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A phase II study of neoadjuvant ipilimumab-nivolumab-relatlimab (INR) combination immunotherapy in high-risk resectable melanoma.

9501 Background: Advances in the neoadjuvant (neo) setting of locoregionally advanced melanoma have recently transformed practice. However, there continues to be a need to enhance efficacy while deescalating the duration of systemic therapy for those who achieve major pathologic (path) responses (MPR). Recent data support an important role for triplet INR checkpoint inhibitor therapy targeting CTLA4, PD1 and LAG3 in the treatment of advanced melanoma. Methods: A phase II trial of INR in patients (pts) with resectable clinical AJCC8 stages IIIB-D. It planned to enroll 20 evaluable pts to neo ipilimumab 1 mg/kg x1 dose combined with nivolumab-relatlimab (NR) 480/160 mg every 4 weeks x2 doses, followed by definitive surgery. Primary endpoint was MPR consisting of complete path response (pCR; 0% viable tumor) and near-pCR (< 10%). Secondary endpoints included other path responses, recurrence free survival, overall survival, event-free survival [EFS: disease progression (PD), recurrence or death] and safety. Adjuvant therapy was given in the absence of MPR. Biospecimens for research from consenting pts were banked at baseline, during treatment, at surgery and in follow up. Results: The study enrolled 20 pts August 2024-January 2026, including 7 female, 13 male, 16 cutaneous (2 acral) and 4 unknown primary. Median age was 65 (63-80). Baseline clinical stages were 9 IIIB, 9 IIIC, 2 IIID, including 4 pts with in-transit metastases. Among 19 patients who completed the neoadjuvant phase, all received ipilimumab and the median number of neo NR doses was 2. Among 19 pts who initiated treatment, 5 pts (26%) experienced Gr3 related AEs including colitis (1), encephalitis (1), headache (1), hyperglycemia (1), rash (1), and one pt experienced an event of Gr5 myocarditis. Among 18 pts who completed radiologic tumor response assessment, there were 13 (72%) partial response (PR), 4 stable disease (SD) and 1 disease progression (PD) preoperatively. There was 1 event of death before surgery. One patient declined surgery following deep PR, 1 pt is pending surgery and 1 pt continues in the neo phase. Among 16 pts who had surgery, median time from enrollment to surgery was 73 days. Pathologic responses were 5 path non-response (pNR), 1 near-pCR (microscopic residual disease) and 10 pCR (63%; 95% CI, 38.64 – 81.52). MPR rate (pCR + near-pCR) was 11/16 (69%; 95% CI, 44.40 – 85.84) and none of these patients received adjuvant therapy. Median follow up time from enrollment was 9.8 months. Among all pts, no pt experienced recurrence after surgery to date. Conclusions: Neoadjuvant INR demonstrated encouraging clinical activity in pts with resectable clinical stages IIIB/IIIC/IIID melanoma, warranting further investigation. The toxicity profile was consistent with reported data of INR and other combinations in this setting. Mechanistic and biomarker studies related to response, resistance and toxicity are underway. Clinical trial information: NCT06295159 .

A nationwide population-based study on the incidence and prognosis of patients with HER2+ breast cancer eligible for adjuvant pertuzumab in the modern era of neoadjuvant therapy.

e12508 Background: The addition of pertuzumab to adjuvant chemotherapy and trastuzumab improves overall survival (OS) of patients with HER2+ and node positive (N+) breast cancer. Adjuvant pertuzumab, while recommended by ESMO and NCCN for both primary resected pN+ and neoadjuvant treated cN+ breast cancer with pathologic complete response (pCR), is not used in Sweden due to concerns about its cost effectiveness. Here, we aimed to evaluate the relevance of the APHINITY trial during the era of neoadjuvant treatment and the prognosis of patients eligible for adjuvant pertuzumab. Methods: This was a retrospective analysis of a prospectively collected, nationwide, population-based cohort that comprises all patients treated for breast cancer in Sweden between 2007-2023. Patients with non-metastatic, HER2+ and N+ breast cancer were included into an adjuvant cohort comprising patients eligible for the APHINITY trial who underwent primary surgery and had pN1–3 disease, and a neoadjuvant cohort consisting of patients diagnosed with cN+ disease who received neoadjuvant trastuzumab-based therapy and achieved pCR. Median follow-up was 8.4 years (IQR, 4.6-12.0). Results: Of 135080 patients diagnosed with DCIS or invasive breast cancer (all stages) in Sweden during the study period, 3495 were included into the primary resected adjuvant cohort. The proportion of patients eligible for adjuvant pertuzumab declined over the years, in parallel with the increasing use of neoadjuvant treatment. 10-year OS in the adjuvant cohort was 71,6% (95% CI 69,9-73,3%). Tumor size and nodal stage were independently prognostic, while ER positivity was associated with late recurrence (time-dependent HR adj = 1.96, 95% CI 1.21-3.19 at 10 years). On the other hand, patients in the neoadjuvant cohort (n = 465) had excellent outcomes, with 10-year OS of 92,3% (95% CI 84,1-100%). Conclusions: Although the proportion of patients with HER2+ and N+ breast cancer that undergo primary surgery instead of neoadjuvant therapy is steadily decreasing, the poor long-term outcomes at the population level underscore the relevance of adjuvant pertuzumab. In contrast, the recommendation by NCCN and ESMO for adjuvant pertuzumab to patients with cN+ that achieve pCR should be revisited in light of their excellent prognosis and likely marginal absolute benefit with pertuzumab.

Comparable clinical efficacy of pyrotinib in trastuzumab-naive and trastuzumab-exposed HER2-positive advanced breast cancer patients: A prospective, multicenter, real-world study.

e13025 Background: Pyrotinib is an irreversible pan-HER tyrosine kinase inhibitor that has shown significant efficacy in HER2-positive breast cancer. However, in real-world clinical practice, the effectiveness of first-line pyrotinib-based regimens has not been well characterized. This study supplemented the corresponding evidence. Methods: This is a prospective observational study conducted at three centers in China. Patients with HER2-positive advanced breast cancer who planned to receive first-line pyrotinib-based therapy were enrolled. Treatment regimen and the dose of pyrotinib were determined by treating physicians according to routine clinical practice. The primary outcome was real-world progression-free survival (rwPFS). Results: From May 2024 to November 2025, 156 patients were enrolled, with 152 having available baseline characteristics. The majority of patients had trastuzumab-naïve (48.0% [73/152]), trastuzumab-sensitive (disease recurrence more than 12 months after completion of adjuvant trastuzumab therapy 45.4% [69/152]), trastuzumab-resistance (disease progression while on trastuzumab therapy, or relapse/metastasis occurring within 12 months of trastuzumab discontinuation in the (neo)adjuvant phase,.6.6% [10/152]) disease, and had visceral metastases (55.9% [85/152]). As of November 30, 2025, a total of 108 patients had completed tumor response assessments.The real-world objective response rate was 53.7% (58/108), 61.2% (30/49) in the trastuzumab-naïve subgroup and 52.0% (26/50) in the trastuzumab-sensitive subgroup. The estimated 12-month and 18-month rwPFS rates were 81.1% (95% CI: 71.1–92.6) and 65.2% (95% CI: 49.0–86.8) for all the 156 patients, 78.0% (95% CI: 63.1–96.5) and 65.0% (95% CI: 42.9–98.6) for patients with trastuzumab-naïve disease (n = 73), and 89.5% (95% CI: 78.5–100) and 70.5% (95% CI: 49.3–100) for trastuzumab-sensitive patients (n = 69), respectively. The most common grade 3 adverse events (AEs) included alopecia (28.8% [45/156]), diarrhea (20.5% [32/156]), and decreased neutrophil count (9.6% [15/156]). No grade ≥4 AEs were reported. Conclusions: First-line pyrotinib-based regimens showed favorable effectiveness and manageable safety profiles for patients with HER2-positive advanced breast cancer in the real-world setting, including those with trastuzumab-naïve and trastuzumab-sensitive disease. These findings support their use in routine clinical practice. Clinical trial information: NCT06495541 .

Risk factors and outcomes for steroid-refractory immune-related hepatotoxicity in locally advanced and metastatic cancer.

e24162 Background: Immune-related hepatotoxicity (IRH) is one of the common immune-related adverse events caused by immune checkpoint inhibitors (ICIs). Some patients with steroid-refractory IRH (Ref-IRH) are potentially life-threatening. This study was designed to determine the risk factors and outcomes for Ref-IRH. Methods: Advanced or metastatic cancer patients who developed steroid-responsive IRH (Res-IRH) or Ref-IRH were identified between 1 December 2019 and 1 September 2024. Patient characteristics, peripheral blood biomarkers, and cytokine levels were collected. Results: In this cohort of 480 patients treated with immune checkpoint inhibitors, 35 patients (7.3%) developed IRH, including 12 with Res-IRH and 13 with Ref-IRH. Patients with Ref-IRH were more likely to be hepatocellular carcinoma (p=0.035), receive ICIs plus targeted therapy (p=0.046), and have higher CTCAE grades (p=0.044) at diagnosis. Patients with Ref-IRH had lower platelet counts (p=0.006), higher procalcitonin levels (p=0.012), and higher IL-6 levels (p=0.038). Multivariate logistic regression analysis indicated that higher IL-6 at diagnosis was an independent risk factor for Ref-IRH (p=0.031). All Ref-IRH patients were treated with immunosuppressive agents. The survival outcomes of Ref-IRH were comparable to those of Res-IRH. Patients with Ref-IRH were unlikely to quickly recover with a longer time from initial diagnosis of IRH to resolution to grade 1 (p=0.002), from peak ALT (p=0.007), AST (p=0.011), and TBIL (p=0.048) to resolution to grade 1, from initial diagnosis of IRH to use of prednisone ≤20 mg/day (p=0.025), and prolonged hospital length of stay (p=0.017). Among 14 patients who underwent liver biopsy, 3 were diagnosed with vanishing bile duct syndrome (VBDS) and 11 with non-VBDS. The survival outcomes of VBDS were comparable to those of non-VBDS, but patients with VBDS had lower 8-week, 10-week, and 12-week improvement rates compared with non-VBDS patients (p=0.011, p=0.011, p=0.033, respectively). Conclusions: High IL-6 at diagnosis is an independent risk for developing Ref-IRH. There was no significant difference in efficacy and survival between patients with Ref-IRH and Res-IRH, patients with VBDS and non-VBDS, but much more time from the initial diagnosis of IRH to resolution to grade 1 and the use of immunosuppressive agents is needed for Ref-IRH patients.

Feasibility and concordance of a large language model (ChatGPT-5) as a clinical decision support tool in gynecologic oncology tumor boards: A blinded, multi-observer study.

5519 Background: The integration of artificial intelligence (AI) into oncology practice is accelerating; however, the reliability of Large Language Models (LLMs) in complex clinical decision-making remains insufficiently validated. This study evaluated the concordance of ChatGPT-5 with multidisciplinary tumor board (MDT) decisions in gynecologic oncology, assessing accuracy, reproducibility across repeated queries, and specific domains of discordance. Methods: We analyzed 97 gynecologic cancer cases requiring multimodal treatment planning, evaluated at the Cukurova University Faculty of Medicine Gynecologic Oncology MDT between 2024-2025. Cases included ovarian (n=34), endometrial (n=41), cervical (n=16), and rare tumors (n=6). Standardized clinical summaries (staging, pathology, molecular markers, comorbidities, patient preferences) were input using a structured prompt template. Each case was queried independently at three time points within the same day to assess reproducibility. Recommendations were evaluated by two blinded medical oncologists using a 5-point Likert scale (1=completely inappropriate, 5=completely appropriate). A composite performance score was calculated as [(mean Likert score)/5]×100. Inter-rater reliability and concordance were analyzed using Cohen's kappa (κ). Results: Inter-rater reliability was high for both MDT (κ=0.748, p<0.001) and AI evaluations (κ=0.802, p<0.001). Concordance between MDT and ChatGPT-5 recommendations was fair (Rater 1: κ=0.267; Rater 2: κ=0.341), indicating frequent disagreement in specific clinical nuances despite similar overall quality scores. Mean performance scores were significantly higher for MDT versus AI (Rater 1: 94.2%±4.8 vs. 89.8%±6.3, p<0.001; Rater 2: 93.8%±5.1 vs. 90.1%±5.9, p<0.001). Crucially, ChatGPT-5 demonstrated full consistency across three queries in only 38% of cases (37/97), with a mean reproducibility score of 4.10±0.83. Subgroup analysis revealed superior AI performance in early-stage (I–II) versus advanced-stage (III–IV) disease (p=0.024). However, AI performance was significantly inferior in cases requiring genetic testing recommendations (p=0.019), fertility-sparing approaches (p=0.045), and novel therapeutics integration (p=0.012). Conclusions: ChatGPT-5 demonstrates potential as a clinical decision support tool but currently lacks sufficient reliability for independent use in complex gynecologic malignancies. Key limitations include inconsistent reproducibility (62% variability across queries), suboptimal performance in advanced-stage disease, and deficiencies in precision oncology domains. Human expertise remains essential to mitigate risks associated with AI-generated inaccuracies, particularly for novel therapeutic integration.

Evaluation of the impact of regional lymph node depletion on response to immune checkpoint blockade in recurrent and metastatic head and neck squamous cell carcinoma.

6056 Background: Lymphadenectomy remains a central component of definitive treatment for head and neck squamous cell carcinoma (HNSCC). However, lymphadenectomy disrupts the draining regional lymph node basin where anti-tumor immune cell priming can occur. We hypothesized that history of regional lymph node depletion may be associated with decreased efficacy of immune checkpoint blockade (ICB) in patients who suffer recurrent or metastatic (R/M) HNSCC. Methods: This was a single-institution retrospective cohort study including all patients treated with ICB (anti-PD-1 mAb) for R/M HNSCC from 2015 - 2025. Patients with distant metastatic disease at presentation were excluded. Demographic, clinicopathologic, and treatment history prior to ICB were collated and summarized for each patient. We defined regional lymph node depletion (LN depletion) as history (at any time prior to ICB initiation) of bilateral lymphadenectomy, > 4 levels dissected, or ≥18 lymph nodes excised. We then examined history of LN depletion as a predictor of ICB disease control rate (DCR: SD, PR, or CR) and progression-free survival (PFS) after ICB with Kaplan-Meier method and Cox models alone and controlling for tumor HPV status. Results: Our cohort was comprised of 100 patients (median age 72 years, 71% male). Primary tumor sites included oral cavity (n=38) p16+ oropharynx (n=23), larynx (n=21), p16- oropharynx (n=13) and sinonasal (n = 5). Forty-six were treated with first-line ICB, while 54 were treated after platinum chemotherapy failure. Sixty had a history of lymphadenectomy prior to ICB. Of these 60 patients, 51 (85%) had a history of radiation prior to ICB. History of regional LN depletion was significantly associated with lower DCR with ICB when considering bilateral lymphadenectomy (25.9% vs 54.8%, p = 0.03), > 4 levels dissected (25.0% vs. 54.8%, p = 0.02), or ≥18 lymph nodes excised (25.0% vs. 84.6%, p < 0.0001) analyzed alone and on bivariate analysis controlling for HPV status. In patients meeting all three criteria for LN depletion (n = 24), DCR was the lowest at 16% compared to 75% for patients meeting none of the criteria. On bivariate analyses controlling for HPV status, history of bilateral lymphadenectomy (HR: 2.04 [95% CI 1.1 – 3.8] p = 0.02), > 4 levels dissected (HR: 1.82 [95% CI: 1.0 – 3.3] p = 0.05, and ≥18 lymph nodes excised (HR: 3.35 [95% CI: 1.4 – 8.1] p < 0.01) were independently associated with poorer PFS after ICB. Conclusions: In patients with R/M HNSCC, prior regional LN depletion was associated with lower DCR and PFS after ICB. This suggests that greater surgical disruption of draining regional lymph node basins prior to ICB may affect immune response.

A phase I study of HPB-092, a dual FLT3/IRAK4 inhibitor, in relapsed or refractory acute myeloid leukemia.

TPS6599 Background: Fms-like tyrosine kinase 3 (FLT3) is a clinically validated oncogenic driver in acute myeloid leukemia (AML). While FLT3 kinase inhibitors have been approved for AML patients with FLT3 mutations, resistance remains a significant challenge. Interleukin-1 receptor–associated kinase 4 (IRAK4) has emerged as a key signaling node in treatment-induced resistance. Moreover, a subset of AML patient population harbors mutations in RNA splicing factors U2AF1 or SF3B1. These mutations result in expression of an oncogenic long form of IRAK4. Therefore, co-targeting FLT3 and IRAK4 can potentially both address resistance and treat a broader population in AML. HPB-092 is a highly selective dual-target small-molecule kinase inhibitor designed to target mutant FLT3 and IRAK4. HPB-092 demonstrated robust potency against FLT3-ITD ( IC ₅₀ = 0.24 nM), FLT3-D835Y ( IC ₅₀ = 0.18 nM), and IRAK4 ( IC ₅₀ = 3.1 nM). In vivo, HPB-092 elicited dose-dependent regression of the MV4-11 tumor model. HPB-092 received IND clearance in both China and the US, showing a favorable safety profile with no significant genotoxicity or hERG inhibition, supporting its clinical evaluation. Methods: This ongoing, first-in-human, phase 1 study evaluates oral HPB-092 monotherapy in adults with RR-AML. The primary objectives are to evaluate safety, tolerability, pharmacokinetics (PK), and to determine the recommended phase II dose (RP2D). Secondary objectives include preliminary antileukemic activity (ORR, DOR) and exploratory biomarkers analyses. Part A is a dose-escalation phase spanning five dose levels (30–200 mg), utilizing an accelerated titration design followed by a 3+3 scheme in patients with R/R AML, regardless of FLT3, U2AF1 or SF3B1 mutation status. The study initiates with a single-dose administration on cycle 1 day 1 for SAD-PK assessment, followed by multiple ascending doses administered twice daily for MAD-PK and dose-limiting toxicities (DLTs) over a 28-day observation window. Part B is a randomized dose-expansion phase to evaluate selected dose levels in patients with FLT3-mutant AML and those with U2AF1 or SF3B1 mutations. Correlative pharmacodynamic and biomarker analyses are planned. No formal hypothesis testing or sample size calculation was performed. Safety, PK, and efficacy analyses will be descriptive in patients receiving at least one dose of HPB-092. AEs will be graded according to NCI CTCAE v5.0. PK parameters will be derived using noncompartmental methods. Time-to-event endpoints will be estimated using Kaplan–Meier methods, where applicable. Site initiation is complete; enrollment is initiated and ongoing, with the first patient anticipated in Q1 2026. Clinical trial information: NCT07137637 .

Safety and efficacy results of the phase 2 study of silevertinib (BDTX-1535) in previously treated patients with non-small cell lung cancer with non-classical and C797S EGFR mutations.

8620 Background: Despite significant benefit from FDA-approved EGFR tyrosine kinase inhibitors (TKIs), patients with classical EGFR mutation positive non-small cell lung cancer (NSCLC) ultimately develop progressive disease due to mechanisms of resistance, including alterations of the EGFR pathway. A broad group of non-classical EGFR mutations (NCM), including P-loop and αC-helix compressing (PACC) mutations, and acquired C797S are major mechanisms of EGFR resistance. Silevertinib (BDTX-1535) is a fourth-generation covalent EGFR TKI with high CNS penetrance that targets classical mutations, NCM, and C797S mutations. Antitumor activity and safety of silevertinib in advanced NSCLC were evaluated in an open-label Phase 2 trial (NCT05256290). Methods: Patients (pts) with recurrent NSCLC following ≤ 2 lines of therapy with only 1 prior EGFR TKI (osimertinib preferred) and tumors positive for NCM (NCM Cohort) or C797S mutation (C797S Cohort) were enrolled based on a local molecular test. Based on dose optimization of silevertinib at 100 mg and 200 mg orally once daily, all patients after May 2024 received 200 mg once daily. The primary endpoint was ORR by RECIST v1.1, and secondary endpoints included progression-free survival (PFS), duration of response (DOR), dose optimization, and safety. Results: From August 2023 to January 2025, 41 pts were treated in the NCM Cohort (100 mg, n=11; 200 mg, n=30; 80% female; 56% white; 49% with CNS metastases) and 42 pts were treated in the C797S Cohort (100mg, n=9; 200mg, n=33; 62% female; 48% white; 31% with CNS metastases). In both cohorts, 29% of pts had received 2 prior therapies. As of November 3, 2025, median follow-up was 9.5 months for pts treated with the 200 mg dose. ORR and median duration of treatment (DoT) are shown in the table. Alterations of other oncogenic pathways (e.g. MET, RET, RAS, and RAF) were observed at baseline in approximately 20% of pts in post hoc analyses. For the 200 mg dose, serious treatment-related adverse events (TRAEs) were reported in 7 (11%) pts, and 5 (8%) of pts discontinued treatment due to TRAEs. The most common TRAEs at 200 mg included rash (13%, grade 3), diarrhea (8%, grade 3), stomatitis (2%, grade 3), and paronychia (2%, grade 3). Available PFS, DOR, and dose optimization results will be presented. Conclusions: Silevertinib demonstrated antitumor activity at 200 mg orally once daily in patients with recurrent NSCLC, EGFR NCMs, and acquired resistance C797S mutation with a safety profile consistent with the EGFR TKI class. Clinical trial information: NCT05256290 . Cohort Dose n ORR (%, 95% CI) Median duration of treatment, mo (range) NCM Cohort 200 mg 30 16.7% (5.6–34.7) 4.99 (0.99-11.47) PACC mutations 200 mg 23 21.7% (7.5–43.7) 4.86 (1.28-11.47) C797S Cohort 200 mg 33 36.4% (20.4–54.9) 4.76 (0.46-12.55)

Nationwide oncologist survey on biomarker integration and evidence-based gastric/GEJ cancer care: Practice patterns and barriers.

e16059 Background: Biomarker (BM) testing is crucial for guiding first-line systemic therapy in advanced/metastatic gastric and gastroesophageal (advanced G/GEJ) cancer. However, the integration of new and established BMs presents evolving challenges for oncology care teams. This nationwide survey assessed oncologists’ current practices, confidence, and identified barriers related to BM testing and management in advanced G/GEJ cancer. Methods: In 2025, a nationwide survey was conducted among 150 oncologists (oncs) in the US. The survey assessed attitudes, practice patterns, and challenges regarding BM testing and BM-directed therapies for patients with advanced G/GEJ cancers. Results: While guidelines recommend BM testing for all patients with advanced G/GEJ cancers, oncs reported an average of 68% (median: 80%, range: 0%-100%) of their advanced G/GEJ cancer patients receive BM testing. Most oncs reported routinely utilizing PD-L1 (95%) and HER2 (75%) to inform first-line treatment selection in advanced G/GEJ cancers; however, less than half routinely tested for CLDN18.2 (48%), NTRK (47%), BRAFV600E (33%), and microsatellite instability or mismatch repair (MSI/MMR) (27%). Interestingly, subgroup analysis showed differences by practice setting: 26% (32/122) of community oncs vs 44% (12/27) of academic oncs reported routinely incorporating MSI/MMR results into treatment selection. Top challenges in integrating BM testing into treatment selection included difficulty determining whether to begin treatment prior to receipt of BM testing results (56%) and optimizing specimen collection for testing (48%). Oncs emphasized that standardizing panel for BM testing (47%) and arranging with pathologists to perform reflex testing (43%) would most improve incorporation of BM testing into clinical workflows. Some challenges were reported more often in community vs academic care: community oncs reported uncertainty choosing between available immune checkpoint inhibitors (ICIs; 45% vs 19% of academic oncs); in CLDN18.2 testing and treatment selection, community oncs reported uncertainty about CLDN18.2 testing protocols (43% vs 22% of academic oncs) and difficulty interpreting test results and applying them to treatment selection (39% vs 19% of academic oncs). Across practice settings, educating or communicating results to patients or care teams was a top reported challenge for integrating CLDN18.2 testing and zolbetuximab (51%), as well as PD-L1 testing and ICIs (41%). Conclusions: This nationwide survey of oncs revealed persistent gaps in BM testing and interpretation to guide treatment selection for advanced G/GEJ cancers. Despite clear guidelines for BM testing, suboptimal testing persists. Standardized testing, clearer protocols, and targeted education are critical to optimize evidence-based, BM-driven care in advanced G/GEJ cancer.

Timing of chemotherapy in breast cancer: A meta-analytic evaluation of neoadjuvant versus adjuvant approaches on survival, response, and surgical outcomes.

e12543 Background: Neoadjuvant chemotherapy (NACT) has become increasingly utilized in breast cancer management, offering potential advantages including tumor downstaging and increased breast conserving surgery rates. However, the comparative efficacy of NACT versus adjuvant chemotherapy (ACT) across multiple oncologic outcomes remains an area of active investigation. Following systematic review and meta-analysis evaluates the outcomes comparing NACT versus ACT in breast cancer patients. Methods: A systematic literature search was performed across multiple databases to identify randomized controlled trials, non-randomized controlled trials, retrospective studies, and observational cohorts comparing NACT versus ACT in breast cancer patients.outcomes including overall survival (OS), disease-free survival (DFS), distant recurrence, and locoregional recurrence. Risk ratios (RR) with 95% confidence intervals (CI) were calculated using random effects models. Heterogeneity was assessed using I² statistics. Results: The meta-analysis included data from multiple studies encompassing over 4,000 patients. For OS, pooled analysis of 2,365 patients in the NACT group versus 1,995 in the ACT group demonstrated no significant difference (RR 0.83, 95% CI 0.69–1.01; P = 0.07; I² = 91%). Similarly, DFS analysis (n = 3,301) showed comparable outcomes between groups (RR 1.03, 95% CI 0.93–1.14; P = 0.54; I² = 54%). Neither distant recurrence (RR 1.11, 95% CI 0.78–1.60; P = 0.56; I² = 88%) nor locoregional recurrence (RR 1.18, 95% CI 0.80–1.76; P = 0.41; I² = 76%) differed significantly between NACT and ACT groups. Substantial heterogeneity was observed across outcomes, likely reflecting differences in chemotherapy regimens, patient populations, and study designs. Conclusions: This meta-analysis demonstrates that NACT and ACT provide comparable long-term oncologic outcomes in breast cancer, with no significant differences in OS, DFS, distant recurrence, or locoregional recurrence. These findings support current guideline recommendations that NACT is an appropriate alternative to ACT, particularly when tumor downstaging for breast-conserving surgery is desired. The high heterogeneity observed underscores the need for subgroup analyses by breast cancer subtype and treatment regimen in future studies.

Efficacy and safety of GVAX pancreas vaccine with CRS-207 in pretreated metastatic pancreatic adenocarcinoma: A systematic review and meta-analysis.

e15201 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies, with low survival rates and oftentimes an advanced stage of detection. PDAC often shows limited benefits from conventional chemotherapy and poor response to immune checkpoint inhibitors due to immunosuppressive tumor microenvironments, making new immunotherapies a point of interest. One vaccine-based immunotherapy, the GM-CSF gene-transfected vaccine/ Listeria -based mesothelin-targeting vaccine (GVAX/CRS-207), has emerged as a potential approach to enhance antitumor immunity. Therefore, in this systematic review and meta-analysis, we aimed to evaluate the effectiveness of GVAX/CRS-207 in pretreated metastatic pancreatic adenocarcinoma. Methods: We searched PubMed, Cochrane Central, and Embase for randomized controlled trials (RCTs) involving adult patients with chemotherapy-pretreated metastatic pancreatic adenocarcinoma receiving the GVAX/CRS-207 regimen compared to a control (chemotherapy or placebo). Two reviewers independently performed study selection, data extraction, and risk-of-bias assessment using the Cochrane ROB 2.0 tool. Primary outcomes were overall survival (OS), progression-free survival (PFS), and safety/tolerability. Secondary outcomes included tumor response metrics and immune response. Pooled hazard ratios (HRs), risk ratios (RRs), and 95% confidence intervals (CIs) were calculated using a random-effects model. Results: Three RCTs comprising 396 patients were included. The pooled analysis demonstrated no statistically significant improvement in overall survival for the GVAX/CRS-207 regimen compared to control (HR = 0.75, 95% CI: 0.30–1.92; P = 0.55). Pooled analyses for objective response rate (RR = 0.53, 95% CI: 0.06–4.79; P = 0.57) and disease control rate (RR = 1.48, 95% CI: 0.86–2.52; P = 0.15) also showed no significant benefit. Considerable heterogeneity was observed for survival outcomes (I² = 76–86%). The safety profile was acceptable, with the most common adverse events being low-grade, immune-related reactions such as pyrexia, fatigue, chills, and injection-site pain. Conclusions: In patients with pretreated metastatic pancreatic adenocarcinoma, the GVAX/CRS-207 prime-boost vaccine regimen was tolerable but did not confer a statistically significant improvement in overall survival (HR = 0.75, 95% CI: 0.30–1.92; P = 0.55) compared to control therapy. The available evidence is limited, and the high statistical heterogeneity observed among studies hinders definitive conclusions. Therefore, future research should focus on biomarker-driven patient selection and rational combination strategies to enhance vaccine efficacy.

Subgroup analyses by disease volume and <i>de novo</i> /recurrent mHSPC in the PSMAddition study of [ ¹⁷⁷ Lu]Lu-PSMA-617.

5020 Background: In the phase 3 PSMAddition study (NCT04720157), combining [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) with ADT + ARPI significantly improved rPFS in patients with PSMA+ mHSPC vs ADT + ARPI at rPFS interim analysis (data cut off Jan 13, 2025), with a HR of 0.72 (95% CI 0.58, 0.90; p = 0.002). Methods: Patients had treatment-naive/minimally treated mHSPC diagnosed by CT/MRI/bone scan and ≥1 PSMA+ metastatic lesion on [ 68 Ga]Ga-PSMA-11 PET/CT. Patients were randomized 1:1 to 177 Lu-PSMA-617 (7.4 GBq ± 10% q6w, 6 cycles) + ADT + ARPI ( 177 Lu-PSMA-617 arm) or ADT + ARPI (control arm). The primary endpoint of rPFS (centrally assessed rPD per PCWG3/RECIST v1.1 or death) and selected secondary efficacy, safety, and patient-reported outcomes (PROs) were assessed in subgroups of high/low disease volume (DV) per CHAARTED criteria (locally assessed by CT/MRI/bone scan; prespecified) and de novo /recurrent mHSPC (AJCC stage ≥/&lt;IVb; post hoc ) . Results: Of 572 patients randomized to the 177 Lu-PSMA-617 arm and 572 to the control arm, 68.0% and 68.2% had high DV, and 52.1% and 47.9% had de novo mHSPC. Efficacy and PRO HRs for the 177 Lu-PSMA-617 arm vs control arm were generally similar in the overall population and DV and mHSPC subgroups (rPFS HR 0.72–0.74; time to PSA progression HR 0.29–0.51) (Table). Incidences of AEs, grade ≥3 AEs, serious AEs, and selected safety topics of interest (cytopenias, dry mouth) were similar across subgroups within each treatment arm. Conclusions: In patients with PSMA+ mHSPC, combining 177 Lu-PSMA-617 with ADT + ARPI improved rPFS vs ADT + ARPI across high/low DV and de novo /recurrent mHSPC subgroups. Other efficacy outcomes, PROs, and the safety profile were generally consistent across subgroups. Clinical trial information: NCT04720157 . Efficacy and PROs. HR (95% CI) for 177 Lu-PSMA-617 arm vs control arm OverallN = 1144 High DVn = 779 Low DVn = 365 De novo mHSPCn = 572 Recurrent mHSPCn = 523 rPFS a 0.72 (0.58, 0.90) 0.72 (0.56, 0.92) 0.73 (0.42, 1.27) 0.74 (0.54, 1.01) 0.74 (0.53, 1.04) PFS per investigator b 0.64 (0.51, 0.79) 0.61 (0.48, 0.78) 0.80 (0.46, 1.37) 0.65 (0.48, 0.88) 0.64 (0.46, 0.89) Time to: PSA progression 0.42 (0.30, 0.59) 0.43 (0.31, 0.62) 0.29 (0.08, 1.05) 0.51 (0.32, 0.79) 0.35 (0.21, 0.60) Symptomatic skeletal event 0.89 (0.62, 1.26) 0.93 (0.64, 1.37) 0.67 (0.27, 1.66) 0.97 (0.60, 1.57) 0.82 (0.48, 1.40) mCRPC 0.70 (0.58, 0.84) 0.67 (0.54, 0.82) 0.87 (0.55, 1.37) 0.61 (0.47, 0.80) 0.75 (0.56, 1.00) BPI-SF pain intensity worsening c 1.02 (0.87, 1.18) 0.98 (0.82, 1.18) 1.09 (0.83, 1.44) 1.06 (0.85, 1.31) 0.97 (0.78, 1.22) FACT-P total score worsening c 1.14 (0.98, 1.33) 1.13 (0.94, 1.37) 1.16 (0.88, 1.53) 1.13 (0.90, 1.41) 1.16 (0.92, 1.46) EQ-5D-5L worsening c 1.13 (0.97, 1.31) 1.04 (0.87, 1.25) 1.34 (1.01, 1.77) 1.17 (0.93, 1.45) 1.09 (0.87, 1.37) N may differ across outcomes. a rPD by BIRC or death. b Composite of radiographic, clinical, and PSA progression and death. c Composite with clinical progression and death.

Adjuvant erlotinib versus observation after complete resection of <i>EGFR</i> -mutant NSCLC: Final overall survival results of Alliance A081105.

8001 Background: The ALCHEMIST clinical trial platform, launched by the National Clinical Trials Network (NCTN) in 2014, screened patients with resected non-small cell lung cancer (NSCLC) for molecular markers and tailored post-operative adjuvant therapy trials. A081105 evaluated whether adjuvant erlotinib improved overall survival (OS) following complete resection in patients with early stage EGFR mutated lung adenocarcinoma. Methods: A081105 was a randomized phase III trial enrolling patients with completely resected stage IB (≥4 cm), II, or IIIA non-squamous NSCLC (per the 7 th TNM staging classification) harboring EGFR exon 19 deletion or L858R mutations. Patients were randomized 1:1 to erlotinib 150 mg daily for up to 2 years or placebo/observation, stratified by stage, prior chemotherapy, EGFR mutation subtype, and ECOG performance status. The primary endpoint was OS in the per-protocol (PP) population with centrally confirmed EGFR mutations, designed to detect a hazard ratio (HR) of 0.67 in favor of erlotinib with a power of 86% and one sided type I error rate of 5%. Secondary endpoints included OS and disease free survival (DFS) in a modified intent-to-treat (mITT) population with local or centrally confirmed EGFR mutations, and safety. A prespecified backstop analysis was conducted after a minimum of 5 years of follow-up on all patients. Results: Trial enrollment was discontinued when 390 of the intended 450 patients had been enrolled due to the proven benefit of adjuvant osimertinib. Among 390 enrolled patients, the arms were balanced for age (median: 67.0 years), sex (70% female), race (70% white), stage (II: 51%, IIIA: 37%), prior chemotherapy (82%), ECOG PS 0 (60%), and exon 19 deletion (57%). Adjuvant erlotinib did not significantly improve OS compared with placebo/observation in the overall PP population (364 patients, 108 events, HR 0.89; 95% CI, 0.59–1.34; 1-sided P = 0.29) or within exon 19 deletion (HR: 0.94) or L858R mutation (HR: 0.82) subgroups. Five-year OS rates were 78.6% versus 77.9%, respectively. Results were consistent in the mITT analysis (379 patients, 113 events, HR 0.86; 95% CI, 0.58–1.28). Erlotinib improved DFS (mITT: 181 events, median: 68 vs 50 months, HR 0.74; 95% CI, 0.55–1.01). Across both arms, 11% of patients started non-protocol treatment (Osimertinib: 9%) prior to disease progression, and 9% withdrew consent for all follow-up prior to recurrence. In the erlotinib arm, 3 deaths on study were reported; grade 3 or higher adverse events were reported on 39% of patients. Median duration of treatment on Erlotinib arm was 16 months; only 37% of patients completed the planned treatment. Conclusions: In resected EGFR -mutant NSCLC, adjuvant erlotinib did not improve overall survival but improved DFS. Additional studies are exploring efficacy in selected subsets of patients using genomics and proteomic analyses. Clinical trial information: NCT02193282 .

Convergence of molecular biology and nanobiotechnology: Advances in precision therapeutics and next-generation diagnostics

Simultaneous Passive Water and Electricity Generation in Arid Regions via Fe ³⁺ /Li ⁺ Cross‐Linked Hygroscopic Hydrogels

ABSTRACT Humans are confronting global water scarcity and energy shortages in data centers, and utilizing moisture from the air to address both water and electricity issues is a promising direction. Here, a porous hygroscopic hydrogel is integrated, which is composed of sodium alginate that is co‐loaded with Fe 3+ and Li + . Hydrophilic adsorption sites are constructed via ionic cross‐linking and salt loading, enabling low desorption enthalpy (&lt;40 kJ mol − 1 ) for efficient water desorption. The water uptake of the dual‐ionic hydrogel is over 5.1 g g −1 at 90% RH, and this value is 1.1 g g −1 at 30% RH. By designing a water harvesting device with rotating adsorption/desorption zones, with a daily production of 11.8 L kg hydrogel −1 at 70% RH. The hydrogel not only provides abundant sites for moisture adsorption and storage but also offers channels for ion transport to enhance electricity generation. By constructing an asymmetric humidity structure, the dissociated cations in the hydrogel will diffusion to the substrate by concentration gradient and the electricity is evocated, producing a highly short‐circuit current (250 µA) and open‐circuit voltage (7.6 V), illuminating the multi‐LED lights.

An Ion Pump Enhanced High‐Current‐Density Moisture‐electric Yarn

ABSTRACT Moisture‐electric generators (MEGs) offer a promising route for clean energy harvesting. However, most existing MEGs suffer from low current densities due to limited ion concentration and migration rates, while often lack of capability for direct integration of wearable systems. Here, a moisture‐electric yarn (MEY) featuring high current density and continuous power generation is designed. An ion pump strategy is introduced to facilitate the establishment of ion concentration gradients and enhance ion migration rates, enhancing electrical output. The MEY continuously generates ∼1 V and a high current density of 5.7 mA cm −3 at 25 °C and 60% RH, outperforming most reported MEGs. A scalable continuous fabrication process enables single‐batch production of hundreds of meters of yarn. Owing to its yarn structure, the output current increases with length, reaching 4.3 mA for a 1 m yarn (∼0.1 g). Harvesting atmospheric and body moisture, a 2 m MEY can sustainably power LED strips. This lightweight and sewable yarn provides a safe and eco‐friendly auxiliary power source for wearable electronics and real‐time positioning applications.

Trends in mortality from malignant neoplasms and Alzheimer's dementia in adults aged 55 and older in the United States: A retrospective analysis from 1999 to 2020.

e22603 Background: There are a large number of studies in literature that have described an inverse association between Alzheimer's dementia and cancer. Multiple biological mechanisms have been theorized to explain this association as well. Despite the reported inverse association, the two conditions tend to coexist. The main purpose of our study was to assess the mortality trends among adults aged 55 and older with concomitant diagnosis of both Alzheimer's dementia and malignant neoplasms. Methods: The CDC WONDER database was utilized to extract mortality data using ICD-10 codes. The age-adjusted mortality rates (AAMR/100,000) for the population were extracted, and trends were analyzed for age, gender, race, and year. Results: There was a total of 124447 deaths from malignant neoplasms and Alzheimer's disease from 1999 to 2020 in patients older than 55 years of age. Gender analysis of this cohort showed that both genders have shown an overall gradual decline in AAMR over the course of years. Males have a consistently higher AAMR as compared to females. In fact mean AAMR in males is 7.78 (range: 7.26–8.30; SD: 1.13), and mean AAMR in females is 7.03 (range: 6.64–7.42; SD: 0.83). And the difference in mean AAMR is statistically significant (7.78 vs. 7.03 per 100,000, p &lt; 0.05). Race analysis showed that AAMR from malignant neoplasms and Alzheimer's disease in Asians is significantly and persistently less as compared to Whites and African Americans. The mean AAMR for Asians is 3.9 (range: 3.5–4.3; SD: 1.1) as compared to Whites 8.2 (range: 7.7–8.7; SD: 1.3) and African Americans 8.6 (range: 8.1–9.1; SD: 1.4). Conclusions: The mortality from malignant neoplasms alone has shown upward trends in both genders. Similarly, mortality trends from Alzheimer's disease has also shown an upward trend over the course of years. But our study shows a decreasing mortality trend from both conditions combined. These findings to a certain extent support the hypothesis that these two "beasts" (Alzheimer's and malignant neoplasm) tend not to coexist. The decreasing trend in mortality is noted in both genders and all races. Among all races, Asians have the lowest AAMR. It can be explained by decreased incidence of both Alzheimer's dementia and malignant neoplasms in Asian population. Mean AAMR from Alzheimer's disease and malignant neoplasms. Sex Mean Rate (per 100,000) SD 95% CI (Lower–Upper) Male 7.78 1.13 7.26 – 8.30 Female 7.03 0.83 6.64 – 7.42

Individualized radiosensitivity-guided radiation therapy for cervical cancer.

e17526 Background: Concurrent chemoradiotherapy combined with image-guided brachytherapy is the standard for locally advanced cervical cancer, yet failures persist due to heterogeneous radioresistant sub-volumes. While Dose Painting by Numbers (DPbN) enables voxel-level modulation, current strategies relying on static baseline metrics often ignore temporal biological evolution. Since longitudinal 18F-FDG changes better reflect intrinsic radiosensitivity, we propose a voxel-level Biologically-guided Adaptive Radiotherapy (BgART) framework using sequential PET/CT to quantify early metabolic response and guide patient-specific dose prescriptions. Methods: We retrospectively analyzed 18 cervical cancer patients treated with radical intensity-modulated radiation therapy (IMRT). Sequential 18F -FDG PET/CT scans were acquired at baseline (SUV0) and mid-treatment (after 12–15 fractions). Using in-house software and deformable image registration, we extracted voxel-level metabolic changes to construct a Dose Response Matrix (DRM). The DRM quantifies intrinsic radiosensitivity by mapping the rate of SUV change to the in vitro surviving fraction index (SF2). In the feature space of (SUV0, DRM), a boundary curve distinguishing controlled from uncontrolled voxels was fitted using clinical outcome data. Subsequently, voxels were stratified by SUV0 and DRM, and a dose-Tumor Voxel Control Probability (TVCP) model was established using maximum likelihood estimation. Finally, a voxel-wise prescription function was inversely derived to calculate the minimum dose required for each voxel to achieve a target control probability, thereby generating individualized dose distribution maps for adaptive planning. Results: Model-predicted Tumor Control Probability (TCP) showed high concordance with 3-month clinical outcomes (AUC=0.86). Under a uniform reference dose of 56 Gy, predicted TCP varied substantially (range: 0.27–0.89). To attain 95% TCP, calculated voxel-specific minimum doses ranged from 86.3 to 100.4 Gy, aligning closely with typical cumulative clinical doses (external beam plus brachytherapy). Consequently, the tumor voxel fraction controlled by standard prescriptions varied widely (41%–94%). The resulting voxel-based dose maps accurately identified radioresistant "hotspots," offering essential guidance for personalized adaptive strategies. Conclusions: This study validates a voxel-level BgART framework that effectively translates early metabolic response into actionable dose prescriptions. By targeting intrinsic radioresistance identified via longitudinal PET/CT, this approach offers a promising strategy to individualize treatment and potentially improve local control in locally advanced cervical cancer.

Spatial organization of immune surveillance by germline mutation status in the Breast Cancer Family Registry.

10566 Background: Germline pathogenic variants (gPVs) are associated with increased immune infiltration in resulting tumors; we previously reported increased CD4+ and CD8+ T-cells in gPV-associated tumors using single-cell spatial profiling. Here, we report the spatial features, including cell-cell co-localization, underlying these immune differences. Methods: We analyzed CosMx 6K single-molecule RNA transcriptomics in 222 samples from 144 women in the population-based Northern California Breast Cancer Family Registry. Across 1,083,345 cells and 6,583 genes, multicellular niches were identified by clustering cells based on spatial proximity and cell-type identity using a k-nearest neighbors approach, with the number of niches selected by elbow analysis. Niche proportions were compared between gPV-associated and wild-type tumors using linear models. Linear mixed-effects models were used to identify niche-specific enrichment of cell-type densities and pairwise cell–cell colocalization relative to all other niches. P-values were corrected using Benjamini–Hochberg. Results: Of 144 participants, 31 (22%) carried at least one gPV, including BRCA1 (n = 12), BRCA2 (n = 8), PALB2 (n = 3), FANCM (n = 3), ATM (n = 2), and CHEK2, RAD50, and TP53 (n = 1 each). We identified eight cell niches, two of which were enriched in gPV-associated tumors, including within ER/HER2 subtypes: niche 2 (10% of cells in gPV tumors vs 3.7% in non-gPV tumors; Wilcoxon FDR = 0.01) and niche 5 (17% vs 9.4%; FDR = 0.03). Niche 2 and niche 5 proportions were uncorrelated across tumors (r = −0.13, FDR = 0.14). Compared with other niches, niche 2 had higher proportions of immature B cells (FDR = 0.006), CD8⁺ T cells (FDR = 0.03), dendritic cells (FDR &lt; 0.001), and macrophages (FDR &lt; 0.001), with no specific cell-cell colocalization pattern. Niche 5 had higher proportions of CD4⁺ T cells (FDR &lt; 0.001), myoepithelial cells (FDR &lt; 0.001), and macrophage-derived stem cells (FDR &lt; 0.001); niche 5 demonstrated increased colocalization across 95 cell-type pairs at FDR &lt; 0.1, including cancer cells with macrophage-derived stem cells and pericytes with natural killer cells (FDR = 0.01 each). Comparing BRCA1 to BRCA2 gPV carriers, niche 2 was more prevalent in BRCA1 tumors (16% vs &lt; 1% in BRCA2; p = 0.01); no significant difference was observed for niche 5. Conclusions: In this population-based cohort, gPV-associated breast cancers exhibited distinct spatial immune niches. Niche 2, especially enriched in BRCA1 gPV tumors, appears to reflect an inflamed immune environment, whereas niche 5 may represent a more spatially organized stromal-adaptive immune niche characterized by CD4⁺ T-cell enrichment and extensive non-random cell-cell interactions. These findings demonstrate that inherited cancer risk is associated with reproducible immune spatial architectures, with implications for immune-based prevention and interception strategies.

Five-year survival disparities in two population-based cohorts of adults with early-onset colorectal cancer.

11155 Background: Early-onset colorectal cancer (EO-CRC) is now the leading cause of cancer-related death in those under the age of 50 despite advances in treatment. However, the impact of specific sociodemographic and clinical factors on long-term survival remains poorly characterized. We evaluated 5-year survival patterns and risk factors across two diverse, population-based cohorts to optimize risk reduction strategies and survivorship care delivery. Methods: We constructed two cohorts of adults &lt; 50 years of age with newly diagnosed EO-CRC from 2015 to 2018 (stages I-III) and treated with curative-intent surgery. One cohort was derived from three SEER registries (Georgia, Los Angeles County, Kentucky; n = 2995) and one cohort was derived from the Veteran’s Health Administration (VHA) (n = 295). Pathologic-confirmed recurrence was identified in the follow-up period 6 months to five years after curative-intent surgery via human review of electronic pathology reports. Five-year survival was estimated from the date of curative-intent surgery to five years post-surgery. Adjusted risk of CRC-specific mortality was estimated in both populations using multivariable proportional hazards regression, adjusting for key demographic and clinical characteristics. Results: The proportion of patients surviving 5 years was 86% in the SEER cohort and 92% in the VHA cohort. Overall, 14% experienced recurrence in SEER and 18% in VHA, and recurrence was strongly associated with reduced survival in both cohorts (both p &lt; 0.01). Five-year survival varied by clinical stage and was higher in the VHA across all stages (SEER: 93% stage I, 87% stage II, and 76% stage III vs. VHA: 97% stage I, 93% stage II, and 88% stage III). Mortality risk varied by race/ethnicity in the SEER cohort only: Hispanic patients (adjusted HR 1.6, 95% CI: 1.1–2.2) and Black patients (adjusted HR 1.9, 95% CI: 1.5–2.5) had a greater risk of 5-year mortality vs. white patients. Age at diagnosis, sex, and living in a rural area were not significantly associated with mortality in either cohort. Rectal tumors (vs. colon) were associated with an increased risk of mortality in VHA (adjusted HR: 2.5, 95% CI: 1.0-6.4), but not in SEER. Lymphovascular invasion was associated with an increased risk of mortality in both cohorts. Conclusions: There are critical sociodemographic and clinical disparities in survival among adults with stage I-III EO-CRC. These distinct patterns observed between the two cohorts underscore the influence of varying population-level risk profiles. Tailoring survivorship care to identify and support these high-risk subgroups is essential to mitigate disparities and improve long-term outcomes in this growing patient population.