Citations

e15146 Background: Wnt/ß-catenin signaling dysregulation is found in approximately 25% of hepatocellular carcinoma (HCC) patients. The impact of B-catenin activation on HCC overall survival has remained controversial. Prior studies suggest activating CTNNB1 mutations may predict for immunotherapy (IO) resistance while others did not corroborate this finding. Here we describe the clinical outcomes of advanced HCC patients (pts) with CTNNB1 (+) and without CTNNB1 (-) mutations treated with novel first line IO/anti-VEGF therapies. Methods: We conducted a multicenter, retrospective analysis of pts with HCC who had molecular analysis performed between 2019 and 2023 at Mayo Clinic in Minnesota, Arizona, and Florida. The study was reviewed and approved by the IRB. Clinical and molecular features were compared descriptively. The primary outcomes were time to treatment failure (TTF), defined as time from first-line treatment initiation to off treatment or death, and overall survival (OS), defined as time from first-line treatment initiation to death, compared between the two cohorts using the Kaplan-Meier method. Results: We identified 29 CTNNB1+ and 62 CTNNB1- (wt) pts with HCC. Median age at diagnosis was 66 (range 30-86), 80 (88%) were Caucasian, 68 (75%) were male gender, and 22 (24%) had etiology as hepatitis B/hepatitis C, 82 (90%) were Child-Pugh A and 77 (85%) were Barcelona Clinic Liver Clinic (BCLC)=C at diagnosis. Eighteen (90%, n=20) CTNNB 1+ pts received first-line IO (Atezolizumab/bevacizumab [AB]) vs 39 (72%, n=54) in CTNNB1- pts. All pts were microsatellite stable (MSS). CTNNB1+ had a similar median tumor mutational burden (TMB), higher rate of TERT co-mutation, and lower rate of TP53 co-mutation (table) compared to CTNNB-. Of 57 AB pts, 5 (27%) of CTNNB1 + had an objective response, compared to 6 (16.7%) CTNNB1- pts. Time to treatment failure with first-line AB and overall survival were similar between the two cohorts (Table). Conclusions: Our study suggests CTNNB1 status is not prognostic in HCC pts receiving IO based therapy. Prospective study is warranted to further investigate predictive biomarkers for HCC sensitivity to immune checkpoint inhibitors and VEGF-targeted therapy. [Table: see text]

Abstract Aim To assess the efficacy of ctDNA measurement at different time intervals in predicting response and prognosis in patients diagnosed with locally advanced rectal cancer (LARC) who underwent neoadjuvant treatment prior to curative resection. Method English language randomized controlled trials and observational studies, published from 1946 to January 2024, comparing outcomes between ctDNA‐positive and ctDNA‐negative patients with LARC undergoing neoadjuvant treatment prior to curative surgical resection were included in the search. The search included Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and the Cochrane Database of Systematic Reviews (CDSR). Results Data for 1022 patients were analysed. Patients with positive ctDNA in the preoperative period had more than five times the risk of developing distant metastasis (RR [95% CI] 5.03 [3.31–7.65], p < 0.001), while those with positive ctDNA in the postoperative period had more than six times the risk (RR [95% CI] 6.17 [2.38–15.95], p < 0.001). There was no significant relationship between ctDNA status at baseline, pre‐, or postoperative periods and achievement of pCR (RR [95% CI] 1.21 [0.86–1.7], 1.82 [0.94–3.55], 1.48 [0.78–2.82], p = 0.27, 0.08, and 0.23, respectively). However, patients with positive ctDNA in the pre‐ and postoperative periods had more than 13 and 12 times the risk of overall disease relapse after curative‐intent treatment (RR [95% CI] 13.55 [7.12–25.81], 12.14 [3.19–46.14], p < 0.001), respectively. Conclusion ctDNA could potentially guide treatment and follow‐up in LARC, predicting high‐risk patients for disease relapse, allowing individualized surveillance and treatment strategies. Prospective studies are needed for standardization.

Background: The predictive and prognostic role of BRAF alterations has been evaluated in colorectal cancer (CRC); however, BRAF alterations have not been fully characterized in non-CRC gastrointestinal (GI) malignancies. In the present study, we report the frequency and spectrum of BRAF alterations among patients with non-CRC GI malignancies. Methods: Patients with CRC and non-CRC GI malignancies who underwent somatic tumor profiling via a tissue-based or liquid-based assay were included in this study. Gain-of-function BRAF alterations were defined as pathogenic/likely pathogenic somatic short variants (SVs), copy number amplifications ≥8, or fusions (RNA or DNA). Results: Among 51,560 patients with somatic profiling, 40% had CRC and 60% had non-CRC GI malignancies. BRAF GOF alterations were seen more frequently in CRC (8.9%) compared to non-CRC GI malignancies (2.2%) (p < 0.001). Non-CRC GI malignancies with the highest prevalence of BRAF GOF alterations were bile duct cancers (4.1%) and small intestine cancers (4.0%). Among BRAF GOF alterations, class II (28% vs. 6.8%, p < 0.001) and class III (23% vs. 14%, p < 0.001) were more common in non-CRC GI malignancies. Among class II alterations, rates of BRAF amplifications (3.1% vs. 0.3%, p < 0.001) and BRAF fusions (12% vs. 2.2%, p < 0.001) were higher in non-CRC GI malignancies compared to CRC. Conclusions: Non-CRC GI malignancies demonstrate a distinct BRAF alteration profile compared to CRC, with a higher frequency of class II and III mutations, and more specifically, a higher incidence of BRAF fusions. Future studies should evaluate clinical implications for the management of non-CRC GI patients with BRAF alterations, especially BRAF fusions.

Colorectal cancer (CRC) poses a significant global health challenge. Notably, the risk of CRC escalates with age, with the majority of cases occurring in those over the age of 65. Despite recent progress in tailoring treatments for early and advanced CRC, there is a lack of prospective data to guide the management of older patients, who are frequently underrepresented in clinical trials. This article reviews the contemporary landscape of managing older individuals with CRC, highlighting recent advancements and persisting challenges. The role of comprehensive geriatric assessment is explored. Opportunities for treatment escalation/de-escalation, with consideration of the older adult’s fitness level. are reviewed in the neoadjuvant, surgical, adjuvant, and metastatic settings of colon and rectal cancers. Immunotherapy is shown to be an effective treatment option in older adults who have CRC with microsatellite instability. Promising new technologies such as circulating tumor DNA and recent phase III trials adding later-line systemic therapy options are discussed. Clinical recommendations based on the data available are summarized. We conclude that deliberate efforts to include older individuals in future colorectal cancer trials are essential to better guide the management of these patients in this rapidly evolving field.

Background: Identifying the projected incidence of hepatobiliary cancers and recognizing patient cohorts at increased risk can help develop targeted interventions and resource allocation. The expected incidence of subtypes of hepatobiliary cancers in different age groups, races, and genders remains unknown. Methods: Historical epidemiological data from the Surveillance, Epidemiology, and End Results (SEER) database was used to project future incidence of hepatobiliary malignancies in the United States and identify trends by age, race, and gender. Patients ≥18 years of age diagnosed with a hepatobiliary malignancy between 2001 and 2017 were included. US Census Bureau 2017 National Population projects provided the projected population from 2017 to 2029. Age–Period–Cohort forecasting model was used to estimate future births cohort-specific incidence. All analyses were completed using R Statistical Software. Results: We included 110381 historical patients diagnosed with a hepatobiliary malignancy between 2001 and 2017 with the following subtypes: hepatocellular cancer (HCC) (68%), intrahepatic cholangiocarcinoma (iCCA) (11.5%), gallbladder cancer (GC) (8%), extrahepatic cholangiocarcinoma (eCCA) (7.6%), and ampullary cancer (AC) (4%). Our models predict the incidence of HCC to double (2001 to 2029) from 4.5 to 9.03 per 100,000, with the most significant increase anticipated in patients 70–79 years of age. In contrast, incidence is expected to continue to decline among the Asian population. Incidence of iCCA is projected to increase, especially in the white population, with rates in 2029 double those in 2001 (2.13 vs. 0.88 per 100,000, respectively; p < 0.001). The incidence of GC among the black population is expected to increase. The incidence of eCCA is expected to significantly increase, especially among the Hispanic population, while that of AC will remain stable. Discussion: The overall incidence of hepatobiliary malignancies is expected to increase in the coming years, with certain groups at increased risk. These findings may help with resource allocation when considering screening, treatment, and research in the coming years.

759 Background: BRAF V600E mutations are present in 5-10% of patients with advanced colorectal cancer (CRC) and associated with poor prognosis. Recently, there was tumor agnostic FDA approval of dabrafenib + trametinib for BRAF V600E mutated solid tumors. However, the frequency of BRAF alterations ( BRAF alt), especially non-V600E, in other gastrointestinal (GI) cancers are not well described. This study characterizes BRAF alt in CRC vs other GI cancers (non-CRC). Methods: De-identified records from 51,560 patients diagnosed with GI cancers were retrospectively analyzed from the Tempus database. The molecular landscape including presence of pathogenic/likely pathogenic BRAF alt was evaluated by panel-based tissue DNA, RNA or ctDNA NGS sequencing (Tempus Labs, Inc.). The frequency of BRAF alt, co-mutations, MSI, TMB and MMR were compared between CRC and (non-CRC) by Chi-squared/Fisher’s Exact or Wilcoxon rank-sum tests. False-discovery rate correction was used for multiple testing. Results: BRAF alt were identified in 8.9% of CRC and 2.2% of non-CRC cohort. BRAF alt frequency varied by tumor type with the highest observed in colon (11%), jejunum (9.6%), intrahepatic bile duct (5.3%), rectal (4.5%), and ampulla of vater (4.5%) and lower in esophageal (0.9%) and gastric (1.6%). BRAF alt CRC had higher frequency of females (57% vs 45%, p <0.001) and older age at diagnosis (67 vs 66 yrs, p=0.029) compared to non-CRC group. Race was also significantly different, with white patients being more predominant in both groups (85% CRC,77% non-CRC). Among the BRAF alt, fusions (12% vs 2.2%, p <0.001) and amplifications (3.1% vs 0.3%, p <0.001) were higher in non-CRC vs CRC (Table). BRAF V600E was most common in all GI tumors, but higher in CRC vs non-CRC (75% vs 27%, q<0.001). Mutations higher in non-CRC vs CRC (q<0.009) included class II (G469A, K601E, BRAF-SND1, and BRAF amplification) and class III (D594N & N581S) BRAF alt. BRAF co-occurring mutations in CRC were TP53 (70%), APC (42%), RNF43 (30%), SMAD4 (22%), and PIK3CA (21%), and in non-CRC: TP53 (52%), CDKN2A (32%), CDKN2B (20%) SMAD4 (17%) and MTAP (16%). Among tissue samples, MSI-H (30% vs 4.%, p <0.001) and TMB-H ≥10 mut/MB (32% vs 6.7%, p <0.001) were more frequent in BRAF alt CRC vs non-CRC. Conclusions: Meaningful differences were found between the groups in terms of demographics, frequency, and type of BRAF alt and co-occurring mutations. In particular, certain BRAF fusions were present in a higher proportion of other GI cancers and could be an important therapeutic target for this patient population.[Table: see text]

55 Background: Nearly one-half of deficient mismatch repair (d-MMR) metastatic colorectal cancers (mCRC) demonstrate durable responses to immune checkpoint inhibitors (ICIs). Given preclinical data indicating that liver metastases sequester activated CD8+ T cells from systemic circulation, we examined clinical outcome by metastatic site. Methods: In a retrospective cohort of patients with d-MMR mCRCs treated at multiple centers in France (n=66), we sought to validate data from a U.S. cohort, and then performed pooled analysis (n=104). All patients received first-line ICI monotherapy. Metastatic site was analyzed in relationship to tumor response (RECIST version 1.1), and progression-free survival (PFS) by multivariable stratified Cox regression after adjustment for covariates. Results: Objective responses were achieved in 38/66 (58%) patients in the validation cohort. Best tumor response included 13 (20%) complete responses (CR), 25 (38%) partial responses (PR), 16 (25%) stable disease, and 11 (17%) progressive disease (PD). One-year and 5-year PFS rates were 73% and 67%, respectively; 18 (27%) patients progressed during immunotherapy. Best tumor response was attenuated in patients with liver metastasis ( P=0.03). Presence of liver metastasis, but not other sites, was associated with significantly poorer PFS after adjustment for covariates (HRadj 2.82; 95%CI, 1.08-7.39; Padj=0.03). In a pooled analysis, liver metastasis remained significantly and independently associated with poorer PFS (HRadj 3.18; 95%CI, 1.52-6.67; Padj=0.002) and with attenuated tumor best response (P=0.01). Conclusions: Metastasis to the liver, but not other sites, was validated as an independent factor associated with poorer response and survival after ICI treatment in d-MMR mCRCs. These data underscore the need for novel therapeutic strategies in these patients. [Table: see text]

31 Background: Incidence of early-onset colorectal cancer (eoCRC, <50 years of age at diagnosis) is increasing globally. However, little is known regarding symptom burden in this sub-population. We compared symptoms in patients with eoCRC to those of patients with average-onset CRC (aoCRC, diagnosed at age ≥ 50). Methods: E2C2 is a stepped-wedge, cluster-randomized pragmatic trial evaluating a collaborative care model for the assessment and management of six symptoms [Sleep disturbance, Pain, Physical function impairment, Anxiety, emotional Distress, and Energy deficit (SPPADE)]. Patients were asked to complete assessments rating each of these symptoms on an 11-point numerical rating scale. Symptom severity was classified as mild (0-3), moderate (4-6), or severe (7-10). We conducted a subgroup analysis of patients with CRC, comparing SPPADE symptoms on an initial survey, regardless of timing in treatment course, between patients with eoCRC and aoCRC. Results: Patients with CRC (n=4281) completed a survey between March 2019 and December 2022. Patient demographics and SPPADE symptoms are reported in the table. Patients with eoCRC were more likely to report severe sleep disturbance ( p<0.0001), pain ( p=0.03485), anxiety ( p<0.0001), emotional distress ( p<0.0001), and fatigue ( p=0.01083). In patients with eoCRC, women were more likely to report severe pain (12.6% vs 6.9%, p=0.0069), anxiety (16.1% vs 10.0%, p=0.012), emotional distress (12.1% vs 5.4%, p=0.00066), fatigue (18.9% vs 13.4%, p=0.038), and physical function impairment (10.1% vs 5.8%, p=0.026) compared to men. Conclusions: Patients with eoCRC reported higher symptom severity than patients with aoCRC. This suggests unique needs for symptom management in patients with eoCRC. Additional research is needed to evaluate how time since diagnosis, disease characteristics, cancer-directed treatment patterns, and co-occurring symptoms are associated with specific symptoms in this population. [Table: see text]

26 Background: Local therapies have the potential to cure a portion of patients with colorectal cancer with liver-only metastatic disease (CRLM). Peri-operative chemotherapy has not been shown to improve overall survival when added to local therapy in CRLM. Circulating-tumor DNA (ct-DNA) may have potential to help guide management decisions following local therapy. Methods: We conducted a retrospective analysis of health records of CRLM patients who had tumor-informed ct-DNA (Signatera) measurement following curative-intent local therapy prior to August 30th, 2023. Disease-free survival (DFS) was defined as the time from ct-DNA test until radiographic evidence of disease. Descriptive characteristics of the cohort, ct-DNA results and their impact on adjuvant therapy decisions were recorded. Survival analysis was carried out using R software v4.3.1 with survival and survminer packages. The Kaplan–Meier method was used to estimate the survival distribution. Log-rank test was used for comparison. A multivariable Cox proportional hazards model was used to assess prognostic factors associated with DFS ( coxph). Results: 27 patients with CRLM underwent local therapy followed by ct-DNA collection. The median age was 61 years, 67% were male, and 85% were White. Molecular characteristics: KRAS 31%, NRAS/BRAF 0%, microsatellite instability 4%. The median time from initial diagnosis to treatment of liver disease was 21.0 months. 63% of patients received less than 6 months of systemic therapy prior to local therapy. ct-DNA was checked prior to definitive therapy in 12 cases and was positive in 5 cases (detection rate of 42%). Liver-directed therapy involved: resection (n=15), ablation (6), radiation (2) or a combination (4). The median follow-up time from liver-directed therapy was 13.2 months. Post-local therapy chemotherapy was initiated prior to recurrence in 59% of cases. ct-DNA results contributed to immediate post-management decisions in 15% of cases. There were 14 radiographic recurrences (11 to liver only, 3 to other sites). Positive ct-DNA on initial testing following local therapy was associated with poorer DFS in univariate analysis and was the only prognostic factor identified on multivariable analysis. Conclusions: ct-DNA positivity following local therapy for CRLM is associated with earlier recurrence. Baseline testing before local therapy may be important for interpretation of testing results post-local therapy, given frequent missed disease detection. Additional clinical trial data is needed to explore ct-DNA-guided treatment decisions in CRLM. [Table: see text]

356 Background: Autologous anti-claudin 18.2 (CLDN18.2) CAR T cell, satricabtagene autoleucel (satri-cel), was developed to treat solid tumors. We report the completed results of the Phase 1b ELIMYN18.2 study (Cohort A) in gastric/gastroesophageal junction (GC/GEJ) and pancreatic cancer (PC). Methods: This single-arm, open-label, Phase 1b/2 study (NCT04404595) evaluated the safety and efficacy of satri-cel in patients with CLDN18.2-positive advanced GC/GEJ or PC. Cohort A consisted of a modified 3+3 design. After a conditioning regimen of fludarabine, cyclophosphamide, and nab-paclitaxel, patients were administered 1-3 cycles of satri-cel. The primary objectives were safety and determination of the recommended Phase 2 dose (RP2D). Adverse Events (AEs) were graded per CTCAE 5.0, objective response rate (ORR), and clinical benefit rate (CBR) including CR, PR, and ≥6-month SD were assessed by the investigator per RECIST 1.1. Results: As of May 14, 2023, twenty-four patients underwent leukapheresis in Cohort A. Nineteen patients (7 GC/GEJ and 12 PC) with a median of 3 (range: 1-8) prior therapeutic lines had satri-cel at three dose levels (DLs) between 250×106 and 600×106 cells. Seven patients received a 2nd dose and two patients received a 3rd dose of satri-cel at a median of 113 and 259 days, respectively, post-first infusion. All 19 patients experienced at least one AE. No DLTs occurred and 17 patients experienced cytokine release syndrome (CRS). Two cases of Grade 3 CRS were reported, and all other CRS were Grade 1 or 2. Two Grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) occurred. All CRS and ICANS were resolved. No severe gastrointestinal-related AEs were found. No increased toxicities were reported after any reinfusion. No satri-cel treatment-related death occurred. For all patients, the best ORR was 26.3%, the median DOR was 3.7 months and the CBR was 42.1%. The median PFS was 5.2 months, and overall survival was 12.8 months (95% CI 5.7-NE) after leukapheresis, and the median PFS was 3.3 months, and overall survival was 8.9 months (95% CI 3.3-NE) after the first infusion. In the GC/GEJ group, the ORR was 42.9% (3/7), the median DOR was 6.9 months and the CBR was 57.1%. In the PC group, the ORR was 16.7% (2/12), the median DOR was 3.4 months and the CBR was 33.3%. An ORR of 42.9% (3/7) and a CBR of 71.4% were reported at the DL3 of 600×106 cells which was selected as RP2D. At DL3, one GC patient achieved a CR and two PC patients had PR, suggesting the PC group achieved an ORR of 40% (2/5) and the GC group achieved an ORR of 50% (1/2). In addition, tumor shrinkage was detected in 73.7 % (14/19) of patients. Conclusions: The safety profile and therapeutic efficacy of satri-cel were shown to be promising in heavily pretreated patients with CLDN18.2-positive advanced GC/GEJ and PC . In the Phase 2 study, the first patient with GC received satri-cel in May 2023. Clinical trial information: NCT04404595 .