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Imaging-based quantitative assessment of biomolecular condensates in vitro and in cells

Implication of the novel microtubule targeting agent, AUS_001, in pancreatic cancer cellular signaling.

748 Background: Pancreatic cancer (PanCa) is considered a major therapeutic challenge due to its poor prognosis, high mortality rate and resistance to most therapies, underlining the need for new treatment approaches. Our previous investigations revealed that the prenylated hydroxy-stilbene, AUS_001, inhibits β-tubulin polymerization via its unique binding to the colchicine site of tubulin. A cell-based profiling platform identified sensitivity of 12 out of 13 PanCa lines to AUS_001 with a median concentration causing 50% growth inhibition of 0.227µM. The goal of the current study was to elucidate the signaling activity and cellular responses following treatment with AUS_001 and explore the prospect of the latter in PanCa treatment. Methods: A series of functional and biochemical assays were performed to delineate the effect of AUS_001 on the growth, colony formation ability, invasive capacity and oxidative status of PanCa cells. Tumor growth was evaluated in PANC-1 implanted CB.17 SCID mice and MIA PaCa-2 implanted nude mice upon intraperitoneal administration of AUS_001 once weekly. Metabolic profiling was carried out using the Seahorse XF Analyzer. RNA silencing and adenovirus-mediated overexpression of the Dominant-Negative Mutant of c-Jun were employed to explore the link of c-Jun activation and AUS_001-induced cytotoxicity. Results: The potential of AUS_001 to disrupt PanCa cell functions was established in vitro and in vivo . Viability and compromised membrane integrity were multiplexed and resulted in half maximal effective concentration agreement indicating drug-induced cytotoxicity. AUS_001-treated cells underwent apoptosis followed by secondary necrosis, exerted diminished anchorage-independent growth and metastatic potential in vitro . Importantly, tumor growth was significantly reduced in PanCa murine xenograft models by AUS_001 as a monotherapy. Pretreatment with N-acetyl-l-cysteine did not alter cellular sensitivity to AUS_001, suggesting that the time-dependent induction of reactive oxygen species upon AUS_001 exposure is not the primary cause of cytotoxicity. Notably, the oxygen consumption rate, extracellular acidification rate and function of all mitochondrial complexes (I-IV) of live MIA PaCa_2 cells were significantly impaired in both glucose- and galactose-containing media 48h after AUS_001 administration. Integration of transcriptomic and proteomic data originating from AUS_001-challenged cells uncovered the dramatic induction of c-Jun and FosB stress responders. Further studies demonstrated that c-Jun transcriptional activation acts as a partial mediator of AUS_001-induced cytotoxicity. Conclusions: Collectively, our findings provide critical insights into the molecular events triggered by AUS_001 in PanCa cells and serve as supporting data for future exploration of AUS_001 as a novel PanCa therapeutic agent.

Surrogacy between pathological complete response and overall survival: An individual patient data analysis of eight RCTs on neoadjuvant treatment plus surgery for esophageal cancer.

498 Background: Overall survival (OS) is the gold standard endpoint of treatment efficacy but requires an extended follow-up period. This study aimed to determine the validity of pathological complete response (pCR) as a surrogate endpoint for OS. Methods: The individual-level surrogacy between categorical outcome and OS was assessed using Kendall correlation coefficient, τ. Because no method has been reported to estimate τ between categorical variables and OS, we proposed the new method using an inverse probability of censoring weighting (IPCW) estimator adjusted for tied data that occur when applied to categorical outcomes. To evaluate the validity of this new method, we conducted simulations to compare its estimation accuracy with existing methods. A systematic review for all phase III RCTs comparing therapies in perioperative settings for resectable advanced esophageal and gastroesophageal junction cancer was performed and individual patient data (IPD) were requested from all included trials. Finally, surrogacy between pCR and OS was assessed using our proposed method. Results: Across all scenarios with varying τ values, sample sizes, and censoring proportions, the proposed method showed the lowest bias compared to the existing statistical methods. In total, 23 eligible trials were identified and IPD were available from eight RCTs (JCOG1109, JCOG9907, JCOG9204, FFCD9901, FFCD9102, SAKK75/08, CROSS, and KOK), including 1688 patients who received neoadjuvant therapy. For trial-level analysis, pCR showed a strong correlation with a determination of correlation of 0.65 when limited to neoadjuvant chemotherapy (NAC) trials. For individual-level analysis, in patients who received NAC, the hazard ratio (HR) for OS of pCR was 0.25 (95% CI: 0.13 - 0.47), and τ between OS and pCR was 0.225. While in patients who received neoadjuvant chemoradiotherapy (NACRT), the HR was 0.54 (95% CI: 0.45 - 0.66), and τ was 0.189. Additionally, τ between OS and pathological grade (pGrade), OS and tumor regression grade (TRG) was 0.196 and 0.143, respectively. As a reference, hypothetical data showed that in order to achieve a τ of 0.8 between pCR and OS, it is necessary to be able to clearly identify the prognosis to the extent that an HR of 0.09 (95% CI: 0.08 - 0.11) can be obtained. Conclusions: While pCR is sensitive enough to stratify prognosis and exhibit strong trial-level surrogacy, no individual-level surrogacy was demonstrated, making them insufficient to replace OS. It should be noted that there are substantial differences in prognostic stratification and potential use of pCR as primary endpoints in clinical trials.

UNITEPANC: Using organoids to predict efficacy of adjuvant treatment to improve outcome in resectable pancreatic cancer—Prospective, multicenter, proof-of-concept trial of the AIO Pancreatic Cancer Group.

TPS791 Background: Pancreatic cancer (PDAC) is a highly heterogeneous disease and there is a lack of predictive biomarker to guide treatment. Patient tumor derived organoids (PDO) have been demonstrated to faithfully recapitulate morphological and genetic features of the parental tumor and also retain patient-specific heterogeneity. Retrospective studies show that PDO can be used to predict treatment sensitivity and can support the selection of an optimal treatment in terms of efficacy and also lower toxicity, e.g. by selecting a double rather than a triple combination. Methods: UNITEPANC is a prospective, proof of concept, multicenter IIT of the German AIO PDAC Group and funded by the German Cancer Aid. UNITEPANC examines the feasibility of an organoid-educated adjuvant treatment approach with respect to organoid establishment, expansion and characterization and its potential role for selecting an optimal adjuvant treatment in PDAC in a multicenter setting. Preparatory activities like harmonizing SOPs and round-robin-tests for generation of organoids and organoid-based pharmacotyping in the trial centers and the different Organoid Facilities has been completed and evaluated. UNITEPANC examines selection of adjuvant chemotherapy by pharmacotyping of tumor organoids. Options for adjuvant treatment are gemcitabine, gemcitabine/capecitabine, gemcitabine/nab-paclitaxel or mFOLFIRINOX. Major inclusion criteria are R0 or R1 resected, histologically confirmed PDAC and patients in principle, suitability for mFOLFIRINOX treatment in the adjuvant setting, postoperative Ca19-9<180 U/ml, and a timely PDO-based chemotherapy recommendation by the UNITEPANC Organoid Board within 11 weeks to guarantee a start of the adjuvant treatment within 12 weeks after resection. Design: UNITEPANC is an interventional, prospective, multicenter, single-arm trial. 95 patients shall be allocated to the trial for the generation of organoids, 38 patients shall be enrolled for PDO-based adjuvant treatment and 34 patients need to be analysed as ITT population in in the follow-up period. Efficacy: The efficacy endpoint of the trial is purely descriptive and intended to obtain a signal for further development of the strategy. This requires the proof of an efficient 1) generation and 2) expansion of PDO and 3) a clear sign that an organoid-educated treatment selection is superior to standard treatment with mFOLFIRINOX. For 1) and 2) we have chosen a rate of 75% and 60%, respectively, according to the literature. For 3): The approach would be considered promising, if the true 18-months-DFS rate is 77% (corresponding to a hazard ratio of 0.5 compared to Prodige-24, 80% power, one-sided type I error 0.1. HR-QoL data will be analyzed (QLQ-C30, Pan26). Additionally, an extensive translational program is enclosed.

Development of new therapeutic strategies to enhance the effectiveness of irinotecan in colorectal cancer treatment.

217 Background: Chemotherapy plays an important role in the treatment of colorectal cancer. Irinotecan, a topoisomerase I inhibitor, is used in therapies such as FOLFIRI and FOLFOXIRI. However, many patients become resistant to irinotecan, and the detailed mechanisms of resistance are not fully understood. The aim is to develop new therapeutic strategies by elucidating the mechanisms of irinotecan resistance. Methods: We used in vitro approach to demonstrate the mechanism of topoI degradation. Immunohistochemistry staining was used to explore the biomarker for irinotecan, Finally, in vivo approach was used to develop a new strategy for irinotecan treatment. Results: Mechanism of topoisomerase I (topoI) degradation: We investigated the molecular mechanism of topoI degradation in detail. After irinotecan administration, double-strand breaks occur in the DNA, activating DNA-PK. This activated DNA-PK phosphorylates the S10 residue of topoI, and BRCA1-BARD1 ubiquitinates the phosphorylated topoI. Eventually, topoI is degraded by the proteasome. Colorectal cancer cell lines where topoI degradation occurred after irinotecan administration showed irinotecan resistance. Development of a biomarker for irinotecan sensitivity: We created a monoclonal antibody that labels the phosphorylated S10 residue of topoI (topoI-pS10). We examined topoI-pS10 expression in colorectal cancer cases with a history of irinotecan treatment. The results showed a sensitivity of 87.5%, accuracy of 70%, positive predictive value of 70.7%, and negative predictive value of 87%, indicating that topoI-pS10 expression could serve as a biomarker for irinotecan sensitivity.Development of new therapeutic strategies: The degradation of topoI, which causes irinotecan resistance, is carried out via the ubiquitin-proteasome pathway. It is expected that combining irinotecan with a proteasome inhibitor, which blocks this pathway, will enhance irinotecan’s effectiveness. When irinotecan was combined with a proteasome inhibitor in irinotecan-resistant colorectal cancer cell lines, cell death occurred at a higher rate compared to when they were not combined. Similar results were observed in experiments using mice. Conclusions: Based on the mechanism of topoI degradation, we developed a biomarker for irinotecan sensitivity and a new therapeutic strategy. This study suggests the potential for further improvements in irinotecan therapy.

DLL3 draws two antibody–drug conjugate deals

Ningxiang pig-derived Lactobacillus reuteri improves the gut health of weaned piglets by regulating intestinal barrier function and cytokine profiles

Structure of blood cell-specific tubulin and demonstration of dimer spacing compaction in a single protofilament

OP-TNT: Phase II study of total neoadjuvant chemoradiotherapy followed by local resection for early distal rectal carcinoma.

177 Background: Surgery is standard of care for pMMR early distal rectal cancer (RC), which can be partially exempted by totally neoadjuvant chemoradiotherapy (TNT) followed by watch and wait. But long-term data showed that 1/3 patients had local growth( mostly in the rectal wall)in two years. This study investigates the efficacy and safety of TNT followed by local excision( LE) for early distal rectal carcinoma (cT1-3N0M0) in order to preserve organs. Methods: In this single-arm, phase 2 prospective trial, patients were eligible if they were aged 18 years or older, with a performance status of 0-1,newly diagnosed, biopsy proven pMMR/MSS RC which located ≤5cm from the anal verge and staged as cT1-3N0M0. Patients were assigned to receive TNT: 6 courses of CapOx(capecitabine 1000 g/m2 PO BID D1-14, oxaliplatin 130 mg/m2 IV QD D1,Q3W), combined with concurrent long-course radiotherapy (LCRT)(45 Gy/25 Fx to the pelvis with an SIB of 50 Gy/25 Fx to the tumor bed). Evaluation was performed 12 weeks after completion of LCRT. Patients who achieved a clinical complete response (cCR) or near clinical complete response (ncCR)were assigned to LE, whereas those with >ypT1, positive margin, or neurovascular invasion after LE were recommended for total mesorectal excision (TME). The primary endpoint is the 3-year organ-preserving rate. Secondary endpoints include the pathological complete response (pCR)(encompassing response after LE and TME), adverse effects rate, 3y-disease-free survival (DFS)and 3y-overall survival (OS)rate. Results: From October 2022 to August 2024, 52 patients had completed therapy. Median age at evaluation and follow-up duration were 58.3 years and 11 months. Of the patients 78.8% (41/52) were defined as MRI stage T3, and 76.9%(40/52) located ≤3cm from the anal verge. Of 52 evaluable patients ,82.7% (43/52) achieved cCR/ncCR and had LE (6 via endoscopic resection and 37 through trans-anal minimally invasive surgery). Among these patients, 25.6% (11/43) were found to have residual tumors after LE, of which 6 were radical-operated while 5 refused this intervention. Nine patients who did not achieve cCR or ncCR received TME resection, and 6 of them were confirmed as pCR. The total pCR rate was 73.1% (38/52). Of all patients, 3 underwent abdominoperineal resection, and sphincter-preserving rate was 94.2%(49/52). No grade 3 or 4 adverse events were reported, and there were no treatment-related deaths. The main adverse event after local resection was the 1-3 months anterior resection syndrome. Conclusions: The results of interim analysis showed that tumor residue was found in patients with cCR/ncCR after TNT, similar to the regrowth rate previously reported. LE strategy may become prevention. Long-term outcomes are being followed up. Clinical trial information: NCT05563922 .

Preoperative botensilimab (BOT) with or without balstilimab (BAL) for patients with resectable locally advanced pMMR or dMMR colon cancer: Results from the UNICORN trial by GONO.

158 Background: Standard treatment for patients (pts) with localized colon cancer (CC) is surgery and adjuvant chemotherapy where indicated. Neoadjuvant strategies allow for earlier exposure to systemic therapy, potentially leading to tumor downstaging, micro-metastases eradication, improved survival, and may pave the way for non-operative management (NOM). BOT, a novel Fc-enhanced multifunctional anti-CTLA-4 antibody plus BAL, an anti-PD-1 antibody, have demonstrated activity in proficient mismatch repair (pMMR) CC pts with durable responses in metastatic CC and unprecedented rates of pathological complete response (pCR) in the localized setting. Methods: UNICORN is a window-of-opportunity, multicohort, umbrella platform phase II trial enrolling non-metastatic, radiologically staged rT3-4 N0-2, resectable CC pts to be treated with a short course preoperative targeted treatment according to a prespecified molecular profile assessed by immunohistochemistry and next-generation sequencing on tumor biopsy. Pts with pMMR or deficient (dMMR) tumors received intravenous (IV) BOT at 1 mg/kg on day 1 (cohorts 4 or 6) or IV BOT 1 mg/kg on day 1 and BAL 3 mg/kg on days 1 and 15 (cohorts 5 or 7, enrolled after 4 and 6) and underwent radical surgery on day 35 ± 5. Pathological response (pR), major response (pMR) and pCR rates were defined as ≤ 50%, ≤10% and 0% residual viable tumor. The primary endpoint was centrally assessed pMR rate in each cohort. According to a Fleming 1-stage design, choosing β=80% and α=5%, 14 pts were enrolled in each cohort and the treatment was judged promising if ≥5/14 pMRs were observed. Results: All 56 enrolled pts completed preoperative treatment and underwent surgery. Timely surgery was performed in most pts (98%), except 1 who underwent surgery with a delay < 4 weeks due to treatment-related hyperthyroidism. Among pts with pMMR disease, activity was limited for BOT monotherapy (pMR 0%, pR 43%). With BOT + BAL, pCR was 29%, pMR 36% and pR 71%. Among those with dMMR status, BOT led to pCR, pMR and pR in 29%, 36% and 64% pts, respectively. Notably, BOT + BAL led to pCR and pMR in 93% and 100% pts. Adverse events (AEs) of any grade occurred in 28/56 pts (50%), and 22 (39%) were deemed immune-related. Serious AEs occurred in 9 pts (16%) and were treatment-related in 3 pts (5%). Conclusions: The primary endpoint was met in all cohorts except for BOT monotherapy in pts with pMMR status. Despite limited sample size, the activity of 1 neoadjuvant cycle with BOT + BAL favorably compares to ipilimumab/nivolumab in both pMMR and dMMR subgroups. pCR rate was remarkable in pMMR and the highest ever reported in dMMR pts, paving the way to NOM studies irrespective of MMR status. Clinical trial information: EU-CT 2022-501308-90-00 . Molecular status n° Treatment pCR, n (%) pMR, n (%) pR, n (%) pMMR 14 BOT 0 (0) 0 (0) 6 (43) 14 BOT/BAL 4 (29) 5 (36) 10 (71) dMMR 14 BOT 4 (29) 5 (36) 9 (64) 14 BOT/BAL 13 (93) 14 (100) 14 (100)

Expanded biomarker analysis of an international, open-label phase 2 study of regorafenib plus pembrolizumab in patients with advanced hepatocellular carcinoma (HCC) previously treated with immune checkpoint inhibitors (ICI).

635 Background: The optimal treatment for patients (pts) with advanced HCC who progress on an ICI-containing regimen has not been defined. In pts who progressed on one prior ICI regimen, regorafenib plus pembrolizumab (rego + pembro) showed modest anti-tumor activity (primary completion analysis: overall objective response rate 7.4%, all partial responses [PR]) and an expected safety profile (NCT04696055; El-Khoueiry, ASCO 2024). We conducted additional exploratory analyses of tumor markers to gain insights into the clinical results. Methods: Overall, 95 adults with unresectable advanced HCC (C-P Class A, BCLC stage B/C, ECOG PS 0/1) received oral regorafenib 90 mg once daily 3 weeks on/1 week off plus pembrolizumab 400 mg i.v. every 6 weeks. Prior treatment: Cohort 1 = atezolizumab + bevacizumab (n=68); Cohort 2 = any other ICI alone or in combination (n=27). Biomarker analyses in subsets of pts explored potential correlations with clinical benefit (defined as tumor response or stable disease [SD] ≥ 4 months). Immune cell subtypes in blood were analyzed by flow cytometry. Tumor immune markers were assessed by immunohistochemistry. Gene expression profiling in tumor samples was by RNAseq. Results: Twenty-one pts had baseline samples for RNAseq, 7 of whom had clinical benefit (n= 3 Cohort 1 [including 1 PR], n=4 Cohort 2). Pts with clinical benefit had differential gene expression at baseline including enriched expression of genes associated with Notch, Hedgehog, fibroblast, TGF-β, and insulin-like growth factor binding protein signaling; in contrast, there was higher expression of genes associated with myeloid derived suppressor cells in pts without clinical benefit. Of note, tumor samples from pts in this study had increased Tregs and T-cell exhaustion signatures compared with pts treated with rego + pembro in a first-line study (NCT03347292).Analyses of available paired tumor samples from 4 patients (n=2 SD, n=2 progressive disease) found reductions in activated fibroblast, TGF-β, and collagen gene expression signatures from baseline to Week 6 Day 1 of treatment. Conclusions: Rego + pembro had modest activity in pts who progressed on one prior ICI-based regimen. Exploratory biomarker analyses suggest different gene expression in pts with or without clinical benefit. Clinical benefit was associated with enriched expression of genes in Notch, Hedgehog, fibroblast, and TGF-β pathways. Pre- and post-treatment biopsies showed reductions in fibroblast, TGF-β, and collagen gene expression, which are known features of HCC. In the context of the limitations of small sample size and absence of a control arm, these findings are hypothesis generating and consistent with HCC biology and regorafenib mechanism of action. Clinical trial information: NCT04696055 .

Natural history study of patients with pancreatic acinar cell carcinoma: A 3-year prospective longitudinal analysis.

764 Background: Pancreatic acinar cell carcinoma (PACC) is a rare exocrine tumor of the pancreas that comprises 0.2-2% of all pancreatic malignancies. There are no prospective randomized studies in this disease and most data about PACC comes from retrospective database analyses and case reports. Methods: The Cancer Moonshot-funded My Pediatric and Adult Rare Tumor (MyPART) network’s Rare Solid Tumor Natural History study (NCT03739827) is a prospective, single-institution observational study that enrolls patients of all ages with rare solid tumors (<15 cases per 100,000 people per year), including PACC. Patients can participate remotely (field cohort) or visit the NIH for annual evaluations (in-person cohort). All participants complete medical and family histories, patient reported outcomes (PROs) measures, and provide saliva for DNA analysis. Relevant data such as clinical and family histories, surgical and molecular pathology, and imaging results are extracted from patient medical records and entered in the central study database. Archival tumor samples (when available) are analyzed using a 500+ gene panel (TruSight500, Illumina) and discussed in a molecular tumor board. Patients participating in the in-person cohort undergo additional evaluations including clinical examination, imaging studies, genetic counseling, and blood sample collection for clinical and research purposes (standard clinical labs, germline DNA/RNA, immune phenotypes, cytokines) as indicated. Results: From 09/2021 until 09/2024, 17 PACC patients (n=13 for the field cohort, n=4 for the in-person cohort) were accrued. The mean age of diagnosis is 64.7 (48-78) years, and the male to female ratio is 14:3. At the time of diagnosis, 6 patients had Stage I or II, 1 had Stage III, and 10 had Stage IV disease. The median follow-up time since accrual is 7.6 months, and 4 patients have died. No patients have been lost to follow-up. Of the 6 patients diagnosed with early-stage disease, 5 had surgery and all received adjuvant chemotherapy, while 1 patient is receiving neoadjuvant chemotherapy. Among the 9 patients diagnosed with advanced disease, 8 received platinum-based regimens as a first-line therapy. Tumor molecular profiling was available for 16 patients. The most common tumor mutations observed were in CDKN2A (29.4%), BRCA2 (29.4%), and SMAD4 (23.5%). Six patients received targeted therapies matched to their tumor molecular profile. Conclusions: The demographic profile of our cohort aligns with previous studies, with a mean age of diagnosis in the early-to-mid 60s and a high male to female ratio. Our cohort highlights a shift in first-line treatment to platinum-based therapies over the past decade. Many PACC tumors have targetable mutations found in molecular profiling, and the efficacy of matched therapy warrants further exploration. Clinical trial information: NCT03739827 .

Targeting inherited mutations to prevent metastasis

Enhancing maize seed resistance to chilling stress through seed germination and surface morphological changes using high voltage electrostatic field

Laser-capture microdissection for spatial transcriptomics of immunohistochemically detected neurons

Impact of sirtuin genes expression on first-line treatment outcomes in patients (pts) with metastatic colorectal cancer (mCRC) enrolled in CALGB/SWOG 80405 (Alliance).

269 Background: Sirtuins (SIRT1-7) are class III histone deacetylases with different roles in CRC as tumor suppressive and oncogenic, mainly influencing proliferation, migration, invasion, DNA damage and chemoresistance. In the present study, we explored the association between tumor gene expression of sirtuins and first-line treatment outcomes in mCRC pts. Methods: We evaluated the impact of the tumor gene expression of sirtuin genes ( SIRT1 -7) on treatment outcomes (overall survival: OS; progression free survival: PFS) in 433 pts enrolled in the randomized, phase III CALGB/SWOG 80405 (NCT00265850) trial. RNA extracted from FFPE tumor samples was sequenced using the HiSeq 2500 (Illumina). Subgroup analyses were based on treatment (bevacizumab [bev] (N = 226) vs. cetuximab [cet] (N = 207)). For each gene, expression was divided into tertiles of high, medium and low. The associations between tumor gene expression and outcomes (PFS and OS) were assessed using log-rank test in univariate analysis. Multivariable Cox proportional hazards regression model was used to compute hazard ratios (HR) and 95% confidence intervals while adjusting for baseline characteristics. Treatment-gene interactions were analyzed using the likelihood ratio test. Results: Of the seven genes analyzed, SIRT3 high was associated with both longer PFS (HR: 0.59 [95% CI: 0.46-0.74], P < 0.001) and OS (HR:0.64 [95% CI: 0.50-0.83], P = 0.002) overall. Treatment-gene interaction testing found significant interactions for SIRT1 and SIRT5 with PFS ( P values: 0.021 and 0.016, respectively) and OS ( P values: 0.038 and 0.014, respectively) with targeted therapies (bev vs. cet). Multivariate analysis showed SIRT1 high associated with longer PFS (HR: 0.62 [95% CI: 0.42-0.89], P = 0.014) and OS (HR: 0.59 [95% CI: 0.40-0.89], P = 0.036) in cet-treated pts; in contrast with shorter observed PFS (HR: 1.38 [95% CI: 0.96-1.99], P = 0.22) and OS (HR: 1.31 [95% CI: 0.90-1.93], P = 0.23) in bev-treated pts. SIRT5 high showed similar results and associated with longer PFS (HR: 0.64 [95% CI: 0.45-0.91], P = 0.039) and OS (HR: 0.57 [95% CI: 0.39-0.83], P = 0.013) in cet-treated pts, with no similar associations in bev-treated pts. Conclusions: Our results highlight a potential role for SIRT3 as prognostic and, SIRT1 and SIRT5 as predictive biomarkers for first-line treatment in mCRC, with differential effects based on targeted agents. Significant interaction favored cet treatment in SIRT1 high and SIRT5 high tumors. However, previous reports suggest an opposite role of SIRT5 that has been linked to chemotherapy and/or cet resistance in CRC via the inactivation of succinate dehydrogenase complex subunit A. Therefore, further studies are warranted to dissect the mechanism behind the interaction of SIRT5 with cetuximab activity and establish the potential of targeting SIRT1/5 in CRC.

A multicenter, prospective observational study of chemotherapy in elderly patients with biliary tract cancer.

567 Background: In addition to gemcitabine (GEM) plus cisplatin (GC), GEM plus S-1 (GS) and GC plus S-1 (GCS) have been used as standard treatments for advanced biliary tract cancer (aBTC) based on results from phase III trials in Japan prior to the introduction of immune checkpoint inhibitors. The aim of this study was to evaluate the efficacy and safety of these chemotherapies in elderly patients (pts) with aBTC. Methods: This was a multicenter, prospective observational study (UMIN000045156). Inclusion criteria were: age >=70 years; unresectable or recurrent BTC; and scheduled for chemotherapy with GCS, GC, GS, GEM, or S-1. Data were prospectively collected on treatment tolerability, safety and geriatric assessments (G8, IADL, CCI), and overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were evaluated. Inverse probability-weighted propensity score analyses were performed for comparisons of GCS versus GC and of GC versus GEM. Results: A total of 305 pts were enrolled from 53 Japanese hospitals between August 2021 and January 2023. Of these, 294 received chemotherapy (GCS, n=75; GC, n=131; GS, n=26; GEM, n=52; S-1, n=10). Median follow-up was 11.8 months for all pts. Median age was 76 years (range: 70-89 years). Adverse events are summarized in the Table 1. Rates of pts without G8 deterioration after 3 months were 58.7% for GCS, 55.7% for GC, 34.6% for GS, 42.3% for GEM, and 20% for S-1. Rates of pts without IADL deterioration after 3 months were 82.7% for GCS, 73.3% for GC, 42.3% for GS, 57.7% for GEM, and 40.0% for S-1. With inverse probability-weighted propensity score analyses, median OS was 16.4 months (95% confidence interval [CI], 14.7–20.6 months) in the GCS group and 13.3 months (95%CI, 11.7–21.9 months) in the GC group (hazard ratio [HR] 0.80, 95%CI 0.55–1.17; p=0.258). Median PFS was 11.8 months (95%CI, 9.7–14.5 months) in the GCS group and 7.7 months (95%CI, 6.0–10.2 months) in the GC group (HR 0.55, 95%CI 0.38–0.80; p=0.002). ORR was 31.0% in the GCS group and 15.5% in the GC group (p<0.001). Median OS was 13.3 months (95%CI 11.1–19.4 months) in the GC group and 15.5 months (95%CI 6.4–18.7 months) in the GEM group (HR 0.74, 95%CI 0.42–1.29; p=0.282). Median PFS was 6.9 months (95%CI 6.0–9.6 months) in the GC group and 5.1 months (95%CI 3.0–12.0 months) in the GEM group (HR 0.79, 95%CI 0.42–1.49; p=0.463). ORR was 14.1% in the GC group and 7.5% in the GEM group (p=0.305). Conclusions: GCS is an effective therapy compared to GC in elderly pts with aBTC without increasing toxicities or deteriorating activities of daily living. Clinical trial information: UMIN000045156. Chemotherapy-related adverse events (grade 3 and 4). Events, n (%) GCS(n=75) GC(n=131) GS(n=26) GEM(n=52) S-1(n=10) Neutropenia 20 (26.7) 54 (41.2) 8 (30.8) 10 (19.2) 0 Thrombocytopenia 8 (10.7) 9 (6.9) 2 (7.7) 1 (1.9) 0 Anorexia 2 (2.7) 6 (4.6) 2 (7.7) 3 (5.8) 3 (30.0) Malaise 0 8 (6.1) 4 (15.4) 4 (7.7) 3 (30.0) Febrile neutropenia 1 (1.3) 1 (0.8) 2 (7.7) 1 (1.9) 0

Precision medicine and multidisciplinary care in gastric and gastroesophageal junction (G/GEJ) cancers: Challenges and practice gaps in community cancer clinics.

385 Background: The advent of biomarker-driven therapeutic strategies brings increasing precision to the treatment of G/GEJ cancer, placing biomarker testing at the forefront of patient management. The management of evolving logistics for testing and related decision-making can be challenging, especially in community clinics. As part of a multi-center quality improvement initiative, we evaluated current gaps in biomarker testing and practice patterns including multidisciplinary care for G/GEJ cancers in community oncology centers. Methods: Between 5/2024 and 8/2024, oncology team members (N = 60) from 5 US-based community oncology practices completed surveys assessing attitudes, knowledge, competence, practice patterns, challenges, and gaps regarding biomarker testing and multidisciplinary care in G/GEJ cancers. Results: Despite practice guidelines, many patients with G/GEJ cancer did not receive testing for recommended biomarkers. While most providers report that biomarkers HER2 (67%) and PD-L1 (62%) are routinely reported in pathology reports, less than half said testing for MSI/MMR, TMB, and BRAF p.V600E were reported, and less than 25% reported analysis of NTRK1/2/3 , RET , CLDN.18.2, and FGFR2 . Biomarkers most frequently requested if not included in the original pathology work-up were PD-L1 (48%), TMB (32%), and BRAF p.V600E (32%). Top challenges reported by providers in integrating biomarker testing into practice were prioritizing testing for limited tissue (38%), determining whether to begin treatment prior to receipt of molecular testing results (35%), and optimizing specimen collection for molecular testing (27%). Only 23% of providers reported feeling very or extremely comfortable (4/5 on 5-point Likert scale) with interpreting and applying biomarker testing results to treatment decision-making. Additional challenges included turnaround time for biomarker testing, uncertainty interpreting biomarker results, and inconsistent or infrequent multidisciplinary tumor boards. Indeed, some providers (12%) reported not participating in multidisciplinary tumor boards at all, while others reported participating weekly (16%), once or twice a month (21%), every other month (12%), or less frequently (23%). Providers believed improving test ordering process (47%), decreasing testing turnaround time (42%), and standardizing panels for biomarker testing (40%) would be most impactful in implementation of biomarker testing into clinical workflows. Conclusions: Although most oncology teams reported use of some form of biomarker testing in treatment of G/GEJ cancer, testing was inconsistent and not as comprehensive as currently recommended. These data will be leveraged to develop multidisciplinary action plans with participating clinics to improve biomarker testing for treatment selection in G/GEJ cancers.

Comprehensive analysis of Native Hawaiians and other Pacific Islanders with early-onset colorectal cancer.

31 Background: Rates of early-onset colorectal cancers (EOCRC) are increasing in Hawaii across all racial groups. Although previous studies have shown that Native Hawaiians have a higher mortality rate compared to other racial groups, the adjustment for sociodemographic factors have been limited. Our objective is to perform a comprehensive analysis of outcomes among patients with EOCRC in a racially diverse population accounting for tumor factors and patient sociodemographics. Methods: Patients diagnosed with EOCRC between 2000 and 2022 in Hawaii. Overall survival of Asians, Whites, and Native Hawaiian or Other Pacific Islanders (NHOPI) were calculated using the Kaplan-Meier method. Cox proportional hazard regression models assessed survival predictors adjusting for clinical and sociodemographic factors. Results: We included 379 patients in the final analysis. NHOPI had higher prevalence of underinsured status and higher histopathology grade compared to Whites and Asians. In unadjusted Cox regression, NHOPI race, underinsured status, grade, and stage were prognostic for survival. After adjusting for confounders, underinsured status, grade, and stage remained prognostic, but race was not significantly associated with survival. Conclusions: This study concludes that while NHOPI patients with EOCRC demonstrated poorer survival outcomes compared to other racial groups, this disparity was largely explained by the large percentage of underinsured NHOPI patients. Addressing treatment disparities in underinsured or uninsured is essential to improve survival outcomes. Univariate and multivariate analysis of survival. Univariate Multivariate HR (95% CI) p-value HR (95% CI) p-value Insurance Private Insurance - - - - Underinsured & Uninsured 1.865 (1.331-2.612) <0.001 1.843 (1.285-2.643) <0.001 Race White - - - - Asian 1.179 (0.746-1.865) 0.48 0.936 (0.585-1.496) 0.781 NHOPI 2.005 (1.231-3.265) 0.005 1.051 (0.714-1.547) 0.8 Age at diagnosis 0.996 (0.967-1.025) 0.771 1.002 (0.971-1.034) 0.901 Histopathology grade Grade 1&2 - - - - Grade 3&4 2.785 (1.958-3.963) <0.001 2.278 (1.571-3.303) <0.001 Stage Stage 1 - - - - Stage 2 1.104 (0.49-2.487) 0.81 1.028 (0.451-2.342) 0.948 Stage 3 3.255 (1.666-6.359) <0.001 2.873 (1.447-5.706) 0.003 Stage 4 14.851 (7.499-29.41) <0.001 12.778 (6.283-25.987) <0.001 Unknown 3.738 (1.506-9.275) 0.004 3.008 (1.189-7.608) 0.02 Sex Male - - - - Female 0.812 (0.587-1.123) 0.22 0.852 (0.609-1.194) 0.352 Microsatellite status Stable - - Unstable 0.481 (0.148-1.562) 0.204 Not done/Unknown 1.08 (0.737-1.582) 0.739 Time to Treatment Less than 1 month - - - - More than 1 month 1.221 (0.863-1.727) 0.26 1.123 (0.784-1.609) 0.527 Location of Tumors Right - - - - Left 1.239 (0.76-2.02) 0.391 1.466 (0.886-2.425) 0.137 Rectal 1.391 (0.86-2.249) 0.178 1.211 (0.738-1.986) 0.449 NHOPI: Native Hawaiians and Other Pacific Islanders; HR: Hazard Ratio; CI: Confidence Interval.

FDA approves next-generation triple therapy for cystic fibrosis