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Utility of circulating tumor DNA in patients with unresectable pancreatic cancer using a patient-specific panel: ARTEMIS-PC study.

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 .

Comprehensive analysis of socioeconomic and clinical factors contributing to treatment delay in early-onset colorectal cancer.

32 Background: The prevalence of early-onset colorectal cancers (EOCRC) is rising globally. Disparities in social determinants of health can delay access to treatment and impacting outcomes. This study aims to analyze factors influencing time from diagnosis to treatment among EOCRC patients in a racially diverse population, considering tumor factors and sociodemographics. Methods: We analyzed EOCRC data from patients diagnosed between 2000 and 2022 at Queen’s Medical Center in Honolulu, Hawaii. Time from diagnosis to treatment for Asians, Whites, and Native Hawaiian or Other Pacific Islanders (NHOPI) was assessed using the Kaplan-Meier Method. Cox proportional hazards regression models were used to identify predictors, adjusting for clinical and pathological factors. Results: A total of 379 patients were analyzed. NHOPI were more like to be underinsured compared to Whites and Asians. In the unadjusted Cox model, underinsured/uninsured status, older age, unknown stage, left sided, and rectal locations were associated with delayed treatment. After adjustment, underinsured/uninsured status, older age, and rectal location remained significant predictors of delayed treatment. Conclusions: EOCRC patients with underinsured/uninsured status, age, and rectal tumor location are significantly associated with delayed in cancer treatment. While age was statistically significant, its clinical impact appears minimal. The need for a multidisplinary approach and additional preoperative staging in rectal cancer may explain treatment delays even after adjustment. Improving treatment accessibility and reducing delays, especially for underinsured EOCRC patients, is important. Univariate and multivariate analysis of time from diagnosis to treatment. Univariate Multivariate HR (95% CI) p-value HR (95% CI) p-value Insurance - - - - Private insurance - - - - Underinsured/Uninsured 0.692 (0.545-0.878) 0.003 0.706 (0.55-0.906) 0.006 Race White - - - - Asian 0.912 (0.696-1.195) 0.503 0.817 (0.619-1.077) 0.151 NHOPI 0.749 (0.548-1.025) 0.071 0.779 (0.562-1.08) 0.134 Age 0.978 (0.96-0.997) 0.021 0.968 (0.949-0.987) 0.001 Histopathology grade Grade 1&2 - - - - Grade 3&4 1.046 (0.798-1.371) 0.746 1.083 (0.813-1.441) 0.587 Stage 1 - - - - 2 1.022 (0.718-1.456) 0.902 1.071 (0.744-1.539) 0.713 3 1.227 (0.896-1.682) 0.203 1.387 (0.997-1.931) 0.052 4 0.964 (0.673-1.381) 0.842 1.039 (0.716-1.507) 0.842 Unknown 0.631 (0.406-0.981) 0.041 0.748 (0.473-1.182) 0.213 Sex Male - - - - Female 1.029 (0.836-1.267) 0.785 1.072 (0.868-1.325) 0.518 Microsatellite status Stable - - Unstable 1.074 (0.616-1.875) 0.8 Not done/Unknown 1.259 (1.004-1.577) 0.046 Location of Tumors Right - - - - Left 0.631 (0.468-0.851) 0.003 0.735 (0.535-1.011) 0.058 Rectal 0.43 (0.317-0.582) <0.001 0.448 (0.327-0.613) <0.001 NHOPI: Native Hawaiians and Other Pacific Islanders. HR: Hazard Ratio CI: Confidence Interval.

Multi-target stool-DNA test for colorectal cancer screening and effects on health and economic outcomes compared to blood-based tests: Influence of adherence.

88 Background: There are an estimated 60 million individuals in the US who are not up-to-date with average-risk colorectal cancer (CRC) screening, as screening rates and adherence have remained stubbornly below the national target of 80%. Efforts are ongoing to improve CRC screening performance and participation, including the development of new blood-based tests. Despite high expectations for these tests, performance remains lower than other guideline-recommended strategies, particularly with respect to advanced precancerous lesion (APL) sensitivity. We conducted a simulation study of estimated clinical and economical outcomes for CRC screening with a blood-based test (at perfect adherence) compared to the multi-target stool-DNA (mt-sDNA) test (at published adherence rates). Methods: Utilizing CRC-AIM, a calibrated and validated microsimulation model, CRC screening outcomes were calculated for 1 million average-risk individuals screened between ages 45-75 years with triennial blood-based versus mt-sDNA testing. CRC and APL sensitivity and specificity inputs were derived from two large clinical validation studies for these screening modalities: ECLIPSE (NCT04136002) and DeeP-C (NCT01397747), respectively. To demonstrate the maximum benefits and burdens of blood-based screening, adherence to initial screening and follow-up colonoscopy after a positive blood test was modeled at 100%, while real-world adherence estimates of 65.6% were used for the mt-sDNA test. Outcomes of interest included life years-gained (LYG) and CRC cases missed by the blood-based test compared to the stool-based test, additional treatment costs imposed by theblood-based test, and additional CRC-related deaths per 1 million screened. Results: Compared to triennial screening with mt-sDNA at real-world adherence, blood-based screening at perfect adherence resulted in a higher number of incident (n=18,464) and fatal (n=6,483) CRC cases that would been avoided with the mt-sDNA test. Over a lifetime, screening with blood-based tests required 1,276,310 more tests (21% more) and 52,942 additional follow-up colonoscopies (7% more) compared to mt-sDNA screening. This increased testing burden did not generate additional benefits and instead reduced life-years gained by 67,645 per 1 million screened, resulting in an additional $1.6 billion in treatment costs compared to the mt-sDNA strategy. Conclusions: Data from this CRC-AIM modeling study show that even with perfect adherence, blood-based screening yields inferior clinical and economic benefits compared to mt-sDNA screening, due to suboptimal APL detection with the former test.

An OMV‐Based Nanovaccine as Antigen Presentation Signal Enhancer for Cancer Immunotherapy

Abstract Antigen‐presenting cells (APCs) process tumor vaccines and present tumor antigens as the first signals to T cells to activate anti‐tumor immunity, which process requires the assistance of co‐stimulatory second signals on APCs. The immune checkpoint programmed death ligand 1 (PD‐L1) not only mediates the immune escape of tumor cells but also acts as a co‐inhibitory second signal on APCs. The serious dysfunction of second signals due to the high expression of PD‐L1 on APCs in the tumor body results in the inefficiency of tumor vaccines. To overcome this challenge, a previously established Plug‐and‐Display tumor vaccine platform based on bacterial outer membrane vesicles (OMVs) is developed into an “Antigen Presentation Signal Enhancer” (APSE) by surface‐modifying PD‐L1 antibodies (αPD‐L1). While delivering tumor antigens, APSE can activate the expression of co‐stimulatory second signals in APCs due to the high immunogenicity of OMVs. More importantly, the surface‐modified αPD‐L1 binds to the co‐inhibitory signals PD‐L1, potentially restoring CD80 function and ensuring efficient co‐stimulatory second signals and activation of anti‐tumor immunity. The results reveal the importance of PD‐L1 blockage in the initiation process of anti‐tumor immunity, and the second signal modulation capability of APSE can expand the application potential of cancer vaccines to less immunogenic malignancies.

Social determinants of health and financial burden among patients with pancreatic cancer at a tertiary cancer center.

678 Background: Financial toxicity (FT) represents a challenge for cancer patients that impacts treatment decisions, patient satisfaction, and quality of life. Social determinants of health (SDoH) screening may predict who is at risk of FT and could potentially benefit from financial interventions. Methods: This is a retrospective study of all cancer patients presenting to Mayo Clinic sites between Sept 2023 – Jun 2024. Patients completed SDoH questionnaires and were given risk scores of Low Risk, Medium Risk, and High Risk for SDoH categories: Financial Strain Risk, Transportation Risk, and Food Insecurity Risk. Patient financial data including active debt amounts, insurance coverage, and financial aid were collected. Patients with pancreatic ductal adenocarcinoma (PDAC) were compared to those with pancreatic neuroendocrine tumors (PNET) and patients with other cancers (Others). Categorical variables were compared with Pearson's Chi-squared test, continuous variables with Kruskal-Wallis rank sum test. P values < 0.05 were considered significant. Results: Data was obtained from 88,039 patients, 2,607 of whom had PDAC and 449 had PNET. Compared to PDAC patients, PNET patients and Others were more likely to have Medium/High risk scores for Financial Strain Risk (6% vs 6.5% and 8.5%, respectively) and Food Insecurity (1.7% vs 3.8% and 3.2%) (Table). There was no statistically significant difference in median medical debt and need of financial assistance between the groups. Among PDAC patients, there were differences in distributions among race, primary language spoken, and patient electronic record access depending on Financial Risk categories. African American patients had the greatest proportion of Medium/High risk (12.9%) compared to Asian (4.4%) and White (5.8%) patients (P<0.001). Among patients with English as their primary language, 64.9% had Low Risk scores compared to 27.7% with other primary languages (P<0.001). Patients with electronic record access were more likely to report High Risk scores (6.9%) compared to those without access (1.6%). Conclusions: Per patient responses collected, PDAC patients presenting to our center have lower risk of financial strain and similar medical debt levels compared to the remainder of cancer patients. Among PDAC patients, higher financial strain was experienced by non-whites (7.9% vs 5.8%). Diagnosis PDAC (N=2607) PNET (N=449) Other (N=84983) p value Current Financial Risk (Grouped) < 0.001 - Low Risk 1662 (63.8%) 304 (67.7%) 59298 (69.8%) - Medium/High Risk 157 (6.0%) 29 (6.5%) 7209 (8.5%) - Unknown/Missing 788 (30.2%) 116 (25.8%) 18476 (21.7%) Food Insecurity Risk < 0.001 - Low Risk 1764 (67.7%) 308 (68.6%) 63235 (74.4%) - Medium Risk 45 (1.7%) 17 (3.8%) 2703 (3.2%) - Unknown/Missing 798 (30.6%) 124 (27.6%) 19045 (22.4%) Median Active Debt in USD 1102.230 1020.010 1141.135 0.593

Can an alteration of the gut microbiome increase risk of gastrointestinal malignancies? Insights from the National Inpatient Sample.

841 Background: The gut microbiome is composed of trillions of microorganisms, inhabiting the lining of the gastrointestinal (GI) tract. The gut microbiome plays multiple roles in upholding human health including maintaining metabolism and regulating immune homeostasis. Dysregulation of the gut flora is known as gut dysbiosis. Studies have shown that gut dysbiosis is linked to the development of malignancies such as colorectal cancer. The purpose of this study is to assess the correlation between an altered gut flora and development of GI malignancies. Methods: The National Inpatient Sample was queried between 2016-2020 for all adult patients with altered gut flora, defined by history of gastrointestinal/bariatric surgeries, history of clostridium difficile infection, long-term antibiotic use, and inflammatory bowel disease. Rates of various cancers were compared between this cohort and all other patients utilizing chi-squared tests. Binary logistic regressions were utilized to calculate odds ratios of developing the various cancers, adjusted for age, sex, Charlson Comorbidity Index (CCI), and smoking status. Results: A total of 7,758,168 hospitalizations with altered gut flora were identified. Esophageal cancer (aOR 3.16, 95% CI 3.08 - 3.24) and colorectal cancer (aOR 3.15, 95% CI 3.11 - 3.18) were observed to have the highest odds of occurring in patients with altered gut flora. Gastric, hepatobiliary, pancreatic, and neuroendocrine cancers also all had significantly higher odds of occurring in patients with altered gut flora. Conclusions: Our study shows that conditions altering the gut flora are associated with increased odds of malignancies of the GI tract. This suggests that the gut microbiome may play an intricate role in regulation of tumor cell proliferation. Optimization of gut health and restoration of gut flora may prove beneficial to patients at high risk for malignancies of the GI tract. Altered Gut Flora (%) Intact Gut Flora (%) Adjusted Odds Ratio (CI) p-value Esophageal 0.4 0.1 3.16 (3.08 - 3.24) <.001 Gastric 0.3 0.1 1.67 (1.64-1.69) <.001 Colorectal 2.5 0.6 3.15 (3.11 - 3.18) <.001 Hepatobiliary 0.4 0.3 1.04 (1.02 - 1.07) <.001 Pancreatic 0.6 0.3 1.34 (1.31 - 1.37) <.001 Neuroendocrine 0.2 0.1 1.38 (1.33 - 1.44) <.001

Nationwide analysis of Medicare expenditure and utilization of EGFR inhibitors from 2018-2022.

112 Background: EGFR inhibitors are used extensively for treatment of metastatic colorectal cancer ranging from first line drugs in combination with chemotherapy to monotherapy for refractory disease. As we increasingly move towards targeted treatments for cancer, financial implications of these drugs must be taken into consideration. In this study we aim to analyze changes in Medicare spending for Cetuximab and Panitumumab to better understand the financial impact of these therapies. Methods: We obtained data from the publicly available Medicare Part D database from Centers for Medicare and Medicaid Services. Data on total spending, total claims, total beneficiaries, average spending per claim, and average spending per beneficiary was extracted from the database. We adjusted the data for 2018 for 2022 using a standard annual inflation rate. Percentage change was calculated using the adjusted data. Results: For Cetuximab, we saw a sharp increase in total spending by 38.77%, from $4,912,903.87 in 2018 to $6,811,781.05 in 2022. The number of claims rose by 31.96%, while the total number of beneficiaries saw a modest increase of 2.44%. Average spending per claim increased by 16.04%, and average spending per beneficiary grew by 49.44%. Panitumumab showed a similar rise in total spending by 43.23%, from $1,594,347.66 in 2018 to $2,283,142.83 in 2022. Claims increased by 25.42%, and beneficiaries grew by 47.83%. Average spending per claim increased by 25.97%, and average spending per beneficiary saw a substantial rise of 65.75%. Conclusions: Our results indicate a significant increase in the financial burden related to EGFR inhibitors. As we move away from chemotherapy and shift our focus to targeted therapies, it is imperative to explore generic alternatives and direct policy changes to ensure equitable access across various racial and socio-economic groups. These findings highlight the need for further research into healthcare policy reforms to ease the burden on our health system. Drug Year Total Spending ($) Total Claims Total Beneficiaries Avg Spending/Claim ($) Avg Spending/Beneficiary ($) Cetuximab 2018 4,912,903.87 551 123 8,072.80 36,163.51 2022 6,811,781.05 727 126 9,369.71 54,061.75 % Change 0.3877 0.3196 0.0244 0.1604 0.4944 Panitumumab 2018 1,594,347.66 5,955 184 242.72 30,714.91 2022 2,283,142.83 7,470 272 305.81 50,736.51 % Change 0.4323 0.2542 0.4783 0.2597 0.6575

Clinical validation of plasma circulating-tumor DNA assay using highly sensitive Safe-SeqS technology for detecting <i>RAS</i> and <i>BRAF</i> V600E in metastatic colorectal cancer.

50 Background: We developed a circulating-tumor DNA (ctDNA) test assay for RAS/BRAF mutations using next-generation sequencing-based Safe-SeqS technology. The clinical performance of detecting RAS and BRAF mutations were evaluated versus approved liquid biopsy and tissue testing, respectively. Methods: Metastatic colorectal cancer (mCRC) patients (pts) were enrolled. The concordance of the RAS mutational status in ctDNA between Safe-SeqS assay and OncoBEAM RAS CRC kit, which is approved as a companion diagnostic in Japan, was evaluated using archival plasma samples. The primary endpoints were positive percent agreement (PPA) and negative percent agreement (NPA). The concordance of the BRAF V600E mutational status between plasma-Safe-SeqS assay and tissue-based testing using MEBGEN RASKET-B kit, which is approved as a companion diagnostic in Japan, was prospectively evaluated. The primary endpoints were sensitivity and specificity of Safe-SeqS assay compared to tissue-based testing. Multivariate analysis using LASSO regression model was performed to evaluate the discordance of BRAF V600E mutational status between Safe-SeqS assay and tissue-based testing. Results: In 125 eligible plasma samples, the PPA and NPA for RAS mutational status in ctDNA were 87.1% (95% confidence interval [CI]: 76.1–94.3) and 95.2% (95% CI: 86.7–99.0), respectively. On the other hand, in 103 eligible pts, the sensitivity and specificity of Safe-SeqS assay for BRAF V600E mutational status were 69.2% (95% CI: 48.2–85.7) and 98.7% (95% CI: 93.0–100.0), respectively. Multivariate analysis revealed the baseline longest diameter and the number of lesions in pts with peritoneal and/or lung metastasis were factors associated with discordance. The sensitivity for BRAF V600E mutations increased to 81.0% (95% CI: 58.1–94.6, fisher’s exact test p =0.02) when the 5 pts with lower tumor burden (peritoneal metastasis with the longest diameter &lt;20 mm, and lung metastasis with the longest diameter &lt;20 mm and &lt;10 lesions, according to the previous report [1] ) were excluded. Conclusions: The clinical validity of the ctDNA assay for detecting RAS/BRAF V600E mutations using Safe-SeqS technology was confirmed in pts with mCRC. Careful attention should be paid for mCRC pts with only peritoneal and/or lung metastases having fewer metastases or smaller diameter lesions. 1. Kagawa Y, et al. Clin Cancer Res 2021.

Efficacy and safety of surufatinib in unresectable or metastatic grade 3 pancreatic neuroendocrine tumors (NET G3): Real-world analysis.

657 Background: Currently, there is limited exploration regarding the treatment of NET G3, resulting in restricted treatment options. Therapeutics for NET G1/2 may serve as an alternative. Surufatinib, with its potent targeting of VEGFRs, FGFR1, and CSF-1R, not only exerts inhibitory effects on tumor angiogenesis but also modulates the immune microenvironment. Due to its demonstrated efficacy and manageable safety profile, it has secured approval for the treatment of G1/2 NETs. Methods: This is a multi-center real-world study that retrospectively analyzes the clinical data of pts with NET G3 who received surufatinib-based treatment from December 2021 to February 2024, aiming to assess its efficacy and safety. Eligible pts were unresectable or metastatic p-NET with ki-67&gt;20%. The primary endpoint was PFS, with secondary endpoints were ORR, DCR, and safety. Results: As of September 2024, data from 37 pts were analyzed. The median age was 54 years (range: 32-80), with 59.5% male. The median Ki-67 index was 30% (range: 25-70%), and 94.6% of the cases were non-functional p-NETs, with 89.2% having liver metastases and 35.1% having bone metastases. In terms of prior treatments, 18.9%, 40.5%, and 40.5% of pts had received 0, 1, and ≥2 systemic therapies, respectively. Among them, 81.1% had previously undergone chemotherapy, 35.1% had received interventional therapy of liver metastases, and 13.5% with everolimus or anti-angiogenic agents. 48.6% pts had surufatinib-based combination treatment. The median PFS was 9.30 months (mo, 95% CI: 8.02–13.02), with an ORR of 21.6% and a DCR of 81.1%. First-line (1L) treatment showed a higher ORR (42.9% vs. 16.7%) and a trend of better PFS (9.67 vs. 9.04 mo, p=0.7) compared to ≥2L treatment. Combination therapy improved ORR (33.3% vs. 10.5%) with a similar PFS (9.30 vs. 9.44 mo, p=0.93) compared to surufatinib monotherapy. Liver metastases had limited impact on PFS (9.93 vs 9.30 mo, p=0.55). Common grade ≥3 adverse events included hypertension (8.1%), proteinuria (5.4%), and elevated bilirubin (5.4%). Conclusions: Surufatinib has demonstrated initial efficacy and manageable safety in pts with NET G3, providing a new treatment option for these pts. First-line therapy may be a favorable factor for improving PFS. To delve deeper into these findings, additional subgroup analyses, with a particular emphasis on pts with ep-NET G3 will be conducted in the future.

Efficacy of PD-1 inhibitor plus chemotherapy versus chemotherapy in advanced esophageal carcinoma: A meta-analysis of phase III clinical trials.

397 Background: Programmed death cell death protein-1 (PD-1) inhibitors combined with chemotherapy have demonstrated survival benefits in patients with advanced esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC). Our pooled analysis aims to analyze the efficacy of PD-1 inhibitor plus chemotherapy in advanced esophageal carcinoma (EC) in phase III randomized clinical trials (RCTs). Methods: We collected data from eligible phase III RCTs searched through PubMed, EMBASE, ClinicalTrials.gov, and meeting abstracts till July 5, 2024. Initial screening revealed 792 articles. We excluded duplicates, review articles and irrelevant studies, and we included eight RCTs that reported objective response rate (ORR), treatment-related adverse events (TRAEs), overall survival (OS) and progression-free survival (PFS). Odds ratio (OR) for ORR and TRAEs, and hazard ratio (HR) for OS and PFS were computed along with a 95% confidence interval (CI) and p-value for pooled analysis, using a random effect model in RevMan v.5.4. We performed a subgroup analysis based on a combined positive score (CPS) for programmed cell death ligand-1 (PDL-1) expression and tumor histology. Results: We included eight phase III RCTs (Jupiter-06, Checkmate 648, Keynote 590, ESCORT-1st, Orient-15, Checkmate 649, ESCORT-NEO, and ASTRUM-007), including 4131 patients with 2137 in group A (PD-1 inhibitor + chemotherapy) and 1994 in group B (placebo + chemotherapy, or chemotherapy). PD-1 inhibitors against EC included nivolumab, pembrolizumab, camrelizumab, sintilimab, toripalimab, and serplulimab. A total of 9.9% of patients were diagnosed with EAC, and 90.1% were ESCC. A pooled analysis showed significant achievement in ORR in group A compared to group B with an OR of 2.19 (CI: 1.77-2.69, p &lt; 0.05, I² = 60%). In terms of OS benefit, group A led to a 29% reduction in death risk compared to group B (HR: 0.71, CI: 0.66-0.76, p &lt; 0.05, I² = 0). Group A also showed a significantly reduced risk of disease progression compared to group B (HR: 0.62, CI: 0.54-0.70, p &lt; 0.05, I² = 60%). Safety analysis revealed more TRAEs (OR: 1.93, CI: 1.43-2.60, p &lt; 0.01, I² = 11%) and grade ≥3 AEs (OR: 1.34, CI: 1.08-1.67, p &lt; 0.05, I² = 54%) in group A compared with group B. Sub-group analysis based on CPS revealed that patients with CPS ≥10 showed more OS (pooled HR: 0.59 vs 0.75) (p = 0.04) and PFS (pooled HR: (0.59 vs 0.64) (p = 0.18) benefits as compared to patients with CPS &lt;10. Survival analysis between ESCC and EAC also exhibited statistically non-significant OS benefits (p = 0.28). Conclusions: PD-1 inhibitor plus chemotherapy as a first-line therapy in advanced EC, mainly in patients with CPS ≥10, showed improved antitumor efficacy in terms of superior ORR, OS, and PFS, with a manageable toxicity profile providing a benchmark for future studies.

MRI imaging and machine learning based radiomics for detection of mixed HCC and CCA tumors: Still a need for liver biopsy?

531 Background: Primary liver cancer (PLC), comprising hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), is a leading cause of cancer mortality globally. The combined hepatocellular cholangiocarcinoma (cHCC-CC) subtype may be less common but is relevant to treatment efficacy. We therefore evaluated the diagnostic accuracy of various approaches in distinguishing these liver cancers. Methods: Patients diagnosed with HCC, CCA, and cHCC-CC at Beijing University Cancer Hospital and Institute, China were included. Radiologists of varying expertise independently assessed MRI scans, and we measured their diagnostic consistency. Radiomic features were extracted from MRI scans, and machine learning was applied to differentiate the cancer types. Results: Standard imaging was insufficient to reliably characterize cHCC-CC. Abdominal imaging experts (AIEs) had a higher mean sensitivity for HCC and CCA, 88% and 84% respectively, while non-experts (NIEs) had a lower sensitivity of 50% for HCC and 38% for CCA (HCC: p=0.03, CCA: p=0.008). Radiomic analysis found ‘Sphericity’ and ‘ClusterShade’ as the most relevant features. However, radiomics algorithms were also not sufficient to distinguish cHCC-CC from either HCC or CCA. Regarding sensitivity, the radiomic-based model was not better than radiologists for any of the three classes (p=0.065 for HCC, p=0.426 for CCA, and p=1.0 for cHCC-CC). The random forest algorithm yielded an accuracy of 76% in the test set, since it correctly classified most HCC and CCA, while only one quarter of cHCC-CC tumors. Conclusions: Until improved diagnostic tools are available, biopsy of liver cancer remains critical to the detection, diagnosis, and effective treatment of these cancers.

Trial in progress for a colorectal cancer detection blood test.

TPS306 Background: Blood-based biomarkers for cancer screening have garnered much anticipation in recent years. Current colorectal cancer screening methodologies such as colonoscopy and stool-based tests are plagued with low compliance rates. While scientific advancement calls for clinical trial recruitment from diverse backgrounds to ensure health equity, traditional clinical trial design has led to the underrepresentation of such populations, resulting in a gap in our understanding of disease conditions, preventative measures, and appropriate treatment across populations. Here, we describe an ongoing, decentralized, prospective sample collection clinical study, PROCEED-CRC, to develop a blood-based CRC screening test in an average-risk population. Methods: The primary endpoint of the study is to achieve the successful enrollment of up to 1500 evaluable patients. Key eligibility criteria include participants aged ≥40 years, planning to undergo an asymptomatic screening colonoscopy, willing to provide a blood sample within 120 days prior to a colonoscopy procedure, and an informed consent prior to participation in the study. Exclusion criteria include individuals who have had a prior malignancy, have undergone diagnostic colonoscopy in the past 9 years, or any other recent CRC screening tests, precancerous findings on recent colonoscopy, or are at high risk for CRC based on germline carrier status. Primary analysis would include summarizing the number and percentage of participants classified to have CRC, advanced adenoma, or non-advanced neoplasia. In order to reach a diverse study cohort that is representative of this average-risk US population aged over 45 years, we implemented several non-traditional recruitment outreach efforts, such as engaging a pharmacy provider to whom individuals may have previously consented to receive messages/notifications. Additional outreach efforts include digital advertisements and referral letters from healthcare professionals and community advocacy groups. Through these efforts, interested participants will have access to a link, a web address, or QR code to be screened for the study. After informed consent and enrollment, participants may schedule a blood draw via a mobile phlebotomy center based on their availability. Participants are considered evaluable if they meet the inclusion criteria, provide informed consent, provide an adequate blood draw, complete the screening colonoscopy within 120 days of the blood draw, and have medical records and pathology reports provided. The data from this study is expected to be completed in May 2025.

Erratum: Risk Stratification in Older Intensively Treated Patients With AML

Understanding the unmet needs in colorectal cancer: Insights from patient and survivor experiences.

59 Background: Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide among men and women combined. Despite improved survival rates, there remains a gap in understanding the specific unmet needs of CRC patients and survivors. These needs include emotional support, information on treatment options, coping strategies, quality of life (QoL), and overall healthcare experience. The stress of a diagnosis is often compounded by the emotional and physical demands of treatment, which extend into survivorship when the disease is not active. Methods: The Colorectal Cancer Alliance launched a survey for colorectal cancer patients, survivors, and caregivers. This IRB-approved cross-sectional study, comprising more than 153 questions, aimed to inform on patient profiles, diagnosis experience, resources, QoL, access to care, and treatment experience. Participation in the survey was solicited from the Alliance network of social media, email, and web-based communities, underscoring the collective effort to understand and address the needs of CRC patients and survivors. Results: The survey included 283 participants, primarily aged 46-55. Key findings showed that 74% of participants had difficulty finding someone who understood their experience, and 41% reported reduced support from others after treatment ended. Additionally, 54% struggled with fatigue, and 51% coped with ongoing stress. CRC significantly impacted careers (64%), dating lives (51%), desire to have children (43%), relationships with spouses or partners (58%), sex lives (80%), and participation in social activities (65%). Although many felt informed before treatment, 46% reported unmet needs for information on complementary or alternative therapies. Conclusions: These results highlight the profound psychosocial and physical challenges faced by CRC patients and survivors, emphasizing the need for healthcare providers to develop tailored treatment and survivorship plans and comprehensive support services. Insights from this survey will guide the Colorectal Cancer Alliance (Alliance) in creating targeted actions, care programs, and support initiatives to address these needs. The Alliance aims to enhance patient care and improve CRC patients' and survivors' QoL, potentially reshaping the future of CRC management and survivorship care.

Impact of HER2-positivity on prognosis and targeted therapeutic outcomes in advanced biliary tract cancer.

629 Background: HER2 overexpression and amplification have been identified as a promising druggable target in biliary tract cancer (BTC). This study aims to characterize the clinical and molecular outcomes associated with HER2 positivity in BTC and evaluate the prognostic implications of HER2-targeted therapies. Methods: A retrospective study was conducted involving patients with advanced BTC diagnosed at Yonsei Cancer Center (YCC) and the University of Texas MD Anderson Cancer Center (MDACC) between 2009 and 2023. Patients were classified as HER2-positive either by immunohistochemistry (IHC 3+ or 2+/ISH+) or by next-generation sequencing (NGS, ERBB2 amplification). Overall survival (OS) and palliative first-line progression-free survival (PFS) were analyzed using Kaplan-Meier and Cox regression methods. Results: A total of 389 advanced BTC patients were initially screened (310 from YCC; 79 from MDACC). Among the 310 BTC patients from YCC with available HER2 IHC results, 78 (25.2%) were HER2-positive and 232 (74.8%) were HER2-negative. HER2 positivity was significantly more common in gallbladder cancer (55.1%) compared to its prevalence in intrahepatic or extrahepatic cholangiocarcinoma (22.8%, p&lt;0.001). Of the 201 patients with available NGS data, 186 (92.5%) were ERBB2 non-amplified; among these, 27 (14.9%) were HER2-positive by IHC. For survival analysis, 310 patients were eligible: 239 from YCC (both HER2-positive and negative) and 71 from MDACC (all HER2-positive). Kaplan-Meier survival analysis indicated a trend towards shorter OS in HER2-positive patients compared to HER2-negative patients (median OS, 13.7 vs. 17.1 months, p=0.084, HR=1.246, 95% CI=0.97–1.60) regardless of exposure to HER2-targeted therapy, while first-line PFS on chemotherapy only was significantly shorter in the HER2-positive group (5.1 vs. 7.4 months, p&lt;0.001, HR=1.906, 95% CI=1.46-2.48). Among HER2-positive patients, 56.8% received HER2-targeted therapy in the second line setting. HER2-positive patients who did not receive HER2-targeted therapy had a significantly poorer prognosis compared to HER2-negative patients (median OS 8.1 vs. 17.1 months, HR=2.46, 95% CI=1.73-3.48), whereas those receiving HER2-targeted therapy had comparable OS to HER2-negative patients (median OS 18.2 vs. 17.1 months, HR=0.95, 95% CI=0.71-1.27). Multivariable analysis identified a history of surgical treatment, radiation therapy, HER2 positivity, and HER2-targeted therapy as independent prognostic factors for OS. Conclusions: HER2 positivity is associated with a poorer prognosis in advanced BTC. However, HER2-targeted therapies improve outcomes, suggesting their potential inclusion in standard care for HER2-positive subgroups. Discrepancies between IHC and NGS in HER2 assessment emphasize the need for optimized testing guidelines in BTC.

Phase 1b portion of the ACTION-1 phase 1b/3 trial of RYZ101 in gastroenteropancreatic neuroendocrine tumors (GEP-NET) progressing after ¹⁷⁷ Lu somatostatin analogue (SSA) therapy: Safety and efficacy findings.

661 Background: RYZ101 ( 225 Ac-DOTATATE) is an alpha-emitting radiopharmaceutical in development for SSTR2+ solid tumors. Alpha-particles have a shorter path length/higher linear energy transfer than beta-particles, causing more frequent double-strand DNA breaks and potentially improving the therapeutic index. ACTION-1 (NCT05477576) is a two-part, global, randomized, controlled, open-label, phase 1b/3 trial of RYZ101 in advanced, well-differentiated SSTR+ GEP-NETs progressing after 177 Lu-SSA therapy. Herein, we report updated results from the phase 1b portion of the trial. Methods: The phase 1b portion of the ACTION-1 trial had a dose de-escalation/Bayesian optimal interval design with boundaries based on a dose-limiting toxicity (DLT) rate of 25%. Patients received RYZ101 IV every 8 weeks for 4 cycles. Planned dose levels (n=6/level): Level 0 (starting dose) 120 kBq/kg; Level 1 90 kBq/kg; Level 2 60 kBq/kg. DLTs were assessed for 56 days after the first RYZ101 dose. Treatment-emergent adverse events (TEAEs) were graded by NCI-CTCAE v5.0. A Data Review Committee oversaw dose de-escalation decisions/safety data. Tumor response was assessed locally by RECIST v1.1. Results: Seventeen patients received at least one dose of RYZ101 at 120 kBq/kg (4 doses: 15 patients; 2 doses: 2 patients; median 8.3 MBq). Baseline patient characteristics: median age 63 years; male (n=11); ECOG PS 0/1 (n=10/7); primary tumor site GI/pancreas (n=12/5). As of 14 December 2023, the most frequent TEAEs were anemia (58.8%), nausea (58.8%), and fatigue (52.9%). Serious adverse events (SAEs) were observed in 6 patients (35.3%, none were treatment-related); grade ≥3 TEAEs occurred in 9 patients (5 were treatment-related, 29.4%). No TEAEs led to treatment discontinuation. Four patients had TEAEs leading to dose modification, dose hold, and/or dose delays. There was one grade 5 TEAE of hepatic failure that was deemed unrelated to the study drug. The confirmed objective response rate was 29.4% (n=5; 1 complete response, 4 partial responses). One additional patient had an unconfirmed partial response at the time of data cutoff, which was subsequently confirmed. Seven patients (41.2%) had stable disease and 3 (17.6%) had progressive disease. The median duration of response was not estimable (95% CI 9.26 months, not estimable), and the median progression-free survival was not estimable (95% CI 12.16 months, not estimable). Conclusions: RYZ101 was well tolerated, and a fixed dose of 10.2 MBq was declared the recommended phase 3 dose. Initial data suggest promising efficacy and a manageable safety profile. Part 2 (phase 3) of the ACTION-1 trial is enrolling and will compare RYZ101 at 10.2 MBq every 8 weeks for 4 cycles with standard of care in patients with advanced SSTR2+ GEP-NETs progressing after 177 Lu-labeled SSAs. Clinical trial information: NCT05477576 .

Frequency and incidence of oncogenic <i>RAS</i> mutations in patients with metastatic pancreatic ductal adenocarcinoma: Derived from the real-world evidence database Foundation Medicine Insights.

777 Background: Approximately 60,000 patients are diagnosed with pancreatic cancer in the United States annually, with half of all cases diagnosed at the metastatic stage. 1 The most common type, pancreatic ductal adenocarcinoma (PDAC), accounts for ~90% of all pancreatic cancers 2 and is characterized by frequent KRAS oncogenic mutations. Newer investigational therapeutics target HRAS and NRAS, in addition to KRAS. To comprehensively characterize the incidence of RAS mutations in patients with PDAC, we analyzed mutational frequency data from the Foundation Medicine Insights (FMI) database. Methods: NGS-based comprehensive genomic profiling (CGP) data from 27,298 PDAC tissue samples were accessed from the FMI database (May 7, 2024 data cut). Only ‘short variants’ in RAS genes ( KRAS , NRAS , and HRAS) occurring at amino acid positions G12, G13, or Q61 that had a frequency 0.1% or greater were included. To estimate the number of new US cases of RAS -mutant PDAC, pancreatic cancer incidence estimates 3 were adjusted by the derived RAS mutational frequency values. All incidence estimates were rounded to the nearest 100. Results: Oncogenic RAS mutations were identified in 92% of PDAC patients, with nearly all being KRAS (91.8%) and the remaining NRAS (0.2%). No HRAS mutations passed our minimum frequency threshold requirement. Individual RAS mutations with frequency &gt;1% included KRAS G12D (39.9%), KRAS G12V (28.6%), KRAS G12R (14.6%), KRAS Q61H (4.2%), KRAS G12C (1.7%), and KRAS Q61R (1.4%). Applying these RAS mutation rates to reported PDAC incidence, we estimate that ~56,000 new patients with PDAC in USA per year will have tumors harboring an oncogenic RAS mutation, including ~51,000 of those with a RAS G12 mutation specifically. Conclusions: Oncogenic RAS mutations are identified from NGS testing in nearly all patients with advanced PDAC. Both the frequency and diversity of RAS mutations in PDAC suggest that PDAC is largely a RAS-driven cancer and that targeting RAS may be useful broadly in this disease. Mutational frequency and incidence at G12, G13, and Q61 amino acid positions in KRAS and NRAS among patients with PDAC. RAS G12 RAS G13 RAS Q61 RAS mutant Mutational Frequency KRAS 85.7% 0.8% 6.3% 91.8% NRAS 0.1% Below threshold 0.1% 0.2% Incidence KRAS 51,300 600 3,700 55,600 NRAS 100 Below threshold 100 200

Tumor tissue modified viral (TTMV)-HPV DNA as a biomarker of treatment efficacy for definitive chemoradiation in anal squamous cell carcinoma: A step towards truly personalized therapy.

10 Background: Cell-free circulating tumor tissue modified viral DNA (ctDNA) has been used as a biomarker to detect recurrence for anal squamous cell carcinoma (ASCC). However, its value in informing treatment modification during definitive chemoradiation (CRT) has yet to be explored. We evaluated ctDNA response during and at completion of definitive CRT to establish patterns of disease response and inform future studies to personalize treatment. Methods: From 11/2022 to 6/2024, 13 consecutive patients with biopsy proven, non-metastatic ASCC received definitive CRT and had ctDNA testing using a commercially available droplet digital quantitative PCR assay. ctDNA testing was done at baseline (pre-CRT), week 4 of CRT, and/or end of CRT, 1-3 months post-CRT, and every 6 months thereafter. CRT included concurrent 5FU/MMC (or capecitabine/MMC) and radiotherapy according to RTOG 0529. Treatment response assessment included: physical exam, anoscopy, and imaging with PET/CT, CT C/A/P +/- MRI abdomen and pelvis. Results: 13 patients had ctDNA testing and 11 patients had HPV-positive ASCC and tested positive for ctDNA. The 11 patients with detectable baseline ctDNA were included in this analysis. The median age at diagnosis was 63 years old. Staging included: 1- Stage IIA, 7- Stage IIB, 1- Stage IIIA, 2- Stage IIIC. 1 patient was cN0, while 11 were cN1. With a median follow-up from completion of CRT of 13 months, 4 patients have persistent or recurrent disease: 2 with distant metastases, 1 with persistent local disease (1 month post-CRT), and 1 with local and distant recurrence. Baseline value of ctDNA did not correlate to stage at diagnosis, rate of clearance during CRT, or likelihood of recurrence. 5 of 11 patients cleared ctDNA by week 4 of CRT. Of 5 patients who cleared ctDNA by week 4 of CRT, 4 remain NED and 1 developed distant metastases. Of 6 patients with persistent ctDNA at week 4 of CRT, 3 have persistent or recurrent disease- 1 local persistence 1 month post-CRT, 1 local and distant recurrence 6 months post-CRT, and 1 with distant recurrence 12 months post- CRT. Among 6 patients who cleared ctDNA by the final week of CRT, 1 patient developed recurrent disease. Among the 4 patients in the series with residual/recurrent disease, 3 of them had not cleared ctDNA by the end of CRT. Of 10 patients with ctDNA testing at 1 month post-CRT, 8 had no detectable ctDNA. 2 patients with persistent (1) or recurrent (1) ctDNA at 1 month post-CRT developed disease recurrence- 1 with distant recurrence and 1 with local and distant recurrence. Conclusions: ctDNA assessment during CRT may provide insight into disease response that can predict patterns of failure and facilitate personalized therapy- treatment intensification, deintensification, or additional testing to detect early metastatic disease. Larger studies and clinical validation are needed.

Intra-arterial gemcitabine versus intravenous gemcitabine: Pharmacokinetic sub-study of the TIGeR-PaC phase 3 clinical trial.

719 Background: Localized, dual balloon catheter-mediated, intra-arterial delivery of gemcitabine (IAG) targeted to tumors/tissue can provide higher local drug potency (1). Furthermore, IAG may result in a decreased systemic drug concentration and associated side effects. In patients with locally advanced pancreatic cancer (LAPC), this approach is currently being tested in the TIGeR-PaC Phase 3 clinical trial. Herein we report the results of a 19-patient pharmacokinetics (PK) sub-study analysis within TIGeR-PaC. Methods: PK analyses were performed for a total of 19 participants across 6 TIGeR-PaC study sites; 11 participants received IAG with the RenovoCath dual balloon catheter at 1000 mg/m 2 over 20 minutes and 8 participants received intravenous gemcitabine (IVG) (5 at 1000 mg/m 2 , 2 at 800 mg/m 2 , 1 at 500 mg/m 2 ) over 30 minutes. IAG target treatment arteries were either the superior mesenteric artery (SMA) (n=5) or branches of the celiac axis (n=6). At T = -5, 10, 15, 20, 30, 40, 60, and 90 minutes from the onset of infusion, 2 mL of blood was collected in heparinized tubing containing 25 mcg/mL of tetrahydrouridine. Plasma from each sample was frozen and shipped to a reference lab for gemcitabine assays. Maximum plasma drug concentration (C max ) and the area under the drug plasma concentration curve (AUC) based on the terminal phase were compared between the two groups; for these dose-dependent parameters, only participants who received 1000 mg/m 2 gemcitabine (IAG, N=11; IVG, N=5) were included in the comparison analysis. Results: As shown in the table, AUC was significantly lower with IAG (4.99) compared to IVG (9.97) ( P = 0.019). Peak plasma gemcitabine concentrations were also lower with IAG (12.9 mcg/mL) vs. IVG (14.6 mcg/mL) despite a 50% higher drug concentration during IAG vs. IVG (1000 mg/m 2 infused over 20 minutes vs. 30 minutes, respectively). There was no difference in plasma levels between IAG treatment sites (SMA vs. celiac axis). Conclusions: In this analysis, localized, dual-balloon catheter-mediated IAG resulted in decreased systemic levels of gemcitabine compared to IVG. Thus, in addition to providing increased local potency, the IAG approach may also be beneficial in decreasing gemcitabine-related systemic side effects. 1. Farsad K, et al. 2024. JVIR 35:1043-48 e3. Clinical trial information: NCT03257033 . Effects of treatment mode on mean pharmacokinetic parameters for gemcitabine. PK parameter IAG Group(N=11) IVG Group(N=5) C max (mcg/mL), Mean (SE) 12.9 (±2.4) 14.6 (±1.2) AUC (hr ⋅ mcg/mL), Mean (SE) 4.99 (±0.96) 9.97 (±1.9) AUC = area under the curve; C max = maximum serum concentration; IAG = intra-arterial gemcitabine; IVG = intravenous gemcitabine; PK = pharmacokinetic; SE = standard error.

RNA communication between organisms inspires innovative eco-friendly strategies for disease control