1010) enrolled heavily pretreated R/R MM patients and administered a single IV dose of a lentiviral anti-BCMA CAR vector without lymphodepletion. All treated patients achieved MRD negativity at 1 month, including one complete response and three partial responses, with in vivo CAR T expansion and persistence comparable to ex vivo BCMA CAR T therapies. Grade ≥3 CRS occurred in 50% of patients, with no ICANS. Early-phase clinical programs for CD20- and CD22-directed in vivo CAR T therapies have initiated enrollment in aggressive B-cell lymphomas after CD19 CAR T failure. Preliminary data demonstrate successful in vivo CAR transduction, circulating CAR T expansion, and rapid B-cell aplasia. CD8-targeted LNP delivery of CD19 CAR mRNA induced efficient in vivo T-cell engineering with complete B-cell depletion and eradication of human DLBCL xenografts. In non-human primates, targeted LNP systems produced deep, rapid, and sustained B-cell depletion without uncontrolled immune activation. Circular RNA-based CAR platforms achieved durable CD19 CAR expression, B-cell depletion, and lymphoma regression. Conclusions: In vivo CAR T engineering has now demonstrated clinical proof-of-concept with deep molecular responses, robust in vivo CAR expansion, and manageable toxicity. Translational and preclinical CD19-, CD20-, and CD22-directed platforms show potent activity in aggressive lymphoma models, supporting direct applicability to DLBCL and HGBCL. Compared with ex vivo CAR T, in vivo systems offer elimination of leukapheresis, no manufacturing delays, outpatient feasibility, repeat dosing, and substantially reduced cost, potentially enabling earlier-line and broader access to CAR-T–level therapy.

NALIRIFOX in combination with adebrelimab for advanced biliary tract cancer: A phase 2 NIOFA-01 clinical trial.

4120 Background: The NIOFA-01 trial was designed to evaluate the efficacy and safety of liposomal irinotecan combined with oxaliplatin, fluorouracil, and leucovorin (NALIRIFOX) plus adebrelimab as first-line treatment for patients with advanced biliary tract cancer (BTC) (ChiCTR2400089696). Methods: This single-arm, phase II study enrolled 27 patients with previously untreated, unresectable or metastatic BTC. Patients received NALIRIFOX (liposomal irinotecan 50 mg/m², oxaliplatin 60 mg/m², leucovorin 400 mg/m², and fluorouracil 2400 mg/m² administered as a continuous intravenous infusion over 46 hours), in combination with the PD-L1 inhibitor adebrelimab (1200 mg administered intravenously), every 2 weeks for up to 12 cycles. This was followed by adebrelimab maintenance therapy until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Additionally, patients were evaluated for tumor gene alterations and PD-L1 expression, and underwent plasma proteomic and serum cytokine profiling. Results: Between September 13, 2024 and January 12, 2026, 27 patients were enrolled, with a median follow-up of 13.8 months (range, 2.8-16.2). Among these patients, the ORR was 55.6% (95%CI, 35.3%-74.5%) and the DCR was 81.5% (95%CI, 61.9%-93.7%). Median PFS was 8.0 months (95% CI, 5.8-9.7), while median OS was not reached (6 months OS rate: 92.6%, 12 months OS rate: 77.8%). Treatment-related adverse events (TRAEs) occurred in 100% of patients, with grade ≥3 TRAEs observed in 55.6%. The most common TRAEs were neutropenia, leukopenia, anemia, and diarrhea. Immune-related adverse events were reported in 74.1% of patients, including hepatotoxicity, hypothyroidism, and cardiac events. Exploratory analyses suggested the ORR was observed to be higher in patients with a CPS score ≥5 compared to those with a score <5 (p = 0.043). Combined analysis of plasma proteomics and metabolomics revealed that in patients who did not respond to treatment, ATP5PD, CTNND2, GALK1, 6nPropyluracil, and 1(Methylsulfinyl) propyl propyl disulfide were significantly elevated, while MMP2 was significantly decreased. A machine learning-based efficacy prediction model was constructed, and ROC curves were generated using the aforementioned four proteins and two metabolites, respectively, with AUC values of 0.961 and 0.883. Additionally, we observed that serum IL2 was significantly elevated in patients who responded to treatment, while IL8 showed a dynamic decreasing trend during the treatment process. Conclusions: NALIRIFOX in combination with adebrelimab demonstrated promising antitumor activity and an acceptable safety profile as first-line treatment for patients with advanced BTC, warranting further validation. Clinical trial information: ChiCTR2400089696.

Balancing effectiveness and toxicity: Cabozantinib versus belzutifan after ICI/VEGF therapy in older adults with renal cell carcinoma.

e16533 Background: First line therapy for favorable and intermediate/poor risk mRCC is Pembrolizumab and Axitinib. Multiple post–pembrolizumab/axitinib options exist, with sequencing still under study. While cabozantinib, everolimus, and lenvatinib have been available for several years, belzutifan is a newer agent. Cabozantinib and lenvatinib are typically used earlier than everolimus; however, the optimal timing of belzutifan remains unclear. Belzutifan’s approval was based on LITESPARK-005, which demonstrated improved progression free survivial in addition to improved overall response rate, when compared to everolimus. The benefit of sequencing belzutifan before cabozantinib remains to be determined. No head-to-head trials guide this decision, and cabozantinib’s toxicity may limit use in older adults, whereas belzutifan’s HIF-2α inhibition may overcome VEGF-TKI resistance. This study compares the real-world effectiveness and safety of these agents in an elderly population. Methods: Using TriNetX database, we conducted a retrospective cohort study of RCC patients aged ≥60 years treated initially with pembrolizumab/axitinib and subsequently with either cabozantinib or belzutifan ≥1 month later. Patients with von Hippel-Lindau syndrome were excluded. 1:1 propensity score matching (PSM) was performed using demographics, comorbidities (COPD, IHD, CVD, HTN, CKD, DM, O₂ dependence), disease factors (bone, liver, brain metastases; partial nephrectomy), baseline CBC, and confounders like non-infective colitis. Outcomes included 3-year overall survival (OS), 3-yr venous thromboembolism (VTE), 90-day hospitalization, 90-day acute renal failure (ARF), and 180-day gastrointestinal (GI) toxicity. Results: Post PSM (n = 95/arm), both cohorts had similar 3-year survival probability (41.7% vs 36.7%) with median OS longer with cabozantinib (25 vs 17 months), though this difference was not statistically significant (HR 0.728, long rank p = 0.175). 3-year VTE risk [24.2% vs 18.9%, RR 1.28 (0.74–2.21) p = 0.38], and 90-day ARF risk [16.8% vs 14.7%, RR 1.143 (0.59–2.21) p = 0.69] were comparable between groups. Notably, Cabozantinib was associated with significantly fewer 90-day hospitalizations [25.3% vs 43.2%, RR 0.58 (0.39–0.89) p = 0.01] but a higher incidence of GI toxicity at 180 days [26.3% vs 13.7% RR 1.923 (1.048–3.528) p = 0.0295] as compared to belzutifan. Conclusions: In elderly RCC patients, previously treated with ICI/VEGF therapy, Cabozantinib and Belzutifan were associated with similar overall survival and rates of serious adverse outcomes. Cabozantinib was linked to fewer early hospitalizations, but a higher incidence of gastrointestinal toxicity. This reflects efficacy-tolerability trade-offs to individualize care in older adults. Further studies combining Belzutifan with other TKI’s have been in progress and show promising results.

Benefit of adjuvant therapy in high-risk GIST: A large-scale real-world analysis of 2,166 patients (DEEPSARC study).

11533 Background: Real-life data on the impact of adjuvant treatment in GIST pts are limited. Methods: We conducted a retrospective study (Deepsarc) merging data from the NETSARC+ dataset of the French Sarcoma Group with the exhaustive health data from the national social security system (SNDS). Eligible pts were treated between January 1, 2012, and December 31, 2017 with localized GIST. The relation between overall survival (OS) and adjuvant therapy was studied univariate and multivariate, using different methods to address confounding factors. Results: A total of 2166 GIST pts were included, with a median age of 68.0 years (interquartile range (IQR): 58.0, 76.0), a sex ratio of 1.01. The two most common primary sites were gastric (1301, 60%) and small intestine (527, 24%). Median tumor size at diagnosis was 5.3 cm (IQR 3.6-8.1). Median mitotic count was 3.0 (IQR 1.0-5.0). According to Miettinen/AFIP classification, 331/1026 (32%) were high-risk, 192/1026 (19%) intermediate risk, and 503/1026 (49%) very low or low risk vs 490/912 (53%) high-risk, 193/912 (21%) intermediate risk, and 229/912 (25%) very low or low risk with Joensuu classification. From 2012 to 2017, the proportion of pts receiving adjuvant therapy remained remarkably stable at around one third of all GIST, with higher use in high-risk (70%; 231/331) than intermediate-risk (43%; 83/192) and low-risk pts (6%; 32/503). Pts receiving adjuvant therapy were younger (p<.001), with less comorbidities (p<.001), larger tumor (p<.001), higher mitotic count (p<.001), higher risk according to Miettinen/AFIP (p<0.001), or Joensuu (p<.001), higher rate of R1 resection (p=.019) and higher rate of tumor rupture (p=.001). Median follow-up was 5.0 years (4.8-5.2). Overall, the 5y OS rate was 81% [79-83%]. Regardless of risk, for the entire population, 5y OS rate of those receiving adjuvant therapy was 82% [79%-85%] and for those not receiving adjuvant therapy was 81% [78%-83%]. For both prognostic classifications, in univariate analysis, adjuvant therapy was associated with improved survival only for high-risk pts. Multivariate analysis propensity-score adjusted analyses for age, sex, social deprivation index, morbidity index, and tumor size (3 categories: ≤5/ 5-10/ >10 cm) highlights a benefit of adjuvant therapy for high-risk pts, according to both AFIP/Miettinen or Joensuu classifications (Table). No clear benefit was observed in intermediate-risk pts. Conclusion: This study confirms the benefit of adjuvant therapy for high-risk pts (according to AFIP/Miettinen or Joensuu), but not for other risk groups. Overall survival (risk of death) in high-risk GIST patients according to adjuvant therapy (reference = No adjuvant treatment), Deepsarc study (2012-2017), France. Risk classification N 1y HR* 95% CI** P -value Miettinen/AFIP 214 0.23 0.06 ; 0.92 0.017 Joensuu 312 0.49 0.24 ; 0.98 0.029 *HR = Hazard Ratio, **CI = Confidence Interval.

Impact of artificial intelligence assistance on combined PD-L1 scoring on whole immunohistochemical slide image of tumors.

e16006 Background: Immune checkpoint blockade targeting PD-L1 has transformed cancer treatment, making accurate evaluation of PD-L1 expression critical for immunotherapy eligibility. In practice, PD-L1 assessment, particularly using the Combined Positive Score (CPS) is challenged by interpretative variability among pathologists. Artificial intelligence (AI) based approaches may help address these limitations by enabling more consistent and exhaustive PD-L1 quantification instead of visual estimation by pathologists. Here, we assess the impact of the DiaKwant PD-L1 CPS, an AI solution, on the scoring of pathologists, evaluated against an expert-consensus reference across multiple tumor types. Methods: A total of 149 immunostained-tissue samples from gastrointestinal and head and neck tumors were digitized and independently scored by three expert pathologists. Discordant cases were jointly reviewed to establish a consensus reference standard. Four different pathologists from various institutions independently reviewed all cases without AI support. Following a washout period of two months, the pathologists reassessed the cases with AI assistance. For each slide, the algorithm provided CPS values along with a PD-L1 expression heatmap to support result interpretability. Pathologist assessments were compared with the reference standard to quantify the impact of AI on scoring accuracy. Performance was assessed using accuracy, sensitivity and specificity for clinically relevant binary cutoffs, and intraclass correlation coefficient (ICC) to evaluate concordance between pathologists. Scoring time was also recorded. Results: Using organ-specific cut-offs, the CPS accuracy increased from 77.6% to 83.9% with AI assistance (p < 0.01), sensitivity increased from 78.5% to 89.6% and specificity increased from 73.4% to 76.2%, while the average scoring time per case decreased from 109s to 78s (p < 0.01). The ICC between pathologists rose from 0.71 to 0.90 when introducing AI assistance. Conclusions: AI-assisted PD-L1 assessment significantly improved agreement with the reference standard, enhanced inter-pathologist reliability, and reduced scoring time while maintaining clinically relevant performance across tumor types. These findings support the potential of AI assistance to exhaustively quantify PD-L1 CPS and facilitate more standardized and robust patient selection for immunotherapy in routine practice.

Using process mapping to improve clinical care for patients receiving cancer treatment in resource-limited settings.

e23249 Background: Process mapping is a low-cost, low-technology approach that can be used to understand and improve clinical processes. It is particularly useful for improving clinical care for patients receiving cancer treatment in resource-limited settings. Neutropenic fever is associated with particularly high rates of mortality, particularly for people receiving cancer treatment in sub-Saharan Africa. In this study, we used process mapping to identify barriers to antibiotic delivery and understand ways in which to improve the antibiotic delivery process at the Uganda Cancer Institute (UCI) in Kampala, Uganda. Methods: In our study, we used a five-phase process mapping framework to build a multidisciplinary process mapping team, develop an antibiotic delivery process map, identify barriers to antibiotic delivery, and begin the process by which to prioritize the barriers to care that should be addressed using implementation strategies. Throughout this framework, we used focus discussion groups as the basis for data collection and analyzed the process map using low-cost supplies and open-access software. Results: From March 2023 – May 2024, we conducted a series of 13 focus discussion groups to develop the process map and 13 additional focus groups to identify barriers to antibiotic delivery in a resource-limited setting. Frequently identified barriers included challenges with communication between team members, limited access to appropriate antibiotics, and the need for patient family members to travel to outside pharmacies to procure medications. Conclusions: Process mapping is a simple, low-cost way to understand the healthcare delivery system and identify areas in which it can be improved. In our study, we were able to use process mapping to understand the antibiotic delivery system for a cancer center in Uganda. The process mapping framework can also be used to understand and improve other cancer delivery processes for patients receiving treatment in resource-limited settings.

Cancer-associated bradyarrhythmias and inpatient deterioration in U.S. hospitalizations.

e23107 Background: Cardiac rhythm disturbances in oncology are most often studied in atrial fibrillation and tachyarrhythmias. Bradyarrhythmias may reflect autonomic dysfunction, conduction system toxicity, or paraneoplastic effects, yet their inpatient burden and prognostic significance in hospitalized cancer populations remain poorly characterized. This study evaluated whether bradyarrhythmias identify a high-risk inpatient phenotype among cancer hospitalizations. Methods: We performed a serial cross-sectional analysis of adult hospitalizations with a principal diagnosis of malignancy in the 2018 to 2022 Healthcare Cost and Utilization Project National Inpatient Sample using discharge-level survey weighting. Bradyarrhythmias were identified using any-diagnosis ICD-10-CM codes for atrioventricular conduction disease, sick sinus syndrome, or bradycardia. Outcomes included in-hospital mortality, shock, intensive care unit utilization, and permanent pacemaker implantation. National estimates accounted for survey stratification and clustering. Survey-weighted multivariable logistic regression adjusted for demographics, cancer type, heart failure, sepsis, admission characteristics, payer, income quartile, hospital teaching status, and geographic region. Sensitivity analyses excluded hospitalizations with heart failure or sepsis. Results: Among an estimated 4.81 million cancer hospitalizations nationally, bradyarrhythmias occurred in 3.9 percent. Hospitalizations with bradyarrhythmias had higher in-hospital mortality (5.9 percent vs 4.3 percent), shock (2.8 percent vs 1.3 percent), and intensive care unit utilization (7.0 percent vs 3.4 percent). Permanent pacemaker implantation was uncommon overall but more frequent among bradyarrhythmia admissions (4.0 percent vs 2.9 percent). After adjustment, bradyarrhythmias remained independently associated with in-hospital mortality (adjusted odds ratio 1.11, 95% CI 1.05 to 1.17), shock (adjusted odds ratio 1.71, 95% CI 1.60 to 1.84), intensive care unit utilization (adjusted odds ratio 1.92, 95% CI 1.83 to 2.01), and permanent pacemaker implantation (adjusted odds ratio 1.40, 95% CI 1.32 to 1.49). Associations persisted after exclusion of hospitalizations with heart failure or sepsis. Conclusions: Bradyarrhythmias can occur during cancer hospitalizations and identify a high-risk inpatient phenotype characterized by shock, critical care utilization, mortality, and need for permanent pacing. These findings can guide further research to evaluate bradycardia and its complications as potential cancer related outcomes.

Functional assessment of polymerase proofreading variants to define sensitivity to immune checkpoint blockade (ICB) pan-cancer.

2645 Background: Cancers with inactivating alterations in DNA proofreading polymerases POLE and POLD1 (POLd) are ultra-hypermutated and benefit from ICB. Most mutations in DNA polymerases are synonymous; discerning pathogenic (P) vs variants of unknown significance (VUS) remains challenging. A strategy to define functional mutations in POL with mutational signature deconvolution and AI- protein conformational modeling could better predict ICB benefit. Methods: Solid tumors from patients at MSK and DFCI were selected with DNA panel sequencing datasets to enrich for somatic POL P/likely-P(LP) variants or VUS. Co-mismatch-repair deficiency (MMRd) was defined with MSIsensor and IHC. Tumors were assigned as POL high (>50%), intermediate ([int] 1-49%), or null (0%) based on the proportion of single-base-substitutions (SBS) aligning with POLd COSMIC signatures via the mutational-patterns algorithm. POLE/D1 VUS were functionally evaluated with Swiss-PdbViewer and AlphaFold-derived AI models to infer proofreading efficiency impact. Patient overall survival (OS) from stage IV diagnosis and progression-free survival from ICB start (PFS-ICB) were evaluated with multivariable (MV) Cox regression including MMRd status. Results: POL variants were found in 546 patients across 18 diverse cancers. 84% were P/LP POL alterations, 16% were POL VUS, and 36% overall had concomitant MMRd. Tumors with P/LP variants had high (69%), int (23%), or null (8%) POLd signature intensities, while 62% of tumors with VUS had int POLd signatures. For the subgroup of patients with POL P/LP variants, OS from diagnosis significantly differed based on POLd signature intensity: not reached [NR], 94.5 months [mo], and 32.9 mo for POLd signature high, int, and null, respectively. In MV analysis of POL P/LP tumors, patients with POL signature-null tumors had significantly worse OS than POL-int (HR 0.35, 95%CI 0.16-0.80; p=0.01) and POL-high (HR 0.18, 95%CI 0.08-0.42; p<0.001) patients. POLd signature intensity predicted ICB benefit. Patients with POL P/LP tumors with high and int signatures exhibited favorable PFS-ICB (NR in both) versus POL P/LP–null-signature tumors (12.7 months). In MV model including MMR status, patients with POL-null SBS exhibited significantly worse PFS-ICB versus pts with combined POL signature high or int (HR 0.31, 95% CI 0.10-0.98; p=0.047). Study findings were consistent after adjustment for cancer type. Tumors with POL VUS predicted to be inactivating based on mutational signature deconvolution combined with Swiss-PdbViewer and AlphaFold AI models demonstrated similar OS/PFS to patients with tumors with P/LP variants and high/int signature scores. Conclusions: A strategy combining mutational signature deconvolution with AI proteomic functional assessment predicts survival and ICB benefit in tumors with functional DNA polymerases POLE and POLD1 mutations.

Logic‐Gated Molecular Machines Encapsulate Environment‐Responsive DNA Actuators for Tunable Cellular Lysosome Interference

ABSTRACT Intracellular DNA nanoassemblies have proven to potently induce organelle dysfunction and cell death, while their scale‐dependent capacity of cellular interference remains undefined. To address it, here we engineer a logic‐gated lysosome‐targeted molecular machine that encapsulates ATP‐driven DNA actuators, which can assemble into different‐scaled nanoarchitectures in response to lysosomal microenvironments. Such a design enables the programmable DNA nanoassembly and tunable lysosome interference, straightforwardly visualized by atomic force microscopy (AFM) and bio‐transmission electron microscopy (bio‐TEM), respectively, showing that larger DNA assemblies promote stronger membrane permeabilization and greater cytotoxicity. It evidences the pronounced scale‐dependent lysosome interference and clues how to rationally design DNA nanoassemblies for cell regulation. We further investigate the primary pathway of programmed cell death induced by DNA nanoassemblies, which reveals the cathepsin‐mediated caspase‐independent lysosomal cell death, alongside a minor caspase‐dependent pathway. This work demonstrates a programmable “dual‐signal logic–structural assembly–functional output” cascade at the suborganelle level, which would establish a new paradigm for DNA‐based nanotherapeutics.

Development of a Rosmarinus officinalis extract-loaded nanoemulgel for topical anti-inflammatory delivery: Molecular docking, HPTLC profiling and ex vivo evaluation

Transpiration‐Inspired Radiative Cooling Metafabric for Efficient Personal Thermal and Moisture Management

ABSTRACT Advanced radiative cooling textiles represent a promising avenue for improving human thermal comfort in the face of global warming. However, their limited sweat evaporation capacity and low thermal conductivity significantly reduce the cooling efficiency, particularly in hot outdoor climates. Herein, a novel transpiration‐inspired metafabric that integrates precise solar spectrum regulation, a high heat conduction pathway, and splendid moisture‐wicking capacity was presented through multi‐scale electrospun structural design. The gradient micro‐nano porous metafabric can broadly scatter the solar spectrum while establishing a gradual refractive index transition to enhance mid‐infrared absorption. The solar reflectivity and infrared emissivity of the metafabric reached 99.7% and 93.3%, respectively, inducing a cooling effect of 10.2°C and net cooling power (P net ) of 110.1 W/m 2 . Meanwhile, the metafabric with a gradual wettability gradient and capillary force gradient exhibited a high one‐way transport index (R) of 1330.7% and a reverse breakthrough pressure of 15.0 cm H 2 O, effectively preventing liquid pinning and back penetration. What's more, the coupled strategy of thermal radiation, conduction, and evaporation resulted in a temperature drop of 20.2°C in the sweaty state. The metafabric also demonstrated superb mechanical robustness, breathability, and washability. The work may offer a scalable and energy‐efficient strategy for advanced thermal and moisture management textiles.

Thermo-hydraulic performance analysis of a horizontal slinky-type geothermal heat exchanger under turbulent flow vonditions

Real-world nutritional outcomes assessed by subjective global assessment in community oncology practice in western India.

e13576 Background: Cancer-related malnutrition affects treatment tolerance & survival, yet real-world data from Western India are limited; this study evaluates nutritional status, predictors of malnutrition & survival using Subjective Global Assessment (SGA). Methods: Cancer patients undergoing SGA between March 2023 - December 2025 were retrospectively analyzed. SGA was performed at baseline & post-intervention evaluating demographic, clinical & survival factors. Binary logistics regression Wilcoxon sign rank test & Kaplan Meier methods were used for analysis. Results: A total of 1155 patients were included who underwent SGA, the median age was 57 years (IQR 47–65) with M:F ratio 1:1.8. The most common cancer types evaluated were breast (30.8%), head & neck (16.4%), gastrointestinal (14.5%), gynaecological (14.9%) & lung cancers (5.6%). Baseline ECOG PS was 0–1 in 77.6%. SGA was conducted at baseline with 90.9% of assessments performed at cycle 1. At baseline, 55.6% of patients were well nourished, 44.2% were mild to moderately malnourished & 0.3% were severely malnourished. Post-intervention [mean duration 6.3 months (1-28)], 60.2% were well nourished & 39.3% were mild to moderately malnourished. Overall nutritional status in malnourished cohort was classified as improved in 57.5% & remained stable in 32.7% while 31.9% (205/642) of initially well-nourished patients deteriorated. SGA deterioration was mainly due to treatment related toxicities in head & neck (17.1%) & gastrointestinal cancers (11.2%) due to dysphagia, dysgeusia, gastrointestinal symptoms & appetite loss. Median pre-SGA score of malnourished cohort was 5 vs 6 post-SGA assessment (p = < 0.001).Male gender was independently associated with higher odds of malnutrition (OR 1.7, 95% CI 1.3–2.1; p < 0.001). Compared to breast cancer, higher malnutrition risk was observed in head & neck (OR 4.2, 95%CI 2.9-6.1),gastrointestinal (OR 3.1, 95%CI 2.1-4.6), lung (OR 4.0, 95% CI 2.3-7.0) & gynecological cancers (OR 1.98, 95% CI 1.4-2.9) (p < 0.001). Improvement rates in malnourished varied by cancer type, with lower improvement observed in head & neck cancer (42.5%) compared with gastrointestinal (69.5%), breast (63.5%), gynecological (61.5%) & lung cancer (55%). Improvements were noted across nutritional domains: disease-related requirements (34.0%), muscle mass (34.4%), fat stores (33.3%), weight loss (32.1%), functional status (29.5%), dietary intake (28.7%) & GI symptoms (20.1%).Median overall survival (mOS) was 84.9 mo at baseline in severe/mild/moderate malnourished patients while mOS was not reached in well-nourished patients (p < 0.001). Conclusions: In this study, SGA effectively identified malnutrition, revealed tumor-specific risk patterns & correlated with survival outcomes underscoring its value as a practical & prognostically informative tool in routine oncology care.

Regulatory role of IRF2 in proliferation and invasion of nasopharyngeal carcinoma: Investigation into underlying mechanism.

e18052 Background: The recurrence and progression of nasopharyngeal carcinoma (NPC) are major factors contributing to unsatisfactory treatment outcomes. The role of Interferon Regulatory Factor 2 (IRF2) in NPC progression remains unclear. This study aimed to elucidate the biological functions, underlying mechanisms, and clinical significance of IRF2 in NPC. Methods: Subcellular localization and pan-cancer expression profiling of IRF2 were analyzed using the Human Protein Atlas database. Localization and expression levels of IRF2 were assessed in NPC cell lines (CNE1, HONE1, 58F, 6-10B), 64 NPC tissues, 36 chronic nasopharyngitis tissues, and the immortalized nasopharyngeal epithelial cell line NP69 via immunohistochemistry (IHC), immunofluorescence (IF) and Western blot (WB). Its diagnostic value was evaluated using receiver operating characteristic (ROC) curve analysis. Stable IRF2-overexpressing and knockdown NPC cell lines were established. Functional studies were conducted using CCK-8, colony formation, wound healing, Transwell, and flow cytometry assays, as well as a xenograft tumor model in nude mice. The effects of IRF2 on epithelial-mesenchymal transition (EMT) markers and key proteins of the Wnt/β-catenin pathway (GSK-3β, β-catenin) were examined by WB. Nuclear and cytoplasmic fractionation combined with IF was used to observe β-catenin nuclear translocation. Results: IRF2 was significantly upregulated in NPC, primarily localized in the nucleus, and demonstrated diagnostic value (AUC = 0.837, 95% CI: 0.760–0.915). Its expression level positively correlated with T stage and plasma Epstein-Barr virus (EBV) DNA load. IRF2 overexpression promoted NPC cell proliferation, migration, and invasion, while suppressing apoptosis; conversely, IRF2 knockdown produced opposite effects. In vivo experiments confirmed that IRF2 promoted tumor growth. Mechanistically, IRF2 induced EMT (downregulating E-cadherin, upregulating N-cadherin, Snail1, Snail2, ZEB1) and activated the Wnt/β-catenin signaling pathway by upregulating GSK-3β and β-catenin and promoting β-catenin nuclear translocation. Conclusions: IRF2 is primarily located in the nucleus of NPC cells and functions as an oncoprotein, whose expression is associated with local tumor invasion and plasma EBV DNA load. IRF2 drives NPC progression by promoting cell proliferation, migration, invasion, EMT, and inhibiting apoptosis, potentially through activation of the Wnt/β-catenin signaling pathway, suggesting its potential as a therapeutic target.

New paradigms of cancer and new language: A qualitative study exploring language around goals of cancer surgery.

12099 Background: Cancer interventions are often discussed amongst providers and presented to patients within the dichotomy of “curative” vs. “palliative” interventions. However, as understanding of cancer biology has shifted and as cancer treatments have evolved, some cancers have become chronic diseases for which surgery may have a non-curative but disease-targeted role. Despite new paradigms of cancer care, language has not evolved to reflect new goals of cancer surgery. Methods: Semi-structured interviews were conducted with cancer surgeons from throughout the U.S. via purposive and snowball sampling. Interviews included discussions of two hypothetical scenarios describing non-curative surgical operations and discussion of the term “disease-controlling” surgery as a category of neither palliative nor curative surgical intent. Transcribed and de-identified interviews were analyzed inductively using grounded theory. Results: 18 surgeons from 16 institutions were interviewed. Surgeons collectively outlined how changes in the paradigm of cancer treatment have resulted in challenges describing intent of cancer surgery. Specifically, responses to the term “disease controlling” surgery elicited examples of cancer pathologies and treatment courses which fail to fit existing treatment-intent language and which captured new roles for surgery in cancer treatment paradigms. These roles of surgery include "surgery as curative treatment" (including both curative intent with probability of cure and curative intent with possibility of cure), "surgery as adjuvant treatment" (targeted surgery to assist systemic therapies with possible change in disease course), and "surgery as palliative treatment" (symptom relief surgery without possible change in disease course). Within the 'targeted surgery' category, participants described expanded surgical roles for numerous metastatic diseases including debulking for improved systemic therapy efficacy, resection of treatment-resistant disease sites, and "resetting the clock" for indolent tumors. These operations require multidisciplinary coordination and understanding of available systemic treatments, as surgical goals are increasingly defined by each patient's broader treatment trajectory. Conclusions: Traditional “curative” vs. “palliative” surgical intent categories inadequately describe contemporary cancer surgery. The emergence of life-extending but non-curative treatments necessitates new language frameworks that better align with current understandings of cancer biology and new treatment modalities. New language is necessary to facilitate clearer communication between providers and patients about surgical goals and expected outcomes and to allow for better research evaluating whether surgical treatments achieve those goals and outcomes.