TP53 mutations are among the most frequent alterations in biliary tract cancer (BTC), but their prognostic relevance and predictive value for immune checkpoint inhibitors (ICI) remain unclear. We assessed clinico-molecular features, prognosis, and ICI efficacy by TP53 status in advanced BTC. Patients with advanced BTC from Japan and the United States who underwent tissue- or plasma-based next-generation sequencing were retrospectively analyzed. Tissue-based sequencing was used for the primary analysis, and plasma ctDNA sequencing was evaluated as an exploratory cohort. Outcomes were compared between TP53 wild-type (WT) and TP53-mutated groups. Treatment–TP53 interactions for non-ICI versus ICI-containing regimens were assessed using multivariable Cox models. Whole-transcriptome sequencing data were analyzed using TIDE and Hallmark gene set enrichment analysis. Among 336 patients in the tissue-based cohort, 177 (52.7

4105 Background: Addition of PD-(L)1 inhibitors to CTx has transformed advanced BTC treatment but survival is limited for most patients (pts). R is a monovalent, Fc-reduced PD-1xTIGIT bispecific antibody that delivers coordinated and synchronous PD-1 and TIGIT blockade on immune effector cells. The primary analysis of substudy 2 Cohort A of GEMINI-Hepatobiliary (NCT05775159), a global phase 2 study evaluating R + CTx in pts with advanced BTC, demonstrated promising efficacy and a manageable safety profile. We report updated analyses after ≥18 months of follow-up for the last enrolled pt. Methods: Pts ≥18 years with previously untreated unresectable/metastatic BTC and ECOG PS 0/1 received intravenous R every 3 weeks (Q3W; ≤2 years) + gemcitabine 1000 mg/m 2 + cisplatin 25 mg/m 2 on days 1 and 8 Q3W (≤8 cycles). Coprimary endpoints were 6-month progression-free survival (PFS) and safety/tolerability. Secondary endpoints included median PFS, objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and overall survival (OS). Response and progression were investigator-assessed per RECIST v1.1. Results: As of Oct 24, 2025, the median follow-up for OS was 16.2 months (IQR 10.4–21.5); 6 pts (20.0%) received ≥20 cycles of R. Median OS was 16.8 months (95% confidence interval [CI] 11.0–not calculable [NC]) overall; 18-month OS was 44.8% (95% CI 26.5–61.6). Median OS was > 13 months across all subgroups based on age ( < 65/≥65 years), ECOG PS (0/1), geography, initially unresectable/recurrent disease at enrollment, and primary tumor location (gallbladder or bile duct). Two unconfirmed responses were identified after > 85 weeks follow-up: one complete and one partial response. The safety profile was consistent with the primary analysis. The most common treatment-related adverse events (AEs) were anemia (53.3%), neutrophil count decreased (50.0%), and platelet count decreased (43.3%). Detailed efficacy and safety data are in the Table. Conclusions: R + CTx demonstrated promising efficacy and a manageable safety profile. This study and phase 3 studies of R in BTC (ARTEMIDE-Biliary01, ARTEMIDE-Biliary02, DESTINY-BTC01) are ongoing. Clinical trial information: NCT05775159 . N=30* PFS Events, n (%) 6-month, % (95% CI) 12-month, % (95% CI) Median (95% CI), months 25 (83.3)73.0 (53.2–85.5)25.6 (11.4–42.6)8.2 (6.7–11.1) Confirmed ORR, % (95% CI) 31.0 (15.3–50.8) Best objective response, n (%) Partial response Stable disease Progressive disease 9 (31.0)18 (62.1)2 (6.9) DCR, % (95% CI) 93.1 (77.2–99.2) DoR, median (95% CI), months 6.9 (2.8–NC) OS Events, n (%) 12-month, % (95% CI) 18-month, % (95% CI) Median (95% CI), months 19 (63.3)65.5 (45.4–79.7)44.8 (26.5–61.6)16.8 (11.0–NC) Any / R-related AEs, n (%) Grade ≥3 Serious Led to R discontinuation Led to death 30 (100) / 22 (73.3)27 (90.0) / 5 (16.7)14 (46.7) / 3 (10.0)2 (6.7) / 1 (3.3) † 2 (6.7) / 0 * N=29 for responses. † Hepatic function abnormal.

760 Background: The modified Glasgow Prognostic Score (mGPS), which combines serum levels of C-reactive protein and albumin, has been reported as a prognostic predictor in several malignancies. In this exploratory analysis of JCOG1611, a randomized phase II/III trial comparing gemcitabine plus nab-paclitaxel (GnP), modified 5-fluorouracil, levofolinate, irinotecan, and oxaliplatin (mFFX), and S-1, irinotecan, and oxaliplatin (S-IROX), we evaluated whether mGPS can predict prognosis of patients with metastatic pancreatic cancer. Methods: All patients eligible for JCOG1611 (n = 527) were included in this analysis. Patients were categorized into two groups according to their mGPS score: mGPS 0 and mGPS 1-2. The association between mGPS and overall survival (OS) was evaluated using multivariable Cox regression analysis. Results: The numbers of patients with mGPS 0 and mGPS 1-2 were 128 and 48 in the GnP arm, 129 and 46 in the mFFX arm, and 130 and 46 in the S-IROX arm, respectively. The median OS for mGPS 0 vs. 1-2 was 16.9 vs. 11.2, 14.3 vs. 9.5, and 14.7 vs. 10.6 months in the GnP, mFFX, and S-IROX arms, respectively. The adjusted hazard ratios (HRs) of OS were 1.359 (95% confidence interval [CI]:0.920–2.009) in the GnP arm, 1.289 (95% CI: 0.878–1.892) in the mFFX arm, and 1.612 (95% CI: 1.094–2.374) in the S-IROX arm, respectively. The median progression-free survival (PFS) for mGPS 0 vs. 1-2 was 7.0 vs. 5.6, 6.9 vs. 4.4, and 6.8 vs. 4.5 months in the GnP, mFFX, and S-IROX arms, respectively. The adjusted HRs of PFS were 1.160 (95% CI:0.812–1.657) in the GnP arm, 1.246 (95% CI: 0.866–1.793) in the mFFX arm, and 1.500 (95% CI: 1.033–2.177) in the S-IROX arm, respectively. Conclusions: mGPS showed a trend toward prognostic significance in patients with metastatic pancreatic cancer treated with GnP or mFFX, and suggested potential prognostic relevance in those treated with S-IROX.

Abstract Background & Objectives Patients with advanced biliary tract cancers (BTC) do not have adequate second-line therapy options. Nanvuranlat, a selective inhibitor of L-type amino acid transporter 1 (LATI; SLC7A5), improved progression-free survival in a Phase 2 study in heavily-pretreated patients with drug-refractory BTC. This Phase 3 study will evaluate the efficacy and safety of nanvuranlat for previously treated patients with advanced BTC. Method This is a Phase 3, multicenter, randomized, open-label study to evaluate the efficacy and safety of nanvuranlat versus physicians' best choice (PBC) of standard-of-care regimens in patients with advanced BTC who have received one prior BTC therapy. In Part A, 120 patients will be randomized 1:1:1:1 to receive 1 of3 nanvuranlat intravenous infusion regimens (50 or 75 mg via 90-minute infusion once daily for 5 days followed by 9 treatment-free days, or 375 mg via 46-hour continuous infusion once every 14 days) or PBC. Efficacy, safety, and pharmacokinetic data obtained from Part A will be used to select the optimal nanvuranlat regimen for Part B. In Part B, 360 patients will be randomized 1:1 to receive nanvuranlat or PBC. The primary outcome is overall survival, and key secondary outcomes include progression-free survival, objective response rate, and safety measures. Results This study is in progress and results are not yet available. Conclusion This study will provide robust evaluation of the effectiveness and safety of nanvuranlat compared with standard-of-care therapy for patients with advanced BTC in the second-line treatment setting. This study is underway and patient recruitment was initiated on 19 January 2026.

Many real-world patients with advanced biliary tract cancer (BTC) are excluded by TOPAZ-1 criteria; this study assessed cisplatin and gemcitabine plus durvalumab (CGD) efficacy and safety in these patients. Data from 1358 patients with advanced BTC treated with first-line CGD across 55 international centers were retrospectively analyzed. Patients were classified as TOPAZ-1-in (meeting all inclusion criteria) or TOPAZ-1-out (meeting ≥ 1 exclusion criterion). Primary endpoints were overall survival (OS) and progression-free survival (PFS); secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. Furthermore, OS and PFS of the TOPAZ-1-out cohort were compared with reconstructed survival data from the phase III trial. 912 (67.1%) patients were classified as TOPAZ-1-in, and 446 (32.9%) as TOPAZ-1-out. After a median follow-up of 14.5 months (95% CI: 13.7-36.5), OS was 16.1 months in TOPAZ-1-in and 12.5 months in TOPAZ-1-out (HR 0.69, 95% CI: 14.6-16.5, p = 0.0001); PFS was 8.2 versus 6.5 months (HR 0.73, 95% CI: 7.1-8.1, p < 0.0001). Median OS in the TOPAZ-1-out cohort (12.5 months) was nearly identical to the phase III trial experimental arm (12.9 months; HR 1.15, p = 0.13); for PFS the HR was 1.12 (95% CI 0.93-1.42; p = 0.09). Among TOPAZ-1-out patients, active infection, elevated bilirubin, and ECOG PS > 1 were linked to poorer OS, while no detrimental impact emerged for ALT/AST abnormalities, corticosteroid use, renal or hematologic parameters, or prior surgery within 6 months, suggesting treatment effectiveness was broadly maintained across clinical subgroups. Furthermore, TOPAZ-1-out patients experienced no significant increase in adverse events compared with the TOPAZ-1-in group. Real-world data suggest CGD may be effective in TOPAZ-1-out patients, with no evident increase in toxicity, supporting the potential expanded use of the regimen in clinical practice.

Background: Biliary tract cancers (BTC) are aggressive malignancies with limited treatment options. Homologous recombination deficiency (HRD) may confer increased immunogenicity and potentially augment responsiveness to immune checkpoint inhibitor-based chemoimmunotherapy (CIO), but its predictive value for immunotherapy benefit in BTC remains poorly characterized.Methods: This multicenter retrospective study included 998 patients with advanced BTC treated between 2012 and 2024. HRD status was determined via genomic sequencing of tumor tissue or circulating tumor DNA. Patients were stratified by HRD status and first-line treatment ( Chemotherapy (CT) alone vs. CIO). Primary endpoints were progression-free survival (PFS) and overall survival (OS) analyzed by Kaplan-Meier estimates while predictors were assessed through univariate and multivariate Cox regression.Results: Of 998 patients, 179 (17.9%) were HRD-positive, of whom 15.1% received CIO. The most commonly HRR alterations were ATM (38.5%), BRCA2 (23.5%) and BRCA1 (16.2%). ORR was higher with CIO vs. CT in both HRD- (35.2% vs. 22.5%; p=0.008) and HRD+ patients (51.9% vs. 25.8%; p=0.01), but this did not translate into survival benefit. In HRD+ patients, CIO was associated with worse OS than CT (13.4 vs. 22.5 months; HR 2.07, 95% CI 1.22–3.54; p=0.006). Among BRCA1/2-mutant patients, CT alone yielded better OS than CIO (33.6 vs. 24.8 months; HR 2.90; p=0.045). Multivariable analysis revealed HRD status did not independently predict OS while CIO use (HR 1.58, 95% CI 1.07–2.32; p=0.020) was associated with decreased OS.Conclusions: Adding immunotherapy to chemotherapy did not improve survival in HRD+ BTC patients. These findings are hypothesis-generating and raise the possibility that HRD+ status is associated with a lack of added benefit from IO to CT, underscoring the need for prospective biomarker-driven trials to refine treatment strategies in BTC.

BACKGROUND AND OBJECTIVES:Postoperative early recurrence (ER) of biliary tract cancers (BTCs) leads to significant medical, psychological, social, and economic disadvantages for patients. Approximately 30% of patients with curatively resected BTCs experience recurrence within the first 12 months after the surgery. JCOG1202 randomized phase III trial demonstrated the survival benefit of adjuvant S-1 in patients with resected BTCs. The objective of this exploratory study was to investigate the risk factors for ER in patients with resected BTCs in the JCOG1202 cohort. METHODS:Of the 440 patients enrolled in JCOG1202, 217 who underwent observation and 207 who received adjuvant S-1 were eligible in this analysis. ER was defined as recurrence or death within 12 months after enrollment. RESULTS:ER was observed in 59 and 38 patients in observation and adjuvant S-1, respectively. Multivariable logistic regression analysis identified CA19-9 levels > 37 U/ml (odds ratio (OR): 2.79, 95% confidence interval (CI): 1.26-6.17), poorly differentiation (vs. well-differentiated/papillary) (OR: 4.75, 95% CI: 1.93-11.69), moderate differentiation (vs. well-differentiated/papillary) (OR: 1.96, 95% CI: 1.07-3.57), lymph node metastases ≥ 4 (vs. 0) (OR: 3.99, 95% CI: 1.67-9.51), lymph node metastases 1-3 (vs. 0) (OR: 2.66, 95% CI: 1.47-4.81), and R1 resection (OR: 2.17, 95% CI: 1.07-4.41) as independent risk factors for ER. Adjuvant S-1 chemotherapy significantly reduced ER (OR: 0.49, 95% CI: 0.29-0.83). CONCLUSIONS:Postoperative CA19-9 levels, tumor differentiation, lymph node metastases, residual tumors, and adjuvant S-1 significantly affected ER in patients with curatively resected BTCs. Patients at high ER risk may require more intensive adjuvant therapy. TRIAL REGISTRATION:UMIN000011688.

679 Background: DNA-damaging agents improve outcomes in metastatic pancreatic cancer (mPC) with homologous recombination repair (HRR) deficiency, albeit use is limited to 6-9% of patients (pts) with BRCA1/2 or PALB2 mutations. We hypothesized that BRCA/PALB2 wildtype mPC may exhibit platinum sensitivity driven by altered HRR gene expression. We correlated HRR gene RNA profiles with real-world overall survival (rwOS) following first-line (1L) platinum therapy (PT). Methods: Tempus Lens, a platform used to query multimodal data from millions of de-identified patient records in the Tempus Database was used to identify mPC pts with wildtype somatic BRCA1/2 and PALB2 who had Tempus xT DNA and xR RNA testing. RNA-seq data were normalized to correct for assay/batch effects, quantified as transcripts per million (TPM) and reported as log2(TPM+1) for 17 HRR genes and GATA6 . Pts were classified as high and low expressors based on the top and bottom quartile gene expression. Pts were grouped as PT-treated (received 1L PT) or PT-naïve (never received PT). Real world overall survival (rwOS) was calculated from 1L start to death or loss to follow up. Risk set adjustment was applied to mitigate immortal time bias. Median rwOS was estimated using Kaplan-Meier and univariate Cox models. A multivariate Cox Proportional (CoxPh) model included PT use, RAS status, and expression of genes (as continuous variables). Results: Among 1,068 pts, the median age was 66 years and 609 (57%) received 1L PT. In low RAD51 expressors, PT-treated pts (n=136) had significantly longer rwOS than PT-naïve (n=112): 11.4 months (95% CI, 7.8–13.8) vs 8 months (95% CI, 5.5–9.0); p=0.028. In contrast, in high RAD51 expressors, rwOS was similar between PT-treated (n=150) and PT-naïve (n=97): 7.9 vs 6.9 months (p=0.236). High GATA6 expression was also associated with improved rwOS in PT-treated pts vs PT-naïve: 13.5 vs. 9.3 months; p=0.011. In multivariate analysis, increased GATA6 expression remained a positive predictor of rwOS (HR 0.82; 95% CI, 0.76–0.88; p<0.001), and high RAD51 expression was associated with shorter rwOS with PT (HR 1.18; 95% CI, 1.01–1.39; p=0.043). Conclusions: In BRCA/PALB2 wt mPC, transcriptomic profiling identified low RAD51 and high GATA6 expression as predictors for improved rwOS when treated with PT. Integrating these biomarkers may improve development of DNA-damaging therapies beyond canonically defined HRD. Hazard ratios of mPC mortality by selected HRR genes estimated by multivariate CoxPh models. HR 95% CI p value 1L PT (vs PT-naïve) 0.87 0.75, 1.00 0.054 BRCA1 1.15 0.98, 1.35 0.079 BRCA2 0.89 0.77, 1.04 0.14 GATA6 0.82 0.76, 0.88 <0.001 NBN 0.97 0.81, 1.15 0.7 RAD51 1.18 1.01, 1.39 0.043 RECQL4 0.94 0.84, 1.04 0.2 Any RAS mutation 1.43 1.14, 1.81 0.002

684 Background: Circulating tumor DNA (ctDNA) analysis has proven to be a highly accurate method for assessing treatment efficacy and detecting molecular residual disease (MRD) in cancer patients, outperforming tumor markers and imaging modalities. However, the ctDNA detection rate is reported to be low, and its utility remains unclear in pancreatic cancer (PC). We conducted the prospective “ARTEMIS-PC” study to evaluate the utility of a personalized, tumor-informed MRD assay in patients with unresectable PC. Methods: Eligible patients had histopathologically confirmed unresectable PC, were previously untreated, and had disease measurable per Response Evaluation Criteria in Solid Tumors v1.1. A patient-specific tumor-informed assay (Invitae Personalized Cancer Monitoring) was used for the detection of ctDNA. Blood samples were collected at structured pre- and post-systemic therapy timepoints. Results: A total of 99 patients were eligible for the ARTEMIS-PC study, and personalized panels were successfully created for 92 patients. The median age of patients was 70 years (range 45-81 years), with 43/92 being female. Thirty patients were stage III, and 62 stage IV. Median size of the primary tumor was 38 mm (range 13-100 mm). MRD positivity at enrollment was 88.0%, with 73.3% in stage III patients, and 95.2% in stage Ⅳ (p=0.007). During follow-up, ctDNA clearance was achieved in 33 patients (40.7%). ctDNA clearance was associated with a significantly higher objective response rate (61.5% vs. 17.6%, p=0.001) and disease control rate (100% vs. 64.7%, p=0.002) compared to those who did not achieve clearance. Patients who achieved ctDNA clearance had significantly longer progression-free survival (PFS) than those who did not (9.0 vs. 3.5 months, hazard ratio 0.2, p<0.001). The predictive performance of select biomarkers (variant allele frequency [VAF], CEA, CA19-9) was evaluated using area under the curve (AUC) for treatment response and disease control. For disease control, VAF showed superior predictive performance with AUCs of 0.84 at enrollment and 0.97 at both Week 4 and Week 8, compared to CEA (AUCs: 0.65, 0.73, 0.60) and CA19-9 (AUCs: 0.51, 0.57, 0.56). The predictive performance for treatment response was lower than AUC 0.75 for any of the biomarkers. Among patients who were MRD negative before treatment or became negative during follow-up (n=44), 45.5% (n=20) subsequently turned MRD positive. Of these, disease progression was confirmed by CT in 14 patients. The median time from MRD turning positive to CT-confirmed progressive disease was 88.5 days (range: -28 to 385 days). Conclusions: ctDNA clearance is a useful predictor of improved objective response, disease control, and PFS, with VAF emerging as the more accurate biomarker for disease control, underscoring its potential utility in treatment monitoring in patients with unresectable PC. Clinical trial information: UMIN000043561 .

Chimeric antigen receptor (CAR) T-cell therapies have shown limited promise in solid tumors owing to the immunosuppressive tumor microenvironment. TAK-102 is a next-generation, glypican-3 (GPC3)-targeted CAR T-cell therapy engineered to co-express interleukin-7 (IL-7) and chemokine ligand 19 (CCL19), enhancing T-cell survival and trafficking. In this first-in-human, open-label, phase 1, dose-escalation study (ClinicalTrials.gov: NCT04405778), we evaluated a single TAK-102 infusion in 11 patients with GPC3+ advanced solid tumors refractory or intolerant to standard therapies. Patients received TAK-102 at one of three dose levels following leukapheresis and lymphodepletion chemotherapy. The primary endpoints were the incidences of dose-limiting toxicities, treatment-emergent adverse events, and adverse events of special interest. No dose-limiting toxicities were observed. The most common treatment-emergent adverse events were hematologic, including neutropenia and leukopenia (81.8%), and cytokine release syndrome (54.5%), all grade 1-2. No objective responses were observed; however, five patients achieved stable disease (disease control rate, 45.5%). One patient had a 26.1% reduction in tumor size lasting 9 months, accompanied by a 51.6% decline in serum alpha-fetoprotein. Cellular kinetics showed dose-dependent expansion, with the highest exposure at 5 × 10⁸ CAR+ cells/body. Post-treatment biopsies revealed increased CD8+ T-cell infiltration and activation markers, although CAR+ cells were undetectable in tumor tissue. Serum CCL19 levels increased with dose, suggesting immune priming. These findings support a manageable safety profile for TAK-102 and provide early evidence of biological activity in solid tumors. Further studies are warranted to optimize dosing, improve CAR T-cell persistence, and evaluate efficacy in larger patient cohorts.

Introduction:Atezolizumab plus bevacizumab combination therapy (atezo + bev) has been successfully developed as a standard of care for patients with unresectable hepatocellular carcinoma (HCC) and Child-Pugh A; however, there is no established treatment for those with Child-Pugh B. This study aimed to evaluate the safety and efficacy of atezo + bev in patients with advanced HCC and Child-Pugh B. Methods:This multicenter, open-label, single-arm, phase II study enrolled patients with advanced HCC and a Child-Pugh score of 7 or 8 who had not received prior systemic therapy. Patients were administered atezolizumab (1,200 mg) plus bevacizumab (15 mg/kg) every 3 weeks. The primary endpoint was the frequency of serious adverse events (SAEs), assuming a threshold SAE of 68.5%. A binomial test with a one-sided significance level of 2.5% was employed for the primary analysis. Results:Among the 31 patients enrolled between December 2021 and April 2023, we set 30 eligible patients as the population for the safety and efficacy analyses. The frequency of SAEs was 23.3% (95% confidence interval [CI]: 9.9-42.3, p < 0.0001). Objective response rates according to RECIST v1.1 and the modified RECIST were 40.0% and 46.7%, respectively. The median progression-free and overall survival were 240 days (95% CI: 176-526 days) and 470 days (95% CI: 256-576 days), respectively. The mean ± SD Child-Pugh scores were 7.2 ± 0.4 at the start of treatment, maintained 7.0 ± 1.0 and 7.0 ± 1.2 at the third and sixth cycles, respectively, and was 7.6 ± 1.7 at the end of treatment. Conclusion:The atezo + bev regimen can be safely administered with demonstrable antitumor effects in patients with unresectable HCC and a Child-Pugh score of 7 or 8. Additional studies are warranted to confirm the usefulness of atezo + bev in this patient group.

Abstract Background: Surgery and ablation can be curative for early-stage HCC, but up to 70% recur or develop new primary HCC. ctDNA-based MRD assessment may improve risk assessment and identify recurrence earlier than current tools. Because HCC is often diagnosed radiologically and ablation yields no tissue, tumor-informed assays may be infeasible and unable to detect new primaries. Methods: Patients with completely resected or ablated stage I-III HCC were prospectively enrolled across 13 Japanese sites (Mar 2021-May 2022). Plasma was collected pre- and 4 weeks post-procedure and every 3-6 months with standard imaging and biomarker assessment. ctDNA was analyzed retrospectively using a tissue-free epigenomic assay (Guardant Reveal) evaluating ∼20,000 differentially methylated/control regions. Samples are classified as ctDNA detected/not detected based on a pre-defined threshold. Associations between ctDNA status and recurrence were analyzed. Results: Among 95 patients eligible for this interim analysis, (87% resected, 57% stage I, median age 74), 610/611 samples were successfully analyzed. At 36.9 months median follow-up, 42 recurred. Pre-procedure ctDNA was detected in 75% (70/94) and correlated with shorter time to recurrence (HR 4.4; 95% CI 1.7-14.6; p < 0.001). Post-surgery ctDNA detection at 4 weeks also correlated (HR 3.8; 95% CI 1.7-7.8; p = 0.002) and was the only variable that remained statistically associated with recurrence on multivariate analysis at this timepoint. Surveillance ctDNA sensitivity was 60% (25/42), specificity was 98% (52/53), and median lead time was 63 days. ctDNA outperformed other biomarkers evaluated in this cohort (Table 1). Conclusions: Epigenomic ctDNA analysis enabled tissue-free MRD detection with high accuracy and superior performance vs conventional biomarkers, supporting its use for individualized recurrence risk assessment and surveillance. Citation Format: Masashi Kudo, Mitsuhito Sasaki, Shinji Itoh, Teiichi Sugiura, Tsuyoshi Kobayashi, Keishi Sugimachi, Shinichi Nakanuma, Yuta Abe, Hisashi Kosaka, Nobuhiro Nakamoto, Naoto Yamamoto, Makoto Ueno, Takuji Okusaka, Atsushi Takebe, Minoru Esaki, Kazuyoshi Ohkawa, Hisateru Komatsu, Yu Takahashi, Masatake Tanaka, Takeshi Aramaki, Tomokazu Kawaoka, Rie Sugimoto, Taro Yamashita, Takashi Yamaguchi, Masatoshi Kudo, Masato Ozaka, Chiemi Notake, Hiroshi Uchigata, Masafumi Ikeda, Naoto Gotohda, Yoshiaki Nakamura. Circulating tumor DNA (ctDNA) for molecular residual disease (MRD) detection and recurrence monitoring in hepatocellular carcinoma (HCC); COSMOS-HCC01 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1094.

Polyploid giant cancer cells (PGCCs) are characterized by abnormal enlargement and considerable polyploidy. Though the presence of giant cancer cells has been documented for decades, they remain not fully understood, especially in clinical practice, due to diagnostic challenges, and confusion regarding synonyms for PGCCs still exists. Thus, understanding PGCCs may be a key clue to overcoming them. This review offers a comprehensive overview of PGCCs, integrating insights from basic research and clinical studies to enhance understanding of their complex biology and clinical implications. In basic research, PGCCs are known to emerge under various stressors, including chemotherapy exposure, radiation, viral infection, and hypoxic environments. These cells play crucial roles in tumor progression through multiple mechanisms: enhancing genetic diversity, and facilitating metastatic spread via asymmetric cell division and genomic instability. In clinical studies, PGCC-containing tumors have been shown to exhibit marked treatment resistance and are associated with a poor prognosis across multiple solid tumor types, including prostate, lung, and pancreatic cancers. Despite these therapeutic challenges, paclitaxel-containing regimens have shown promising results in PGCC-containing tumors, such as pleomorphic carcinoma of the lung and undifferentiated carcinoma of the pancreas. Furthermore, emerging targeted therapies directed at specific pathways in PGCCs, particularly those involving TP53, represent potential strategies to improve clinical outcomes of patients with PGCC-containing tumors.

The prognosis of advanced biliary tract cancer remains poor despite up to 40% of tumors harboring actionable molecular alterations. This international collaborative study from Mayo Clinic, Duke Cancer Institute, National Cancer Center East (Japan), and the SCRUM-Japan GOZILA/MONSTAR-SCREEN projects evaluated clinical outcomes in 1049 patients with advanced BTC based on tumor molecular profiling and matched treatment selection. Patients were categorized into non-actionable, actionable with matched targeted therapy (matched), and actionable without matched therapy (unmatched) groups. Among 358 patients (34.1%) with actionable alterations, 160 (44.7%) received matched therapy. The matched group demonstrated significantly longer median overall survival (23.3 months; 95% CI: 19.5-30.4) compared to unmatched (14.7 months; 95% CI: 12.8-17.9) and non-actionable groups (17.1 months; 95% CI: 15.5-18.7; HR 0.57, 95% CI: 0.46-0.71; p 0.0001). In 700 patients receiving ≥2 lines of therapy, matched therapy remained independently associated with improved survival (HR 0.62; 95% CI 0.43-0.90). Notably, patients with actionable tumors who did not receive matched therapy experienced worse outcomes than those with non-actionable disease. These findings highlight the critical need for universal molecular profiling and equitable access to targeted therapies in advanced BTC.

Background:The PRISM study is a nationwide, multicenter, prospective observational study in Japan evaluating the real-world efficacy and safety of systemic therapies for unresectable hepatocellular carcinoma (HCC). HCC patients starting systemic therapy are prospectively enrolled, enabling assessment of outcomes and tolerability across treatment lines. By capturing all patients treated in routine practice, the study is expected to provide a clear picture of the actual treatment outcomes in Japan. Methods:We analyzed the first 1,000 patients enrolled between July 2020 and July 2022, focusing on outcomes of first-line therapy and subsequent patterns. Data on demographics, tumor stage, liver function, regimens, survival, and adverse events (AEs) were prospectively collected and centrally monitored. Survival was estimated by Kaplan-Meier method, and tumor responses were assessed per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and modified RECIST (mRECIST). Results:Of 935 evaluable patients, 82.8% received atezolizumab + bevacizumab (Atezo+Bev) and 15.2% lenvatinib as first-line therapy. Median overall survival and progression-free survival were 21.8 and 7.7 months for Atezo+Bev, respectively, and 20.8 and 6.7 months for lenvatinib, with overall survival numerically longer than that reported in pivotal clinical trials, while progression-free survival remained comparable. Objective response rates were 29.6% (RECIST) and 35.0% (mRECIST) for Atezo+Bev, 24.6% and 35.2% for lenvatinib, and 0% and 6.3% for sorafenib by RECIST and mRECIST, respectively. Grade ≥3 treatment-related AEs occurred in 21.6% and 22.9%, with safety profiles consistent with prior reports. Approximately 50% of patients received second-line therapy, most often lenvatinib after Atezo+Bev and vice versa, with a median progression-free survival of ∼4 months; later-line regimens yielded even shorter benefit. Conclusion:The PRISM study confirms the real-world reproducibility of Atezo+Bev and lenvatinib in Japan, demonstrating their feasibility across diverse patient populations. Ongoing follow-up and subgroup analyses, particularly in special populations, are expected to help optimize long-term outcomes.

Abstract Introduction: CD276 (B7-H3), a modulator of tumor-microenvironment as affecting cadherin expression, has a prognostic impact in the different types of cancers including pancreatic ductal adenocarcinoma (PDAC). In metastatic PDAC, these roles in CD276 have not been fully understood. Using liver metastasis (LM)-derived transcriptome and reversed-phased protein array (RPPA) data, we evaluated CD276 expressions of LMs on clinical outcomes and molecular features in metastatic PDAC. Methods: Needle-biopsied specimens from treatment-naïve LMs of PDAC were collected for protein and RNA extraction. A 435-protein expression was measured on RPPA. The impact of each protein level stratified with median value was tested using univariate Cox regression hazard model. The top 3 prognostic proteins and clinical prognostic factors such as Eastern Cooperative Oncology Group Performance Status (ECOG-PS) and serum level of C-reactive protein (CRP) were evaluated in multivariate Cox regression hazard model. To investigate clinical relevance of CD276, our study population was stratified based on the median value of CD276 mRNA expression level detected on cDNA microarray, followed by differential gene expression analysis and subsequent Gene Ontology (GO) analysis between the two groups surveying for CD276 high-related genes/ pathways. Results: RPPA data was obtained from LMs of 42 patients (Male: 64.2%; median age: 66 years). The tumor proteome data showed that overall survival times were prolonged in the patients with intratumoral high expression of Aurora-A, PGDFR-beta, and CD276 as compared to those without. Independent prognostic impacts were found in CD276 high (hazard ratio: 0.148 [95% confidence interval: 0.005 to 0.434]), ECOG-PS 1 or more (4.651 [1.713 to 12.63]), and CRP high (6.440 [2.498 to 16.60]) in multivariate analysis. Transcriptome data were evaluated in 40 of 42 LMs. The 116 genes were identified as CD276 high-related genes. GO terms associated with CD276 high were cadherin binding (GO:0045296), cell adhesion molecule binding (GO:0050839), and protein binding (GO:0005515). LMs with high CD276 protein expression showed high protein expression in E-cadherin (P<0.001) and tended to be low in protein expression of N-cadherin (P=0.097) as compared to those with low CD276 protein expression. Conclusion: High expression of CD276 protein in liver metastasis of PDAC was an independent favorable prognostic factor and related to increasing E-cadherin expression in tumor. Further study is needed to explore the roles of CD276 in metastatic PDAC. Citation Format: Go Igarashi, Shuichi Mitsunaga, Nobuaki Okumura, Kanae Inoue, Tomonao Taira, Taro Shibuki, Tomoyuki Satake, Masataka Amisaki, Mitsuhito Sasaki, Hideaki Takahashi, Hiroshi Imaoka, Masafumi Ikeda. Clinical and molecular features of CD276 (B7H3) in liver metastases of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5367.

Background/Objectives: Nanvuranlat, a selective inhibitor of LAT1, has demonstrated clinical activity in advanced biliary tract cancer (BTC). We performed post hoc analyses to identify clinical and biomarker-defined populations that may derive greater benefit from LAT1 inhibition. Methods: Data from Phase 1 and Phase 2 studies were analyzed. Clinical outcomes were evaluated according to BTC subtype, prior primary tumor resection status, LAT1 expression, and accumulated drug exposure. Overall survival (OS), progression-free survival (PFS), and tumor size changes were assessed using Kaplan–Meier and Cox proportional hazards analyses. Results: In the Phase 2 study, nanvuranlat improved PFS versus placebo in the overall population (HR 0.56, 95% CI 0.34–0.90). Among the exploratory subgroups, lower hazard ratios were observed in patients without prior primary tumor resection (PFS HR 0.43, 95% CI 0.22–0.85; OS HR 0.53, 95% CI 0.28–1.01). Patients with high LAT1 expression demonstrated lower hazard ratios for PFS and OS than the overall population. Among patients with IHC, EHC, or GBC and high LAT1 2622551206500 expression, PFS and OS hazard ratios were 0.31 (95% CI 0.15–0.64) and 0.50 (95% CI 0.25–1.00), respectively. Clinical outcomes also differed according to accumulated treatment exposure. Conclusions: These exploratory analyses suggest that BTC subtype, prior primary tumor resection status, and LAT1 expression may identify candidate populations for prospective evaluation in future nanvuranlat studies. The findings support further evaluation of biomarker-informed patient selection strategies in advanced BTC.