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Spatially resolved protein profiling in pancreatic adenosquamous carcinoma.

760 Background: Pancreatic adenosquamous carcinoma (PASC) is a rare histopathological type of pancreatic cancer that is more aggressive than pancreatic ductal adenocarcinoma (PDAC). Although PASC has a unique tumor biology and poorer prognosis, there are no guidelines for differentially treating PASC patients, and its rarity makes it significantly understudied. We used Nanostring GeoMX digital spatial profiling (DSP) to provide a targeted proteomic characterization of key tumor-promoting proteins in PASC and PDAC. Methods: FFPE tissue from PASC (n=10 primary, n= 4 met) and PDAC (n=21 primary, n=5 met) cases were analyzed using the DSP platform. Sections were stained with an 82-protein cocktail of antibodies conjugated to UV-photocleavable DNA barcodes. A pan-cytokeratin morphology marker was used to select tumor regions of interest (ROI) and inferred surrounding stromal (i.e., pan-CK negative) ROIs. UV excitation of the defined ROIs was used to release the DNA barcodes and were quantified on the NanoString nCounter system. For PASC, squamous enriched ROI were inferred from corresponding p40 IHC. Corresponding clinical and mutational status for all cases were abstracted from medical records. Results: TP53 (PDAC, 80%; PASC, 83%) and KRAS (PDAC, 76%; PASC, 100%) were the most prevalent mutations . In comparing the tumor ROIs of PASC and PDAC (all cases), DSP-assessed global expression and activation of EGFR-MAPK signaling is significantly increased in PASC, whereas PI3K-AKT signaling is significantly decreased. Compared to PDAC, EGFR expression and phosphorylation (p-EGFR), as well as p-MEK1, are significantly increased in PASC. PASC showed significantly lower levels of PLCG1 and INPP4B, while the majority of other AKT signaling effectors were unchanged. For DNA damage response signaling, PASC showed significantly higher levels of p-ATM, p-CHK2, and p21, but not p-ATR. Likewise, expression of oncoproteins c-MYC and BCL6 were significantly increased in PASC (vs. PDAC). Conclusions: Given that the normal pancreas lacks squamous cells, their histological presence is a uniquely aberrant feature that can be used to guide deep spatially-resolved interrogation of complex cellular and molecular programs. Our preliminary findings show that regions of squamous cell differentiation within PASC have intrinsically higher levels of active EGFR signaling. With emerging RAS-targeted agents poised to alter the treatment landscape, high EGFR signaling in PASC suggest a possible compensatory resistance mechanism that may require additional targeting. Likewise, reliance on ATM signaling highlights this as preferential target for DDR-directed therapies. Building on these results with additional multiomic assays will inform strategies for improving the management of patients with PASC.

Birth cohort effects in appendiceal adenocarcinoma incidence across the United States.

90 Background: Appendiceal adenocarcinoma incidence rates are increasing across all age groups, sexes and histological subtypes in the United States. Birth cohort patterns of appendiceal adenocarcinomas can provide us with new, etiologic clues into these rising rates but have not been examined for this rare malignant tumor type. We estimated appendiceal adenocarcinoma incidence rates across birth cohorts in the United States. Methods: Using the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program data from eight population-based cancer registries, we identified a total of 4,858 persons aged 20+ years when diagnosed with a pathologically-confirmed primary appendiceal adenocarcinoma (non-mucinous, mucinous, goblet cell, signet ring cell carcinoma) between 1975 and 2019. Birth cohorts (1900-1904 to 1990-1994) were created using five-year age groups and time periods. The ratio of age-specific incidence rates was estimated in each birth cohort relative to the 1945-1949 birth cohort and reported as incidence rate ratios (IRRs) with 95% confidence intervals (CI). Results: Compared to persons born in 1945-1949, appendiceal adenocarcinoma incidence rates more than tripled among persons born in 1980-1984 (IRR 3.41, 95%CI 2.54-4.56) and quadrupled among persons born in 1985-1989 (IRR 4.62, 95%CI 3.12-6.82). For all tumor histological types, age-specific appendiceal adenocarcinoma incidence rates increased across successive birth cohorts after 1945-1949—although to varying degrees reported across histological types (e.g., 1980-1984: mucinous adenocarcinoma: IRR 2.71, 95% CI 1.73-4.26; non-mucinous adenocarcinoma: IRR 2.60, 95% CI 1.46-4.63; goblet cell adenocarcinoma: IRR 4.95, 95% CI 2.77-8.85). Conclusions: There are strong, yet distinct birth cohort effects for appendiceal adenocarcinomas across histological subtypes that remain unexplained. These patterns signal that recent exposure changes may be influencing this increasing disease risk for Generation X and Millennials now entering mid-adulthood. With the trend toward more non-operative management of appendicitis, another significant consideration for providers is to keep occult appendiceal tumors in the differential diagnosis of patients who present in this way. The current absence of appendiceal cancer prevention and screening modalities emphasizes the importance of efforts to support earlier detection in a rare malignancy where clinical trials have been historically very limited. Moreover, as similar trends have been reported in other gastrointestinal cancers, this is also suggestive of potential shared exposures contributing to this rising cancer burden across generations.

AMBER part 2F: Cobolimab in combination with dostarlimab in treatment-naïve patients with locally advanced/metastatic and/or unresectable hepatocellular carcinoma (HCC).

TPS650 Background: The introduction of targeted treatment (tx) and immune checkpoint inhibitors (ICIs) has transformed the 1L advanced/metastatic (A/M) HCC tx landscape. 1 Combinations of ICIs with anti-angiogenic agents or other ICIs have demonstrated synergism in patients (pts) with A/M HCC, and shown improved efficacy versus single agents or tyrosine kinase inhibitors. 1,2 Combinations with anti-T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) and anti-programmed cell death protein-1 (PD-1) ICIs have shown promising anti-tumor activity in pts with solid tumors 3,4 including advanced HCC in US pts. 5 AMBER (NCT02817633) part 2F will evaluate the efficacy and safety of anti-TIM-3 cobolimab plus anti-PD-1 dostarlimab in tx-naïve pts with A/M and/or unresectable HCC. Methods: AMBER is a two-part, global, open-label, Phase Ib study assessing cobolimab as monotherapy or in combination with other drugs in pts with advanced solid tumors. For part 2F, ~45 pts are planned for enrollment. Key eligibility includes pts aged ≥18 years, with Eastern Cooperative Oncology Group (ECOG) performance score 0–1, histologically confirmed A/M HCC with measurable disease, Child-Pugh Class A liver function, no prior systemic tx, documented hepatitis B and C test at screening, and a pre-tx biopsy sample. Eligible pts will receive cobolimab (300 mg IV) plus dostarlimab (500 mg IV) every 3 weeks (Q3W) for up to 2 years or until progression, toxicity, discontinuation, or death. The primary endpoint is investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1); secondary endpoints include investigator-assessed disease control rate (DCR), duration of response (DOR) and progression-free survival (PFS) per RECIST v1.1, and overall survival, alpha-fetoprotein response, and safety. Exploratory endpoints include immune-related (ir)-ORR, irDCR, irDOR and irPFS per irRECIST, and biomarker and pharmacokinetic assessments. Disease assessments will consist of CT/MRI evaluations of the chest, abdomen, and pelvis, Q9W from first dose then Q12W after 1 year of tx. Pts will undergo safety follow-up at 30 and 90 (±7) days after last study tx. Efficacy analysis will be based on the safety population (pts who receive ≥1 cobolimab dose) and will include summary statistics and point estimates with 2-sided 95% confidence intervals. Time-to-event analyses will be performed via Kaplan–Meier methods. After ~25 pts have been followed-up for ≥3 scans, an interim analysis may be performed. References: 1. Gordan JD, et al. J Clin Oncol . 2024:42:1830–50; 2. Finn RS, et al. N Engl J Med . 2020;382:1894–1905; 3. Curigliano G, et al. Clin Cancer Res. 2021;27:3620–29; 4. Davar D, et al. J ImmunoTher Cancer . 2023:11(Suppl 1):596; 5. Acoba JD, et al. J Clin Oncol . 2023:41:580. Funding: GSK (213348). Clinical trial information: NCT02817633 .

Gender imbalance in colon cancer screening rates in Texas: A population-based cohort study.

92 Background: Males have a higher risk of acquiring Colorectal Cancer (CRC) than females. In Texas, males are diagnosed with CRC more than females, regardless of race or ethnicity. Texas CRC screening compliance rates are lower than the national average of 72.2%. It is important to understand the gender trends in screening to apply more specific strategies. Methods: We used the Texas Outpatient Public Use Data File (TOPUDF), a deidentified and publicly available statewide dataset, to conduct a population-based cohort study of outpatient colon cancer screenings of residents age 45 -74 years old at hospitals and ambulatory surgery centers during 2021. Colon cancer screenings were identified using Current Procedural Terminology (CPT) and Healthcare Common Procedure Coding System (HCPCS) codes. We queried the National Cancer Institute Surveillance, Epidemiology and End Results Program (SEER) for age grouped populations in 2021 stratified by gender, race, age group, and county of residence. We calculated age-adjusted outpatient colon cancer screening rates per 100,000 population (AASRs) using the direct standardization method based on the age group weights from the 2000 standard US population. Confidence intervals for AASR were derived by estimating the standard error as the AASR divided by square root of number of colon cancer screenings. The statistical significance of the difference between female and male AASR were tested by comparing the intersection of 95% confidence intervals (95% CI) for the individual rates. Subgroup analyses included age group, rural vs urban residence, and race/ethnicity. Results: A total 514,601 outpatient colon cancer screenings were included in the study of which 275, 189 (53.5%) were for female residents. During 2021, 51.1% of state residents age 45-74 years old were female. The overall statewide AASR in 2021 was 6071.5 (95% CI 6054.6 – 6088.4)) with the female AASR (6282.1 [95% CI 6258.1 – 6306.0]) significantly higher than the male AASR (5847.7 [95% CI 5823.9 – 5871.5]). For residents aged ≥ 45 years the statewide AASR was 5580.8 (95% CI 5565.5 – 5596) with the female AASR (5735.2 [95% CI 5715.9 – 5754.4]) significantly higher than the male AASR (5429.8 [95% CI 5410.1 – 5449.6]). Female residents had higher AASR amongst White, Black, and Hispanic race/ethnicity groups with the largest difference observed for Blacks; female AASR 5843.9 (5777.7 - 5910.1) vs male AASR 4733.5 (4668.5 - 4798.5). The difference between male and female outpatient screening rates was significant among both rural and urban residents. Conclusions: Despite a clear relationship between male gender and CRC, females have a higher rate of colon cancer screening. The Black population has the largest gender difference among race/ethnicity groups.

Anlotinib combined with penpulimab and nab-paclitaxel as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): A single-arm, open-label phase II clinical trial.

367 Background: Recently, PD-1 blockades combined with dual chemotherapy regimens in first-line setting exhibited encouraging efficacy for patients with ESCC. However, the safety profile of conventional dual chemotherapy remained unsatisfactory. Therefore, PD-1 blockades combined with anti-angiogenic tyrosine kinase inhibitors (TKIs) and single chemotherapy regimen might offer a promising strategy. Anlotinib, a novel multitarget TKI primarily targeting VEGFR1-3, demonstrated promising therapeutic activity as first-line combination therapy or second-line monotherapy for ESCC patients in China clinically. Therefore, this study was designed to explore the efficacy and safety of anlotinib combined with penpulimab (PD-1 blockade) and nab-paclitaxel as first-line therapy in advanced ESCC. Methods: Patients with previously untreated metastatic or locally advanced ESCC were recruited and treated with anlotinib (12mg, po, d1~14, q3w) and penpulimab (200mg, iv, d1, q3w) plus nab-paclitaxel (220mg/m 2 , iv, d1, q3w) until disease progression or unacceptable toxicity. The tumor response was assessed according to RECIST 1.1 using CT scans every two cycles. Adverse events were recorded by severity in accordance with the NCI CTC AE Version 5.0. The predefined sample size was 30. Primary endpoint was PFS and secondary endpoints included safety, ORR, DCR and OS. Results: From Jul 2022 to Sep 2024, a total of 30 patients were enrolled, with 29 patients who had received first tumor response were included in this analysis. The best overall response indicated that there were 1 CR (3.4%), 23 PR (79.3%), 2 SD (6.9%) and 3 NE (10.3%). Therefore, the preliminary ORR was 82.8% (95%CI: 64.2%-94.2%), DCR was 89.7% (95%CI: 72.6%-97.8%). The primary median PFS of the 29 patients was 10.84 months (95%CI: 7.57-14.11). Additionally, safety profile exhibited that the regimen was tolerable. The most common treatment-emergent adverse events among the 29 patients with the incidence >20% were anemia (62%), leukopenia (31%), peripheral neurotoxicity (28%) and rash (21%). Common grade ≥3 treatment-emergent adverse events were leukopenia (7%), glutamic-pyruvic transaminase was elevated (3%), glutamic oxalacetic transaminase increased (3%), hypertension (3%), diarrhea (3%) and rash (3%). Conclusions: The combination of anlotinib plus penpulimab and nab-paclitaxel as first-line therapy for advanced ESCC demonstrated promising efficacy and manageable safety profile. And the conclusions needed to be confirmed in subsequent trials. Clinical trial information: ChiCTR2400089133 .

Non-metastatic gastric cancer (GC) in patients aged 80 years or older: Immediate and long-term outcomes of combined treatment.

453 Background: Comorbidities and increased risk of chemotherapy-induced toxicity in elderly patients presents significant challenges in management of GC. Here we presents a single-center experience in treatment patients aged 80 years or older with non-metastatic GS, reporting both immediate and long-term outcomes of surgical treatment (ST). Methods: This retrospective analysis includes 61 patients (pts) diagnosed with non-metastatic GC or cardio-esophageal junction (CEJ) cancer. The primary endpoint was relapse-free survival (RFS); secondary endpoints included overall survival (OS) and the incidence of surgical complications (SC). Results: Among the 61 pts (median age 82.7 years, range 80.0-89.2) 39.3% were men. ECOG PS was 0-1 in 49 pts (80.6%) and 2 – in 12 pts (19.4%). The primary tumor site was the stomach in 57 pts (93.4%) and the CEJ in 4 pts (6.6%). Tumor stage had been defined as cT 1-2 in 33.3% pts, cT 3-4 in 57.1%; cN 0 – in 36.1%, stage remained unknown in 6.3%. Radical surgery was performed in pts 78.7% (n=48), 29 pts (47.5%) of them underwent ST only without perioperative chemotherapy (CT). Neoadjuvant CT (NACT) received 23 pts (37.7%): platinum-based doublet regimen – 82.6% (n=19), while 17.4% (n=4) received capecitabine only. ST was performed in 47.8% (n=11) pts received NACT, other 12 pts didn’t undergo ST due to progression of disease (8.3%), comorbidities (33.3%), or patient preference (16.7%) in 1, 4 and 2 cases, respectively. Adjuvant CT was administered to 9 pts (14.3%). Surgical interventions included gastrectomy in 16.6% pts (n=9), proximal or distal resection – in 8.3% (n=4) and 74.1% (n=35), respectively. R0-resection was achieved in 42 pts (88.6%). SC has 20.8% (n=10) pts: classified as Clavien-Dindo grade (G) II – 4.4%, G IIIa – 8.9%, G IIIb - 8.9%; these included anastomotic leakage (6.7%), abscess formation (2.2%), cardiac events and thrombosis (4.4%), and eventration (2.2%). SC G IV or V not reported. The median duration of postoperative hospitalization was 8 days. In the overall cohort, the 3-y RFS was 53% (95%CI 28.9-53.9), 3-y OS – 67% (95%CI 27.9-75.2). Among the pts with stage IA (n=15), the 3-y RFS was 72% (95%CI 49.1-85.1), with a maximum follow-up period of 80 months and no cancer-related deaths. In patients with cT 2-4 N any 3-y RFS was 70% in the overall cohort and 74% in the surgery-only group (HR 1.09; 95%CI 0.45-2.65, p=1). Conclusions: Our findings demonstrate that over 65% of patients aged 80 years or older survive for at least 3 years following surgery for GC, with 53% living without evidence of metastases. Additionally, the rate of SC in this elderly cohort is comparable to that observed in younger populations. The role of perioperative or neoadjuvant CT in this age group remains a topic of ongoing research and discussion. It is critical to manage such population at referral oncological centers with expertise in treating elderly cancer pts.

Proteins that assemble co-translationally lean on their partner for stability

Beyond Inducing Anionic Redox: Controllable Migration Sequence of Li Ions in Transition Metal Layers Toward Highly Stable Li‐Rich Cathodes

AbstractThe energy density of layered oxides of Li‐ion batteries can be enhanced by inducing oxygen redox through replacing transition metal (TM) ions with Li ions in the TM layer. Undesirably, the cathodes always suffer from unfavorable structural degradation, which is closely associated with irreversible TM migration and slab gliding, resulting in continuous capacity and voltage decay. Herein, attention is paid to the Li ions in the TM layer (LiTM) and find their extra effects beyond inducing oxygen redox, which has been rarely mentioned. With the aid of 7Li solid‐state NMR and density functional theory (DFT) calculations, the controllable migration of LiTM is verified. The mystery is uncovered that the preferential migration of LiTM plays an imperative role in preventing the structural transformation by postponing the slab gliding of the layered structure. Integrated with the inhibited TM migration, the structural robustness and reversibility of Li2RuO3 can be drastically improved after Zr‐substitution, providing a solid foundation for achieving ultra‐stable electrochemical performance even after thousands of cycles (2500 cycles). The discovery highlights the significance of LiTM with respect to the structural robustness and provides a potential route toward high‐energy‐density Li‐ion batteries.

Prevalence and clinical characteristics of patients with brain metastases at diagnosis with advanced hepatocellular carcinoma in a retrospective registry.

540 Background: Hepatocellular carcinoma (HCC) is a cancer with poor prognosis and rising incidence. The combination of atezolizumab plus bevacizumab (A+B) prolongs survival as 1 st line therapy in advanced HCC (aHCC) but confers a rare risk of serious bleeding. HCC brain metastases (BM) have high hemorrhage rates and contraindicate the A+B regimen. Alternative immunotherapies also prolong survival without increased bleeding risk. We conducted a retrospective review of a large, diverse, cancer center registry to estimate the prevalence of and identify clinical characteristics associated with BM in aHCC. Methods: The University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center (HDFCCC) registry was queried for new cases of HCC between 2004 and 2022. AJCC stage III or IV were defined as aHCC. Cases with central nervous system (CNS) metastases (including brain as well as skull, face, or orbit as adjacent high-risk sites) at diagnosis were identified. Key clinical covariates including demographics, liver disease etiology, and symptomatology were described. Results: Among 4002 new HCC cases, 832 were classified as aHCC. 12/832 (1.4%, 95% CI: 0.8, 2.5) had synchronous BM. Key demographics are displayed in Table. 10/12 (83%) patients with BM were symptomatic, including headache (25%), neurologic deficits (67%), and/or syncope (8%). Bleeding complications and/or hemorrhagic features were reported in 17%. Conclusions: BM are rare at diagnosis with aHCC, present in only 1.4% of this registry dataset. The majority (83%) were symptomatic, suggesting that routine CNS imaging may not have clinical utility in asymptomatic patients. A high proportion with BM at diagnosis had viral etiology. Limitations of this retrospective registry analysis include potential for underdiagnosis in asymptomatic patients and incomplete data for clinical covariates. Clinical characteristics of aHCC cases with BM at diagnosis between 2004-2022 in UCSF HDFCCC Registry. Overall aHCC Cases (N=832) Cases with BM (n=12) Median age (range) (yrs.) 61 (8-92) 60 (48-65) Race/ethnicity (%)AsianBlackCaucasianHispanic (any race) 29105715 2586717 Gender (%)MaleFemale 7921 7525 Etiology (%)Viral hepatitisUnknown/negative 2971 7525 Symptomatic BM (%)HeadacheNeurologic deficitsSyncope NA 8325678 Hemorrhagic BM (%) NA 17

Neoadjuvant chemoradiotherapy with ipilimumab and nivolumab in rectal cancer (CHINOREC): A prospective randomized, open-label, multicenter, phase II clinical trial.

139 Background: Immune checkpoint inhibitors (ICIs) seem only effective in a primed tumor immune microenvironment (TIME). Neoadjuvant radiotherapy (RT) has been shown to induce an immunogenic cell death (ICD) and thereby restores the susceptibility to ICI. This study evaluates the safety of neoadjuvant chemoradiotherapy (CRT) with concomitant ipilimumab (IPI) and nivolumab (NIVO) in curative rectal cancer (RC) patients. Methods: The CHINOREC study (ClinicalTrials.gov identifier NCT04124601) is a prospective, randomized (ratio 50:30), open-label, multicenter, phase II investigator-initiated trial (IIT). Patients with RC received neoadjuvant CRT (50 Gy in 2 Gy fractions with concurrent capecitabine 1650 mg/m 2 /d) alone or in combination with IPI (1 mg/kg IV at day 7), following 3 cycles of NIVO (3 mg/kg IV Q2W, starting on day 14). Surgical resection was performed 10-12 weeks post CRT. The primary endpoint was surgical safety and feasibility (Clavien-Dindo Classification) of neoadjuvant CRT with sequential IPI and NIVO following surgical resection. Secondary outcome was complete response rate (clinical and pathological). Results: Between June 2020 and November 2023, 145 patients were screened and 80 randomly assigned to CRT (n=30) or CRT+IPI/NIVO (n=50). The primary endpoint (any surgical complication) did not differ between the 2 groups (78% vs. 77%). The reoperation rate (≥Grade IIIb) was comparable low in both groups (8% vs. 7%). No new safety signals were identified. The rate of major pathological response (MPR) and complete response (CR) was also comparable high in both arms (38% vs. 37% and 30% vs. 22%, respectively). Conclusions: Neoadjuvant IPI/NIVO can be safely applied concomitant with CRT in patients with RC, as it does not increase the rate of reoperation or surgical complications. The validity of the encouraging CR rate needs to be elucidated over time. Further translational analyses will elucidate mechanistic insight regarding improved fraction, dosing and timing of CRT and ICI. Clinical trial information: NCT04124601 .

Concordance between human epidermal growth factor receptor 2 (HER2) status by immunohistochemistry (IHC) and next-generation sequencing (NGS) in tissue and blood samples from gastric and gastroesophageal junction cancers (GC/GEJC).

478 Background: An estimated 18% of patients (pts) with GC/GEJC have HER2-positive (HER2+; IHC 3+ or 2+/in situ hybridization–positive [ISH+]) tumors. Although IHC/ISH are the standard testing methods for determining HER2 positivity, NGS can identify HER2 ( ERBB2 ) amplification alongside other biomarkers. This study assessed the concordance of detecting HER2 amplification by tissue/plasma NGS with IHC/ISH HER2 status in pts with GC/GEJC. Methods: Pts were retrospectively identified in the Tempus database. The primary analysis assessed tissue and plasma NGS HER2 copy number (CN) concordance with a HER2+ (IHC 3+ or 2+/ISH+) or HER2− (IHC 0, 1+, or 2+/ISH−) status; NGS samples were collected in ≤30 days of the IHC sample collection date. HER2 amplification was defined as tissue CN ≥8 or plasma log2(CN) ≥0.5; additional amplifications were captured by manual inspection. A secondary analysis assessed the correlation between paired tissue and plasma HER2 log2(CN) in pts with plasma and tissue NGS samples collected ≤30 days apart. The secondary analysis included pts irrespective of IHC sample collection date. Results: Of 1578 pts with GC/GEJC and a curated IHC score evaluated in the primary analysis, 1507 and 305 pts underwent tissue and plasma NGS testing, respectively. Among pts with tissue and plasma NGS results, 902 (59%) and 201 (66%) had primary tumors of the stomach, respectively; all remaining pts had primary tumors of the cardia.According to IHC/ISH, 229 (15%) and 40 (13%) pts were HER2+ among those with tissue and plasma NGS testing, respectively. Of the pts identified as HER2 amplified by tissue and plasma NGS,95% and 92% were HER2+ by IHC/ISH, respectively. Positive percent agreement (PPA) of HER2 amplification by tissue and plasma NGS with IHC/ISH HER2+ status was 70% and 58%, respectively. Concordance rates by PPA, negative PA (NPA), and overall PA (OPA) are summarized in Table. In the secondary analysis, a positive correlation in NGS HER2 log2(CN) was observed in pts with paired tissue and plasma NGS (mutant variant allele frequency >5%; R=0.85; P<2.2e−16; n=307). Conclusions: Based on PPA, we observed moderate concordance between NGS HER2 amplification detection (plasma or tissue) and standard HER2 IHC assessment. NGS is not sufficient to detect all pts with HER2+ GC/GEJC. Further testing is warranted to determine if NGS testing could complement IHC/ISH in identifying pts who may benefit from HER2-directed therapies. IHC 3+ or 2+/ISH+ (HER2+), n IHC 0, 1+, or 2+/ISH− (HER2−), n Total Total 229 1120 Tissue HER2 amplified, n 160 8 168 Tissue HER2 not amplified, n 69 1112 1181 PPA: 69.9% NPA: 99.3% OPA: 94.3% IHC 3+ or 2+/ISH+ (HER2+), n IHC 0, 1+, or 2+/ISH − (HER2 − ), n Total Total 40 233 Plasma HER2 amplified, n 23 2 25 Plasma HER2 not amplified, n 17 231 248 PPA: 57.5% NPA: 99.1% OPA: 93.0%

Mediation of the liver protective effect of the anti-cancer drug candidate namodenoson via adiponectin.

604 Background: Namodenoson (CF102) is a small, orally available, anti-cancer drug candidate, currently in pivotal phase 3 clinical study for the treatment of hepatocellular carcinoma. Adiponectin is a positive cytokine released by adipocytes and endothelial cells, known to induce liver-, cardio-, and neuro-protective effects. We evaluated the potential role of adiponectin as the mediator of the observed namodenoson-induced protective effects. Methods: Proteins extracted fromN1S1 tumor-bearing mice and from murine adipocyte culture treated with namodenoson or vehicle were analyzed using Western blot. Apoptosis was determined in the N1S1 tumor-bearing mice using the TUNEL assay. The effect of namodenoson on hepatic ischemia/reperfusion (IR) was evaluated in Wistar rats by temporarily clamping the hepatic vasculature; the effect on hepatic inflammation was evaluated in Con. A-induced hepatitis in mice. The STAM murine in-vivo model was used to study the effect of namodenoson on metabolic dysfunction-associated steatohepatitis (MASH). Adiponectin levels were determined in the serum of patients in the phase 2 trial evaluating namodenoson vs placebo in patients with metabolic dysfunction-associated steatotic liver disease (MASLD)/MASH. Results: The anti-cancer effect of namodenoson was attributed to its capability to bind to the A3 adenosine receptor, inducing inhibition of PI3K and subsequent de-regulation of the Wnt/β-catenin and NF-kB signal transduction pathways, resulting in apoptosis of liver tumor cells. At the same time, namodenoson demonstrated a liver protective effect manifested by prevention of hepatic IR injury, suppression of liver inflammation, and induction of anti-fibrotic and anti-steatotic effects. In adipocyte cell culture, namodenoson stimulated adiponectin production. An increase in adiponectin levels was also shown in the murine MASH model (STAM). These in-vitro and in-vivo results were consistent with translational data from the phase 2 study of namodenoson in MASLD/MASH where upregulation of adiponectin was observed with namodenoson (mean change from baseline of 539 ng/mL for namodenoson 12.5 mg BID vs -78 ng/mL for placebo, P = 0.032). Conclusions: The anti-cancer effect of namodenoson combined with its protective effects, position it as a unique drug inducing a dual effect in patients with advanced liver cancer.

Molecular and clinical profiling of gastroenteropancreatic (GEP) neuroendocrine tumors (NETs): An analysis of the Oncology Research Information Exchange Network database.

669 Background: The incidence of neuroendocrine tumors (NETs) is approximately 7 per 100,000 persons and rising. By location, tumors in the gastroenteropancreatic (GEP) region, particularly midgut NETs, are most common. The Oncology Research Information Exchange Network (ORIEN) database contains complementary clinical, genomic, and transcriptomic profiling, providing opportunities to identify novel associations between molecular features and clinical outcomes in GEP-NETs. Methods: Survival analyses were performed using the log-rank testing, and clinical features were evaluated using Wilcoxon and chi-squared tests. Mutational analyses utilized sample-level enrichments from whole exome sequencing data, and statistical tests were performed using the one-sided Fisher Exact test. Transcriptomic analyses utilized a student’s t-test. We reviewed 240 samples from 226 patients, with 124 of pancreatic origin, 90 small bowel, 16 gastric, and 10 colorectal. All specimens were well-differentiated; further grading information was unavailable on the ORIEN platform. A p-value <0.05 was considered significant. Results: Patients with metastatic disease were significantly younger at diagnosis (58 vs. 61 years, p=0.0242) and had significantly higher tumor mutational burden (TMB) (0.48 vs. 0.32 mut/Mb, p=0.001). Among the 100 most common alterations across the entire cohort, BPTF (p=0.03) and PRKCA (p=0.007) mutations were more prevalent in pancreatic NETs than in other primary sites. The most frequently mutated genes identified included TTN (27.7%), MUC16 (25.1%), CCDC168 (22.1%), KIR3DL1 (20%), TGIF2LX (20%), MUC17 (19.1%). TTN mutation was significantly associated with higher TMB (p<0.0001). The most common copy number alteration was MUC3a amplification (7q22.1) in 61.5% of samples. This amplification was associated with more prolonged overall survival (OS) with a significance of p=0.0501. Patients with NETs harboring a mutation in CSNK2A2 (p=0.0149), WDR74 (p=0.0386), or NCMAP (p=0.0248) experienced significantly shorter OS compared to the cohort as a whole. Conclusions: We report the first clinical, genomic, and transcriptomic analysis of ORIEN GEP-NET cases. These findings create multiple avenues for further investigation and reinforce the value of multi-institutional consortia such as ORIEN in deepening our knowledge of well-differentiated NETs. Most prevalent mutations in GEP-NETs from ORIEN database. Mutation Prevalence (Percentage of Samples) TTN 27.7% MUC16 25.1% CCDC168 22.1% KIR3DL1 20.0% TGIF2LX 20.0% MUC17 19.1%

Survival associated with metastatic early-onset colorectal cancer among Black patients: A real-world account.

39 Background: Early-onset colorectal cancer (EOCRC), defined as colorectal cancer (CRC) diagnosed under the age of 50, is a growing health concern. The current study explored the racial differences in EOCRC survival in the United States (US). Methods: This retrospective cohort study was conducted using the TriNetX database, a platform that provides access to deidentified medical records on more than 130 million patients across 94 healthcare organizations in the US. The study cohort included patients with metastatic CRC (mCRC), aged 20 to 50, diagnosed between January 1, 2002, and January 1, 2020, and received frontline chemotherapy with oxaliplatin and 5- fluorouracil or capecitabine. The cohort was divided into Black or African American cohort and White cohort. The primary endpoint, 5-year overall survival (OS), was compared between these cohorts after performing 1:1 propensity score matching (PSM) for baseline demographics and comorbid conditions (Table). Kaplan-Meier curves, log-rank chi-square statistics, and hazard ratios (HR) were used to compare the outcome. Results: The entire cohort consisted of 2,923 patients with a mean age of 44 (±6) years; 48.58% were female. The majority were white (56.38%), followed by 15.56% of unknown race, Black/African American (9.16%), Hispanic (9.34%), and Asian (8.96%). After propensity score matching (PSM), there were 262 patients in both the Black and White groups. In the matched population, the Kaplan-Meier survival curves showed that Black patients had significantly lower 5-year OS rates (24.84%) compared to White patients (33.76%) [Hazard Ratio (HR): 1.39, 95% CI (1.06, 1.85), p<0.05]. There is no significant difference between Black and White population over age of 50 [ HR: 1.06, 95% CI (0.966-1.179), P=0.2]. Conclusions: Survival among Black patients with EOCRC appears to be worse than White patients despite adjustment for confounding variables, supporting further research focusing onto this patient population. Characteristics of the cohorts before and after matching. Black cohort (n = 265) and White cohort (n = 1,632) characteristics before propensity score matching Black cohort (n = 262) and White cohort (n = 262) characteristics after propensity score matching Black patients, n (%) White patients, n (%) Sth diff. Black Patients, n (%) White patients, n (%) Sth diff. Age (Mean ± SD) 36.2 ± 6.18 36.3 ± 6.01 0.022 36.1 ± 6.17 36.2 ± 6.43 0.013 Female 144 (54.5%) 774 (47.4%) 0.142 143 (54.5%) 143 (54.5%) <0.0001 Tobacco use 15 (5.6%) 96 (5.8%) 0.0087 15 (5.7%) 11 (4.2%) 0.0703 Hypertensive diseases 67 (25.3%) 214 (13.12%) 0.3147 65 (24.8%) 64 (24.4%) 0.0089 Ischemic heart diseases 10 (3.7%) 40 (2.4%) 0.0769 10 (3.8%) 10 (3.8%) < 0.0001 Type 2 diabetes mellitus 24 (9%) 89 (5.4%) 0.1403 22 (8.3%) 19 (7.2%) 0.0426 Diseases of arteries, arterioles and capillaries 12 (4.5%) 47 (2.8%) 0.0881 11 (4.1%) 10 (3.8%) 0.0195

3D Printed Titanium Scaffolds with Bi‐Directional Gradient QK‐Functionalized Surface

Abstract3D printed titanium scaffold has promising applications in orthopedics. However, the bioinert titanium presents challenges for promoting vascularization and tissue growth within the porous scaffold for stable osteointegration. In this study, a modular porous titanium scaffold is created using 3D printing and a gradient‐surface strategy to immobilize QK peptide on the surface with a bi‐directional gradient distribution. This design featured high peptide density in the interior and low peptide density on both ends, aiming to induce cell migration from ends to interior and subsequently enhance vascularization and osteointegration within the scaffold. In vitro results showed that besides the inherent bioactivity, the gradient distribution of QK positively correlated with endothelial cell migration and promoted angiogenesis. In vivo assay was performed by a segmental bone defect model in rabbit and a spine repair model in sheep. Various staining and Micro‐CT results demonstrated that compared to that with uniformly QK‐functionalized surface, the scaffold with bi‐directional gradient QK‐functionalized surface (Ti‐G) significantly encouraged new tissue growth toward the interior of the scaffold, subsequently facilitated angiogenesis and osteointegration. This study provides an effective strategy for enhancing the bioactivity of peptide‐functionalized scaffolds through the concept of bi‐directional gradients, and holds potential for various 3D printed scaffolds.

Surufatinib combined with TAS-102 as a late-line therapy in patients with metastatic pancreatic cancer (mPDAC): Updated results of a single-arm, phase II trial.

739 Background: Patients (pts) with mPDAC recurrent after FOLFIRINOX and AG chemotherapies have few treatment options. Previous reports of NCT05481463 showed promising clinical benefits of surufatinib (a small-molecule inhibitor of VEGFR1-3, FGFR1 and CSF-1R) plus TAS-102 (combination of trifluridine and tipiracil hydrochloride) in recurrent mPDAC pts. Here, we report the updated results. Methods: This is a single-arm, phase II trial (NCT05481463). Eligible pts with histologically confirmed mPDAC, who had progressed after ≥ 2 lines of previous therapies were treated with surufatinib (250mg, qd, po, q4w) and TAS-102 (35 mg/m 2 , bid, po, days 1–5 and 8–12, q4w). The primary endpoint was progression-free survival (PFS). Key secondary endpoint was overall survival (OS). Other secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. Results: Up to Sep 18, 2024, 20 pts were enrolled (median age 58 years, male 70.0%, TNM stage IV 100.0%, ECOG PS 1 100.0%, liver metastasis 50.0%, peritoneum metastasis 50.0%). Median baseline CA19-9 level of the 20 pts was 996.7u/ml, with a range from 2u/ml to 16612u/ml. 40.0% of pts had received 3L prior therapies before enrollment and 70.0% with primary site on pancreatic body and tail. All pts had received at least one post-baseline tumor assessment (evaluable), among which ORR was 15.0% (3 PRs), DCR was 30.0% (3 PRs, 3SDs). 35.0% pts had stable or shrinking tumors. Median PFS was 2.35m (95% CI 1.91-3.94). Median OS was 6.44m (95% CI 3.81-NR). In subgroup analysis, significantly longer PFS&OS were observed in pts without liver metastasis (mPFS: 3.42m vs 2.01m, p=0.049; mOS: 9.92m vs 3.70m, p=0.026), or with ≤ 2 metastatic organs (mPFS: 3.94m vs 1.91m, p=0.005; mOS: 10.09m vs 3.81m, p=0.003). Additionally, OS was significantly prolonged in pts with baseline CA19-9 level ≤ 996.7u/ml, in contrast with those with baseline CA19-9 level more than 996.7u/ml (9.92m vs 3.70m, p=0.008). All pts experienced treatment emergent adverse events (TEAEs). Most common (≥ 10%) TEAEs (any grade) were anemia (59.1%), neutropenia (54.6%), leukopenia (50.0%), and lymphopenia (45.5%). Grade ≥ 3 TEAEs included neutropenia (31.8%), lymphopenia (13.6%), and anemia (9.1%). Conclusions: Surufatinib plus TAS-102 showed encouraging survival benefits and promising anti-tumor activity with acceptable toxicity in the late-line treatment of refractory mPDAC, especially in patients without liver metastasis, with ≤ 2 metastatic organs, or with baseline CA19-9 level ≤ 996.7u/ml. The results warrant further investigations in a large cohort. Clinical trial information: NCT05481463 .

Role of <i>RAS/BRAF</i> and <i>PIK3CA</i> mutations in tissue and plasma for prognostic assessment in metastatic colorectal cancer (mCRC).

281 Background: Mutations in RAS/BRAF ( RAS/BRAFm ) and PIK3CA ( PIK3CAm ) genes have been described as mechanisms of resistance to anti-EGFR agents in mCRC. However, the utility of liquid biopsy in their baseline detection remains unknown. We aim to analyse oncological outcomes according to RAS/BRAF and PIK3CA mutational status in tissue &amp; plasma in mCRC. Methods: We conducted aretrospective study in patients (pts) with mCRC from 2017 to 2024. RAS/BRAF and PIK3CA mutational status assessment was performed at baseline using Idylla (Biocartis) and Cobas PIK3CA kits, respectively. Cox models were used to analyse overall survival (OS) in RAS/BRAFm and PIK3CAm vs wild-type (WT) population. Results: We analysed 404 paired samples (tissue &amp; plasma) from 202p with mCRC. RAS/BRAFm was described in 45% (91p) in tissue and in 43.6% (88p) in plasma. PIK3CA was tested in 84p, with PIK3CAm detection in 19% (16p) in tissue and 11.9% (10p) in plasma. Liver involvement was more frequent in RAS/BRAFm vs WT (80.6% vs 63.9%; p=0.02), and in PIK3CAm vs WT population (94.4% vs 63.6%; p=0.01). Concordance study (tissue &amp; plasma) for RAS/BRAF and PIK3CA are presented (Table). Subjects with concordant results had worse OS in RAS/BRAFm (18.1m vs 51.1m, HR=2.60; p&lt;0.001) regardless of liver involvement, and showed the same trend in PIK3CAm (22.6m vs 28.1m, p=0.81). Patients with discordant results and plasma RAS/BRAFm or plasma PIK3CAm showed worse OS (23.7 m vs 51.1m; p = 0.006 and 16.4 m vs 42.5 m; p=0.18, respectively) and a lower disease control rate with anti-EGFR therapy (p = 0.04 and p=0.42, respectively). PIK3CAm were evenly distributed in RAS/BRAF WT vs mutated tumors (50% vs 51.5%; p=0.92) and had no independent prognostic impact in OS after stratifying by RAS/BRAF mutational status; RAS/BRAF WT (p=0,93) and RAS/BRAFm (p=0,91). Conclusions: Baseline determination of RAS/BRAFm and PIK3CAm by liquid biopsy in mCRC provide valuable prognostic and predictive information, extending its utility beyond tissue-based analysis. Correlation study of RAS/BRAF and PIK3CA mutational status in tissue and plasma in mCRC. RAS/BRAF tissue PIK3CA tissue RAS/BRAF Plasma Mutated n (%) WT n (%) Total n (%) PIK3CA Plasma Mutated n (%) WT n (%) Total n (%) Mutated n (%) 72 (80) 15 (13.4) 87 (43.1) Mutated n (%) 7 (43.8) 2 (2.9) 9 (10.7) WT n (%) 18 (20) 97 (86.6) 115 (56.9) WT n (%) 9 (56.2) 66 (97.1) 75 (89.3) Total n (%) 90 (100) 112 (100) 202 (100) Total n (%) 16 (100) 68 (100) 84 (100) Positive agreement: 72/90: 80% Positive agreement: 7/16: 43.8% Negative agreement: 97/112: 86.6% Negative agreement: 66/68: 97.1% Overall agreement: 169/202: 83.6% Overall agreement: 73/84: 86.9% KI*: 0.67 KI: 0.49 KI: Kappa Index.

Valemetostat and trastuzumab deruxtecan (T-DXd) in previously treated advanced or metastatic human epidermal growth factor receptor 2 (HER2)-positive gastric cancer or gastro-esophageal junction (GEJ) adenocarcinoma.

TPS508 Background: Valemetostat tosylate (valemetostat), a novel and selective dual inhibitor of enhancer of zeste homolog (EZH)2 and EZH1, has demonstrated clinical efficacy and tolerability in multiple hematologic cancers (200 mg orally [PO] once daily [QD]). EZH2 inhibition by valemetostat is expected to upregulate DNA/RNA helicase Schlafen 11 expression and sensitize tumor cells to DNA damaging agents such as topoisomerase I inhibitor antibody–drug conjugates (ADCs). Topoisomerase inhibitors cause DNA strand breaks, which may synergize with valemetostat. HER2 gene amplification or protein expression has been associated with gastric cancer (GC) and GEJ adenocarcinoma. Patients with HER2+ locally advanced or metastatic gastric adenocarcinoma who progress after first line treatment have poor prognosis and limited therapeutic options. T-DXd is approved globally for HER2+ locally advanced or metastatic GC previously treated with a trastuzumab-based regimen. This study evaluates the clinical activity and safety of valemetostat in combination with T-DXd in patients with GC or GEJ adenocarcinoma as part of a Master Protocol trial evaluating valemetostat in combination with ADCs in solid tumors. Methods: This global, phase 1b, multicenter, open-label Master Protocol study (NCT06244485) will enroll ~ 70 patients per sub-protocol in multiple regions, including the US and Japan. The gastric cohort enrolls patients with previously treated advanced or metastatic HER2+ GC or GEJ adenocarcinoma. The dose-escalation (Part 1) will determine the recommended dose for expansion (RDE), combining valemetostat 50–200 mg PO QD with T-DXd 5.4 or 6.4 mg/kg intravenously every 3 weeks. The dose-expansion (Part 2) will assess the efficacy of valemetostat + T-DXd at the RDE. Primary endpoints include safety and tolerability in Part 1 and the objective response rate in Part 2. Secondary endpoints include response duration, progression-free and overall survival, pharmacokinetics, and HER2 expression by immunohistochemistry and in situ hybridization with clinical response. An interim futility analysis will be performed when 20 patients are enrolled with ≥ 6 months of follow-up. Clinical trial information: NCT06244485 .

Real-world Child-Pugh scores and outcomes of patients with hepatocellular carcinoma at a high-volume center.

569 Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and most often occurs in the setting of cirrhosis. Patients (pts) with advanced HCC are not eligible for curative intent therapies such as ablation, surgical resection, or liver transplantation. For the past five years, immune checkpoint inhibitor (ICI)-based systemic therapy regimens have been the mainstay of first-line treatment for pts with advanced HCC. Most trials assessing ICI-containing regimens, including IMBRAVE150 and HIMALAYA, excluded pts with Child-Pugh (CP) scores worse than A. Unfortunately, fewer than half of pts maintain a CP A score at the time of HCC diagnosis and referral to medical oncology. Real-world data on CP scores of patients undergoing ICI-based therapy for advanced HCC at the time of medical oncology referral and treatment start are lacking. Methods: Pts who initiated treatment with either atezolizumab plus bevacizumab (A+B) or durvalumab plus tremelimumab (D+T) in the Ochsner Health system between 1/1/20 and 12/31/23 were included in this analysis. CP scores were calculated at the time of their initial medical oncology visit and again at the time of their first systemic therapy cycle. Pt demographics and clinical outcomes were analyzed. Results: 200 pts were identified in this study, 159 of whom (79.5%) were male. Median age at treatment start was 66.8 years. 117 pts (58.5%) were Caucasian and 63 pts (31.5%) were African American (AA). 152 and 48 pts received A+B and D+T, respectively. At the time of first medical oncology visit, 58 pts (29%) were classified as CP B (n=51) or C (n=7). At the treatment start date, 82 pts (41%) were classified as CP B (n=73) or C (n=9). The median survival across all groups was 10.5 m. Median survival CP A, B, and C pts were 15.4, 7.6, and 1.6 months (m), respectively. 6-month survival rates for CP A, B, and C pts were 75.7%, 52.2%, and 0%, respectively. 12-month survival rates for CP A, B, and C pts were 58.2%, 35.1%, and 0%, respectively. There was no statistically significant difference in CP score at either time point between Caucasian and AA pts. Conclusions: Although pts with CP scores worse than A were not included in the pivotal studies that have established recent standard of care therapies for pts with advanced HCC, a significant proportion of pts being treated with ICI-based regimens have at least CP B liver disease, with a poorer prognosis in that subset of pts. Extremely poor survival rates for those with CP C scores argue against use of ICI-based treatment for these pts. In this analysis, no significant difference was observed in CP scores between Caucasian and AA pts.

MDM2 amplification in patients with biliary tract cancer in RETUD registry.

615 Background: Antagonism of Mouse double minute 2 homolog ( MDM2 ) can restore p53 activity and represents a novel therapeutic strategy in biliary tract cancer (BTC). We aimed to characterize the epidemiology of total population versus that harbouring MDM2 amplifications; potential associations of MDM2 to other genetic alterations and survival outcomes. Methods: We evaluated a large real-world cohort of patients (pt) diagnosed with BTC from 1st January 2017 to 31st December 2022 from the Spanish RETUD registry. Next generation sequencing (NGS) test was performed in all patients. Data collected included demographic and clinical characteristics, molecular profile, systemic oncologic treatment and effectiveness (best response and survival outcomes). Progression free survival (PFS) outcomes and best response were calculated for pts who received first line therapy. Descriptive statistic was used to analyse sociodemographic data, tumor characterization, molecular analysis, and best response. PFS and overall survival (OS) were estimated by the Kaplan-Meier method. Results: A total of 301 evaluable pt were included in 24 sites. MDM2 amplifications were reported in 19 pt (6.3%) and 2 pt (10.5%) had TP53 mutations. At primary diagnosis, in the MDM2 amplified population the tumour was mostly intrahepatic (63.2%); followed by gallbladder cancer (21.0%). Half of the pt had advanced disease at diagnosis (52.6%) and 21.0% resectable disease. No significant differences were observed in clinical characteristics (age, sex, tumor location, stage, ECOG performance status and metastasis location) and most common actionable genomic alterations (BRAF, HER2, IDH, FGFR2) in pt with MDM2 amplification compared to overall population. Median overall survival (95% Confidence Interval [CI]) in pt with MDM2 amplification was 18.4 months (12.3-19.9), and 17.8 months (95% CI, 12.3-19.9, p=0.247 in pt without amplification. Median PFS in first-line was 5.3 months (95% CI, 2.7-8.9) in MDM2 amplified group, as compared with 6.0 months in non- MDM2 amplified group (95% CI, 5.3-6.8; p=0.4233. The objective response rate in first-line was 21.4% in the MDM2 amplified group versus 29.6% in non-amplified group. The proportion of pt who received systemic therapy in first, second and third line was similar in both groups. The main first-line regimen in MDM2 amplified pt was cisplatin/gemcitabine (n=9, 47.4%), followed by clinical trial (n=3, 15.8%), GEMOX (n=2, 10.5%) and gemcitabine (n=2, 10.5%). The median OS and PFS of patients treated with cisplatin/gemcitabine in first line was similar in both groups. Conclusions: This analysis provides insights into the characterization of MDM2 amplified BTC pt. Similar incidence of MDM2 amplification was observed compared to other cohorts of BTC. No significant differences were observed in clinical characteristics, molecular profile and survival in MDM2 amplified pt compared to non-amplified pt.