Browse Articles

Tumor lysis syndrome in colorectal cancer: A systematic review of clinical characteristics.

122 Background: Tumor lysis syndrome (TLS) is an oncologic emergency resulting from the release of potassium, phosphorus, and nucleic acids from tumor cells. While rare in colorectal cancer (CRC), TLS is linked with high mortality, and literature is limited. This study aims to summarize the clinical characteristics of patients with TLS in CRC. Methods: We conducted a systematic review of TLS in CRC through a comprehensive literature search in PubMed and manual searches from January 1st, 1993, up to September 13th, 2024. Keywords included "Tumor Lysis Syndrome," "Colorectal Cancer," and "Colon Cancer." 32 studies were found, identifying 11 spontaneous and 22 therapy-related TLS cases. Quantitative and qualitative data were extracted for descriptive analysis. Results: A total of 33 patients (16 males and 15 females) had a mean age of 56.5 ± 17.8 years at TLS diagnosis. The mean ages for males and females were 58.3 ± 7.1 and 55.8 ± 13.7 years, respectively (p=0.59). The primary histology was adenocarcinoma (92%) followed by neuroendocrine (8%) (data unavailable for 9 patients). Among 15 patients with grading information, Grade 2 tumors were most common (53%), followed by Grade 3 (40%) and Grade 1 (7%). Staging data was available for 32 patients. Most patients had Stage IV disease (94%), with frequent metastases to the liver (93%), lungs (30%), and bones (10%). Hyperuricemia is present in all patients (1 patient without data). Acute kidney injury (AKI) was present in all patients (4 patients without data). Hyperphosphatemia was found in 82% of patients (5 patients without data). Hypocalcemia was noted in 52% (10 patients without data), and hyperkalemia was found in 74% (6 patients without data). Out of the 33 patients, 11 experienced spontaneous TLS (33%) and 22 had therapy-related TLS (67%). Duration of TLS onset following therapy was available for 17 patients, including one outlier at 30 days on Capecitabine. The mean duration for therapy-related TLS, excluding the outlier, was 3.8 ± 2.5 days. Among the 22 patients on therapy, 59% received 5-Fluorouracil (5-FU)-based treatment. 31% of those receiving 5-FU had combination therapy with Bevacizumab. Death occurred in 59% of patients, with data missing for 4 patients. Conclusions: TLS in colorectal cancer (CRC) is associated with a mortality rate of up to 59% and shows no gender preference. Identifying predictive factors is crucial for TLS prophylaxis. Patients with TLS in CRC often present with Stage IV disease, liver metastasis, hyperuricemia, and acute kidney injury (AKI).

Effect of adjuvant radiotherapy after endoscopic resection of early esophagus cancer to prevent new intraluminal mucosal recurrence.

381 Background: Endoscopic resection (ER) is effective for treating T1a early esophageal squamous cell carcinoma (ESCC). Occasional distant metastasis and recurrence are inevitable invasion in depth of muscularis mucosa(MM). Additional surgical resection is an effective means for cure and prevent recurrence, but it imposes a heavy physical burden. Chemoradiation therapy (CRT) is a comparable alternative to surgery. Not all patients will want those additional treatment. Another problem is the occurrence of new esophagus intraluminal mucosal recurrence. After endoscopic treatment, there is an increased risk of scarring and deformity. But there are few reports of the effectiveness of additional RT in suppressing new lesions. This study was designed to verify the efficacy of not only curability but also suppressive effect the occurrence of new lesions additional treatment of T1a(MM) ESCC. Methods: This study was a retrospective study. We reviewed 71 consecutive patients who underwent ER followed by clinical stage I (T1a: MM) ESCC. We compared patients in the radiotherapy group or non-radiotherapy group after ER. Patients of radiotherapy group received radiation within 3 months after ER. All patients underwent regular follow-up. Recurrence, recurrence-free survival, cancer-specific survival, overall survival, and complications were evaluated. Results: There were 34 cases of radiotherapy group and 37 cases of non-radiotherapy group. 3 patients (8.9 %) in the radiotherapy group experienced intraluminal mucosal recurrence, and 2 patients (6.6 %) experienced local recurrence. On the other hand, in the non-radiotherapy group, 9 patients (24.3 %) experienced intraluminal mucosal recurrence, and 7 patients (18.9 %) experienced local recurrence (intraluminal mucosal recurrence: p< 0.05, local recurrence p=0.14). The recurrent group received chemotherapy. The 3-year cumulative recurrence-free survival was 97 % in the radiotherapy group and 83.7 % in the non-radiotherapy group (p< 0.05). No severe radiation toxicities were recorded. Conclusions: The radiotherapy after ESD reduced the risk of lymph nodes recurrence not only local lymph node recurrence but also new intraluminal mucosal recurrence, and safe and effective therapeutic strategy.

Autophagy-related 7 (ATG7) regulates food intake and liver health during asparaginase exposure

A multimodal deep learning approach for the prognostic stratification of patients with colorectal cancer (CRC).

287 Background: Traditional prognostic systems like the AJCC TNM staging for colorectal cancer (CRC) often fall short in predicting long-term patient outcomes. These systems often rely on limited pathologic features, leading to generalized approaches to treatment despite diverse tumor heterogeneity, such as the complex interaction between the tumor-host microenvironment. There is therefore a pressing need for more accurate, scalable tools to enhance decision-making and predict outcomes for patients with CRC. Methods: Tumor sections from 191 CRC patients were comprehensively stained for CD8 to examine CD8-positive tumor-infiltrating lymphocytes (TILs). To account for tumor heterogeneity, multiple areas of the tumor were evaluated to include intertumoral and peritumoral areas. Slides were digitized and quantitatively analyzed using a cloud-based platform (SpatialX Diagnostics, Inc. USA). Additionally, clinicopathologic features including patient demographics, 8th edition AJCC staging, lymphovascular invasion (LVI), perineural invasion (PNI), mismatch repair (MMR) protein status, tumor location, presence/development of distant metastases, and patient follow-up were collected. Merging CD8 AI findings with clinicopathologic features, a complete data set was available for 175 patients. Cases were randomly assigned into 70% training and 30% validation. In the training set, unsupervised artificial intelligence (AI) models integrated clinicopathologic data and CD8-positive TIL counts using vision transformer models. The final model combined spatially resolved pathologic features with clinical variables to statistically predict overall survival (OS) and distant metastasis risk (DMR). Results: In the validation cohort, the model stratified patients into two groups based on a deep learning-derived risk score, with statistically significant differences between low-risk and high-risk groups for OS (p<0.02) and DMR prediction (p<0.0001), For OS prediction, the model selected tumor site, PNI, MMR status, epithelial and stromal CD8-positive TILs, and 5 deep vision features as the top 10 clinically significant features. For DMR prediction, the age, T- and N-stage, PNI, and 6 deep vision-derived features as key predictors. Conclusions: As captured by vision transformers, the distribution and spatial arrangement of CD8-positive TILs are critical factors in patient stratification for OS and DMR. AI-driven models like the one herein offer the potential for more personalized management strategies, advancing CRC management and improving patient outcomes beyond traditional prognostic staging systems and parameters.

Phase 2 trial of defactinib in combination with avutometinib in patients with advanced diffuse-type gastric cancer.

TPS505 Background: Diffuse-type gastric cancer (DGC) accounts for approximately one third of gastric cancer diagnoses. DGC is characterized by poor differentiation, discohesive growth, frequent peritoneal spread, chemoresistance, and inferior survival compared to intestinal-type gastric cancer. Moreover, DGC is commonly genomically stable and often lacks clinically actionable targets such as ERBB2 amplification. Alterations enriched in DGC including loss-of-function CDH1 mutations and gain-of-function RHOA mutations can facilitate increased focal adhesion kinase (FAK) signaling that drives tumor proliferation, invasiveness, and metastasis. Recent preclinical studies demonstrated that the FAK inhibitor defactinib can inhibitor DGC growth in vitro and in vivo . FAK inhibitor monotherapy leads to compensatory mitogen-activated protein kinase (MAPK) pathway upregulation, which can be overcome with combined FAK and MEK inhibition. In preclinical DGC xenograft models, defactinib plus the RAF/MEK clamp avutometinib led to deep tumor regressions, suggesting synergistic activity of the combination. The goal of this study is to investigate the efficacy and tolerability of avutometinib plus defactinib in patients with advanced DGC refractory to standard therapy. Methods: This investigator-initiated, multicenter phase 2 trial will enroll 27 patients with metastatic/unresectable gastric or gastroesophageal junction carcinoma classified as diffuse, poorly cohesive, signet ring cell, or mixed type with progression on at least one line of therapy including platinum/fluorouracil chemotherapy. Patients with known pathogenic CDH1 and/or RHOA alterations regardless of histology are also eligible. Patients must have ECOG PS 0/1 and can have either measurable or evaluable non-measurable disease per RECIST 1.1 criteria. Avutometinib is given 3.2 mg orally twice weekly and defactinib is given 200 mg orally twice a day, both for 3 weeks on/1 week off for each 28-day cycle. The primary endpoint is 6-month PFS rate, with secondary endpoints including ORR, OS, DOR, and tolerability. Exploratory studies will interrogate FAK/MAPK pathway activation, ctDNA dynamics, and the impact of the combination of avutometinib/defactinib on the tumor microenvironment from pre- and on-treatment biopsies. The trial was opened for enrollment in August 2024. Clinical trial information: NCT06487221 .

Fruquintinib plus best supportive care for patients with metastatic colorectal cancer: Characterization of patients who had an overall survival of ≥10 months in the FRESCO-2 study.

142 Background: Fruquintinib (F) is a highly selective, oral tyrosine kinase inhibitor of all 3 vascular endothelial growth factor receptors (VEGFRs -1, -2, -3) that is approved by the US FDA and in the EU, UK, and Japan for previously treated metastatic colorectal cancer (mCRC), regardless of biomarker status. FRESCO-2 (NCT04322539) met its primary endpoint demonstrating significantly improved overall survival (OS) with F + best supportive care (BSC) vs placebo (P) + BSC. This subgroup analysis assessed landmark survival of all FRESCO-2 patients (pts), and baseline (BL) characteristics and safety data of pts treated with F who had OS ≥10 months (mos) compared with the intent-to-treat (ITT) population (pop). Methods: Pts were randomized 2:1 to receive F 5 mg or matching P, by mouth, once daily, 3 weeks on, 1 week off, + BSC. Pts had received prior chemotherapy, anti-VEGF therapy and, if RAS wild type, anti-EGFR therapy; and had prior exposure to trifluridine/tipiracil (TAS-102) and/or regorafenib. The hazard ratio (HR) between the two treatment arms was calculated from a stratified Cox proportional hazard model with treatment group as the only covariate in the model. Results: In the ITT pop, OS was improved with F vs P (HR 0.66); OS rates (95% confidence intervals [CIs]) at 6 and 9 mos were 60.4% (55.9–64.9) vs 41.5% (35.0–48.0) and 41.1% (36.4–45.8) vs 28.2% (22.1–34.3), respectively. Progression-free survival (PFS) rates (95% CIs) at 6 and 9 mos were 23.8% (19.7–28.0) vs 1.1% (0–2.6) and 11.3% (8.1–14.6) vs 0.5% (0–1.6), respectively. Of 461 pts who received F, 113 (24.5%) had OS ≥10 mos (range 10.0–18.9) with a median duration of F treatment of 6.3 mos (range 0.7–19.1). Among pts receiving F, a higher proportion (≥10% difference) of pts with OS ≥10 mos had no liver metastases (mets) and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 at BL compared with the ITT pop (Table). In pts with OS ≥10 mos, 61.9% experienced a grade ≥3 treatment-emergent adverse event compared with 62.7% in the ITT pop. Conclusions: Longer-term OS and PFS rates at 6 and 9 mos were higher with F vs P in the FRESCO-2 ITT pop. The data show a higher proportion of pts with OS ≥10 mos had an absence of liver mets and ECOG PS 0 at BL than the ITT pop. The safety profile of F in pts with OS ≥10 mos was consistent with the ITT pop. Clinical trial information: NCT04322539 . BL characteristics of pts treated with F with OS ≥10 mos vs ITT pop. BL characteristic Pts with OS ≥10 mos (n=113) ITT pop(n=461) ECOG PS (0 / 1), % 54.0 / 46.0 42.5 / 57.5 Median time since 1 st CRC diagnosis, mos 52.0 47.2 Primary tumor location at 1 st diagnosis (colon / rectum / both), % 51.3 / 35.4 / 13.3 60.5 / 31.0 / 8.5 Primary site at 1 st diagnosis (colon left / colon right), % 42.5 / 15.9 41.6 / 21.0 Liver mets, % 58.4 73.5 Median duration of mCRC, mos 42.7 37.9 Prior lines of therapy for mCRC (≤3 / >3), % 26.5 / 73.5 27.1 / 72.9 Prior TAS-102, % 46.9 52.1 Prior regorafenib, % 12.4 8.7

Epidemiological characteristics of gastric and pancreatic cancers in Latin America: GASPAR (LACOG 0222) study.

369 Background: Gastric (GC) and pancreatic cancer (PC) have poor prognosis representing major public health challenges, particularly in Latin America. Real-world data are limited. GASPAR (LACOG 0222) study addresses this gap by creating a multicenter database to analyze epidemiological, clinical, and pathological data, treatments, and outcomes for patients (pts) with GC and PC. Methods: This retrospective and prospective observational cohort study enrolled pts from 7 research sites in 3 LATAM countries with metastatic/locally advanced not amenable to curative intent GC (Cohort A) and PC (Cohort B) diagnosed from January 2019. Data were collected from medical records. ( NCT05924789 ). Results: 201 pts were included: 122 with GC (Cohort A) and 79 with PC (Cohort B). 150 (75%) from Brazil, 29 (14%) from Argentina, and 22 (11%) from Colombia. Median age at diagnosis was 69 years (IQR 57-78), 70 (35%) had history of tobacco use, and 153 (76%) were covered by private healthcare (Table). In Cohort A (GC), HER2 status was assessed in 105 (86%) pts, with 12 (11%) HER2-positive; PD-L1 was tested in 87 (71%): 55 (63%) had ≥1% expression and 28% had ≥10%; all 88 (72%) patients who had MMR tested had MMR proficient. First-line treatment was given to 107 (88%) pts: 78 (73%) chemotherapy (CT) alone (FOLFOX in 43 [40%]; FLOT in 16 [15%]); 23 (21%) CT + immunotherapy; and 7 (7%) CT + anti-HER2. Only 59 (48%) pts received second-line treatment and 31 (25%) third-line. With median follow-up (mFUP) of 29 months (CI95% 18.2-50.4), the median progression-free survival (mPFS) at first-line was 5.6 months (CI95% 4.2-6.3) and the median overall survival (mOS) was 11.2 months (CI95% 9.2-14.1). In Cohort B (PC), 67 (85%) pts received first-line treatment: 41 (61%) FOLFIRINOX and 14 (21%) gemcitabine-nab-paclitaxel. 27 (34%) pts received second-line treatment and 10 (13%) third-line. With mFUP of 21 months (CI95% 15.6-NR), the mPFS at first-line was 5.4 months (CI95%3.9-6.4) and the mOS was 10.2 months (CI95% 8.6-13.1). Conclusions: The GASPAR study provides valuable real-world data on GC and PC in Latin America. Notably, the mPFS in both cohorts was slightly lower than historical controls for first-line treatments, while the mOS was similar, suggesting earlier disease progression despite comparable overall survival. Improved therapeutic strategies and healthcare access are needed to enhance outcomes for these populations. Clinical trial information: NCT05924789 . Clinical characteristics. Characteristic GC (Cohort A)N=122 PC (Cohort B)N=79 Median age (IQR), yr 66 (51–78) 71.0 (61–79) Male – n. (%) 58 (56) 40 (51) Race – n. (%) White 67 (55) 71 (90) American Indian or Alaska Native 15 (12) 6 (8) Black 7 (6) 0 Other 7 (6) 0 Not reported 26 (21) 2 (2) Disease status at study entry Locally advanced disease 4 (3) 14 (18) Metastatic disease 118 (97) 65 (82) ECOG status in first-line advanced disease – n. (%) 0-1 75 (70) 45 (67) ≥ 2 13 (12) 3 (4.5) Not reported 19 (17.8) 19 (28.4)

Specific recognition mechanism of an antibody to sulfated tyrosine and its potential use in biological research

Response characteristics of tislelizumab (TIS) plus chemotherapy (chemo) in first-line (1L) treatment of locally advanced or metastatic esophageal squamous cell carcinoma (ESCC): A post hoc analysis of RATIONALE-306.

413 Background: The global phase 3 RATIONALE-306 study (NCT03783442) demonstrated superior OS, PFS, ORR and manageable safety profile of TIS + chemo as 1L treatment of ESCC, which was well maintained at 3 years. This post-hoc analysis aims to explore the response characteristics of responders in TIS + chemo arm from RATIONALE-306. Methods: Advanced or metastatic ESCC patients (pts) were randomly assigned (1:1) to receive 1L TIS + chemo or placebo + chemo. Assessments of tumor response were done every 6 weeks for the first 48 weeks, then every 9 weeks thereafter per RECIST v1.1. Time to response (TTR), depth of response (DpR) and time to maximum response (TTMR) were assessed in responders (pts who achieved CR or PR). TTR was defined as the time from randomization to the first occurrence of a CR or PR, DpR as the percentage of maximal tumor reduction from the baseline of target lesion sum of diameters, and TTMR as the time from randomization to the maximum tumor shrinkage. Results: As of 24 November 2023, 207 pts (68.3% of the ITT population) in the TIS + chemo arm achieved responses, with a median TTR of 6.1 weeks (range: 3.3 - 101.3). First response was detected in 64.7% of responders within 8 weeks, 22.2% between > 8 and ≤ 14 weeks, and 13.0% after 14 weeks; the median OS was 21.8, 23.1 and 29.0 mos, respectively in pts within the three TTR categories, and the median OS post first response was 21.3, 21.3 and 23.2 mos (Table). DpR > 30% to ≤ 50%, > 50% to ≤ 80%, and > 80% to ≤ 100% was observed in 29.8%, 50.2% and 20.0% of responders, respectively, and the median OS was 16.1, 23.7, and 34.5 mos. The median TTMR was 19 weeks (range: 3.3 - 201.0), with 32.7% of responders achieved maximum response within 14 weeks, 34.6% between > 14 and ≤ 28 weeks, and 32.7% after 28 weeks, respectively. Median OS of pts with the three TTMR categories was 14.3, 17.4, and 39.9 mos, respectively, and median OS post-maximum response was 12.6, 14.3, and 24.8 mos. Conclusions: In the TIS + chemo arm, 64.7% of responders achieved response within 8 weeks, while still 35.2% of responders achieved response at later tumor assessments, and the OS benefits were comparable between early responders and late responders. Responders with deeper tumor response and/or longer TTMR tended to have longer OS. Clinical trial information: NCT03783442 . Cutoff Patients, n (%) OS, median (95% CI), mos OS from response*, median (95% CI), mos TTR > 0 to ≤ 8w 134 (64.7) 21.8 (16.3, 25.0) 21.3 (16.0, 24.5) > 8 to ≤ 14 w 46 (22.2) 23.1 (16.3, 26.0) 21.3 (14.4, 24.3) > 14w 27 (13.0) 29.0 (20.4, NA) 23.2 (15.9, NA) DpR > 30% to ≤ 50% 61 (29.8) 16.1 (13.2, 20.8) \ > 50% to ≤ 80% 103 (50.2) 23.7 (19.6, 25.6) \ > 80% to ≤ 100% 41 (20.0) 34.5 (23.7, NA) \ TTMR > 0 to ≤ 14w 67 (32.7) 14.3 (8.7, 17.6) 12.6 (8.1, 15.4) > 14 to ≤ 28w 71 (34.6) 17.4 (15.8, 24.1) 14.3 (11.8, 20.1) > 28w 67 (32.7) 39.9 (28.6, NA) 24.8 (17.5, 39.4) *From first response for TTR, and from maximum response for TTMR.

First-line (1L) tislelizumab (TIS) plus chemotherapy (CT) vs placebo (PBO) plus CT in advanced/metastatic esophageal squamous cell carcinoma (ESCC): RATIONALE-306 Japanese subgroup analysis with longer follow-up.

420 Background: In the global phase 3 RATIONALE-306 study (NCT03783442), TIS + CT showed a significant overall survival (OS) benefit vs PBO + CT as 1L therapy for advanced/metastatic ESCC. After a minimum 3-year follow-up, the hazard ratio (HR) for OS was 0.70 for all randomized patients (pts) and for pts with programmed death-ligand 1 (PD-L1) Tumor Area Positivity (TAP) score ≥10%.We report results for the Japanese subgroup. Methods: Eligible pts enrolled in Japan were randomized (1:1) to receive intravenous TIS 200 mg or PBO every 3 weeks + investigator-chosen CT (platinum + fluoropyrimidine/paclitaxel) until disease progression or intolerable toxicity. The primary endpoint was OS in the intent-to-treat (ITT) population. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and OS in pts with PD-L1 TAP score ≥10%. Results: Of 649 randomized pts, 66 (10.2%) were Japanese, median age was 67 years, 89.4% were male, and 28.8% had PD-L1 TAP score ≥10%. At study entry, Eastern Cooperative Oncology Group performance status was 0 for 77.3% pts and 97.0% had metastatic disease. As of Nov 24, 2023, 78.8% vs 84.8% Japanese pts on TIS + CT vs PBO + CT received post-systemic therapy (ITT: 51.5% vs 57.9%). After a minimum follow-up of 37.9 months, TIS + CT showed improvements vs PBO + CT in median OS (24.5 vs 15.1 months [mo]; HR: 0.75) in all pts and in pts with PD-L1 TAP score ≥10% (HR: 0.79), median PFS (HR: 0.77) and ORR (63.6% vs 45.5%) (Table). Treatment-related adverse events (TRAEs) with TIS + CT vs PBO + CT in Japanese pts were 45.5% vs 36.4% for any grade (ITT: 69.8% vs 60.7%); 27.3% vs 6.1% for grade ≥3 (ITT: 32.1% vs 20.2%); 24.2% vs 3.0% for serious TRAEs (ITT: 19.8% vs 8.4%); TRAEs led to treatment discontinuation in 3.0% vs 6.1% (ITT: 13.3% vs 6.5%). No TRAEs leading to death were reported in Japanese pts (ITT: 1.5% vs 0.6%). Conclusions: After 3 years, TIS + CT continued to demonstrate robust efficacy and a tolerable safety profile in Japanese pts as 1L therapy for advanced/metastatic ESCC in the RATIONALE-306 study, consistent with the overall population. Clinical trial information: NCT03783442 . Efficacy outcomes. JapanTIS + CT(n=33) JapanPBO + CT(n=33) OverallTIS + CT(n=326) OverallPBO + CT(n=323) Median OS, mo (95% CI) 24.5 (17.6, 26.9) 15.1 (8.0, 22.5) 17.2 (15.8, 20.1) 10.6 (9.3, 12.1) HR (95% CI) 0.75 (0.43, 1.30) - 0.70 (0.59, 0.83) b - PD-L1 TAP score ≥10%, n (%) 12 (36.4) 7 (21.2) 116 (35.6) 107 (33.1) Median OS by PD-L1 TAP score ≥10%, mo (95% CI) 25.5(10.9, NE) 16.8(0.9, NE) 16.6(15.3, 23.4) 10.0(8.6, 13.3) HR (95% CI) 0.79 (0.26, 2.36) - 0.70 (0.52, 0.95) b - Median PFS a , mo (95% CI) 6.8 (4.4, 8.5) 4.5 (4.1, 6.7) 7.3 (6.9, 8.3) 5.6 (4.9, 6.0) HR (95% CI) 0.77 (0.45, 1.32) - 0.60 (0.50, 0.72) b - ORR a , n (%) 21 (63.6) 15 (45.5) 207 (63.5) 137 (42.4) a Investigator assessed. b Stratified. CI, confidence interval; NE, not estimable.

Outcomes of neoadjvuant chemotherapy versus chemoradiation for esophageal adenocarcinoma: A National Cancer Database analysis.

416 Background: While neoadjuvant chemoradiation (NCRT) has been the acceptable standard of care for esophageal adenocarcinoma (EAC), there has been a paradigm shift from recent trials have shown that neoadjuvant chemotherapy (NAC) is either equivalent or superior to NCRT. We sought to examine the outcomes of NAC versus NCRT in esophageal cancer from the National Cancer Database (NCDB). Methods: Utilizing the NCDB, we identified esophagectomy patients with EAC who underwent multiagent NCT versus multiagent NCRT. Overall Survival (OS) was analyzed with the Kaplan-Meier method and multivariate analysis (MVA) was performed to identify predictors of OS. Propensity score matching (PSM) was used to correct for baseline differences between groups. Results: After PSM, we identified 1007 patients in each group. Groups were equally balanced in age, gender, T/N stage, grade, and facility volume. There was improved lymphadenectomy and higher use of adjuvant therapy in NCT patients. There were significant improvements in R0 resection and pathologic response associated with NCRT patients. There was a significant improvement in OS in NCT versus NCRT. The median and 5-year OS was 42.7 months and 42% in NCT patients versus 34.2 months and 35% in NCRT patients (p = 0.001). For pathologic complete responders, median and 5-year OS was 101 months and 64% in NCT patients versus 71.2 months and 53% in NCRT patients (p = 0.04). On MVA, improved mortality was associated with female gender, pathologic N0, >10 nodes removed, pathologic partial or complete response, R0, well/moderate grade, NCT, adjuvant chemotherapy, and higher facility volume. There was also no survival benefit to adjuvant chemoradiation. Conclusions: Despite higher R0 and pathologic response associated with NCRT, NCT was superior to NCRT for OS in EAC patients. NCRT needs to be re-examined in its role as a treatment recommendation for operable EAC patients. Multivariate analysis for overall survival. Variable HR 95% CI P value Age 1.01 1.00 – 1.02 0.004 SexMaleFemale Reference0.79 0.64 – 0.98 0.03 Charlson Deyo score01 Reference1.05 0.91 – 1.21 0.54 Pathologic N-stageN0N+ Reference1.82 1.58 – 2.10 <0.001 LN removed<10>10 Reference0.81 0.68 – 0.97 0.02 ResponseNonePartialComplete Reference0.810.61 0.69 – 0.940.50 – 0.75 0.008<0.001 Margin statusR0R1 Reference1.24 1.01 – 1.52 0.04 GradeWell/moderatePoor Reference1.35 1.18 – 1.54 <0.001 Preop radiationYesNo Reference0.77 0.67 – 0.88 <0.001 Adjuvant therapyNoneChemotherapyChemoradiation Reference0.770.83 0.65 – 0.920.64 – 1.08 0.0040.17 Facility volumeLow (≤10/year)Medium (11-19/year)High (≥20/year) Reference0.860.78 0.72 – 1.030.67 – 0.90 0.10<0.001

Analysis of lipogenic and metabolic subtypes and survival outcome in patients with pancreatic adenocarcinoma.

775 Background: Delayed diagnosis and rapid progression are major drivers of poor survival outcomes for Pancreatic Ductal Adenocarcinoma (PDAC). In previous studies, molecular profiling in tumor tissue has identified Cholesterogenic, Classical, or Exocrine-Like pathological subtypes associated with improved prognosis. Herein, in a clinical trial called Project Survival, we molecularly and clinically characterized a prospective PDAC biomarker cohort. This multicenter (n=6) clinical trial (NCT 02781012) of PDAC combined with high-fidelity longitudinal phenotypic characterization and multi-omic profiling was utilized to identify biomarkers with diagnostic and therapeutic utility. The study included assessment of plasma, serum, buffy coat, urine, saliva, and tumor tissue samples and followed 269 PDAC subjects for up to 7 years (Median survival was 700 days, with IQR of 822 days). Methods: We assessed plasma samples to identify circulating biomarkers using proteomics, metabolomics, and lipidomics profiling. Multi-omic comparison of patients with Overall Survival (OS) above the 75th percentile (improved survival) against those with OS below the 25th percentile (poor survival) was performed. Results: We identified distinct panels of proteins, metabolites, and lipids that were associated with patient survival outcomes. Protein biomarkers that were increased in improved survival outcomes were associated with cholesterol metabolism (7/14, p-value = 0.00085) and glycolysis/gluconeogenesis (5/12, p-value = 0.00089), however, protein markers associated with immune surveillance and inflammation were associated with poorer survival. For metabolite biomarkers, 19 metabolites were increased in poorer survivors of which 13/19 were carnitine metabolites, and 42 metabolites were increased in patients with improved survival. Interestingly, only two lipid molecular species of the diacylglyceride family were increased in patients with poorer survival. Conclusions: Project Survival, a prospective biomarker-driven clinical trial identified distinct metabolic and molecular subtypes of patients which characterize survival outcome in PDAC. These subtypes go beyond tumor genomic characterization and align with distinct cholesterogenic and glucogenic phenotypes associated with survival outcomes, which can potentially be leveraged for therapeutic intervention strategies.

Axin-binding domain of glycogen synthase kinase 3β facilitates functional interactions with voltage-gated Na+ channel Nav1.6

Predictive role of circulating tumor DNA for locally advanced esophageal squamous cell carcinoma before surgery.

476 Background: A precise preoperative tumor monitoring method that reflects tumor burden during neoadjuvant treatment is required to guide individualized perioperative treatment strategies for esophageal squamous cell carcinoma (ESCC). This study examined the clinical significance of preoperative circulating tumor DNA (ctDNA) in the plasma of patients undergoing neoadjuvant chemotherapy (NAC) followed by esophagectomy. Methods: Plasma samples were collected longitudinally for ctDNA analysis as well as genomic DNA from primary lesions from patients with histologically confirmed ESCC who received neoadjuvant chemotherapy (NAC) followed by subtotal esophagectomy. Next-generation sequencing was used to identify mutations in both the plasma and primary tumors. We evaluated the relation ship between ctDNA alterations and recurrence in patients with locally advanced ESCC. Results: Pretreatment samples from 25 patients (100%) showed the same mutations in both ctDNA and primary tumors; therefore, they were classified as ctDNA-positive before treatment. In the cohort of 25 patients analyzed, those who tested positive for ctDNA after NAC had a significantly higher risk of recurrence; the 36-month recurrence-free survival rates were 92% for ctDNA-negative patients and 8% for ctDNA-positive patients (p < 0.001). Conclusions: Preoperative ctDNA status may be a promising prognostic biomarker that can be assessed before surgery in patients with ESCC who received NAC. Expanded cohort validation will allow for more personalized multidisciplinary treatment approaches for ESCC tailored to ctDNA analysis.

A phase 1 trial of folinic acid, fluorouracil, oxaliplatin, bevacizumab, botensilimab, balstilimab (FOLFOX-3B) in microsatellite stable metastatic colorectal cancer.

180 Background: Botensilimab (BOT) is a novel Fc fragment engineered CTLA4 inhibitor designed to boost innate and adaptive immune response. The combination of BOT and the PD-1 antibody balstilimab (BAL) has been associated with durable and deep responses in microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Given the potential synergistic activity between checkpoint inhibitors and oxaliplatin and VEGF(R) inhibitors, we performed a phase 1 clinical trial of folinic acid, fluorouracil, oxaliplatin, bevacizumab, botensilimab, and balstilimab (FOLFOX-3B). Methods: We enrolled ECOG performance status 0-1 patients (pts) with measurable MSS mCRC, up to 2 prior lines of therapy, and without progression following prior oxaliplatin. FOLFOX was given at a fixed dose, every 2 weeks, across the study: folinic acid at 400 mg/m 2 x 2 hours (hr), oxaliplatin at 85 mg/m 2 x 2 hr, and fluorouracil at 2400 mg/m2 x 46 hrs. BOT was administered at 2 dose levels (DL) of 25 mg and 75 mg IV Q6 weeks x 2. BAL was administered at a fixed dose of 240 mg IV Q2 weeks. The study followed a 3 x 3 escalation design with up to 9 patients per DL. A dose level was deemed safe if < 1 out of 6 pts or < 2 out of 9 pts had a DLT (expansion to 9pts only if 2 DLTs encountered in the 1 st 6 pts). The DLT period consisted of 6 weeks. Pts should have received all intended BOT/BAL and FOLFOX doses in the 1 st 6 weeks to be deemed DLT-evaluable. Results: 14 pts were enrolled on study: 9/14 with liver metastatic disease, 5/14 RAS -mutated, all TMB low. 7 were treated on DL1 and 7 on DL2. 6/7 pts at DL1 had received 1-2 prior lines of therapy, 4 of whom included oxaliplatin. 6/7 of pts at DL2 had 1-2 prior systemic therapy, all of whom received prior oxaliplatin. No DLT were noted at DL1 or DL2. 1 pt at each DL was not DLT-evaluable as they were not able to receive all intended therapy due to treatment interruptions. Grade (G)2 and above immune related toxicities included: one pt at DL1 with transient G3 AST/ALT elevation and transient G2 colitis (resolved with steroids and infliximab), one pt at DL1 with G2 hypothyroidism and one patient at DL2 with G2 hyperthyroidism. At DL1, 4/7 had a partial response (PR) - including 2/4 with prior oxaliplatin exposure. At DL2, 6/7 pts had a PR – including 5/6 with prior oxaliplatin exposure. 3 patients proceeded to surgical resection or ablation and are currently followed with observation only. In the combined cohort of DL1 and DL2, the median progression free survival (PFS) is 8 months and remains unreached for DL2. Overall survival outcome has not matured at the time of this analysis. Conclusions: FOLFOX-3B with BOT at 75 mg IV Q6 weeks x 2 in combination with BAL 240 mg Q2 weeks is well-tolerated and is associated with promising clinical activity with 5/6 PR and prolonged PFS. The study was amended to explore additional DL that explore higher doses of BOT (150 mg) or longer duration of BOT 75mg (4 doses). Clinical trial information: NCT05627635 .

Phase I/II study of cabozantinib alone or in combination with panitumumab in patients with <i>MET</i> -amplified metastatic colorectal cancer.

146 Background: Despite the introduction of anti-EGFR therapies, resistance remains a significant challenge in metastatic colorectal cancer (mCRC). MET amplification is a recognized resistance mechanism. Cabozantinib, a multi-kinase inhibitor targeting MET, has shown promise in overcoming resistance to anti-EGFR therapy. This study aimed to evaluate the efficacy and safety of cabozantinib alone (Cabo) or in combination with panitumumab (Cabo+Pmab) in patients with MET-amplified mCRC. Patients and Methods: The study population included patients with RAS and BRAF wild-type mCRC who had progressed on anti-EGFR therapy and subsequently confirmed MET amplification by circulating tumor DNA. The phase I part aimed to establish the recommended cabozantinib dose in combination with panitumumab by assessing dose-limiting toxicity (DLT) within the first four weeks. The primary endpoint of phase II part was objective response rate (ORR) in patients receiving the study treatment as third-line therapy or later. In phase II part, patients were randomized to Cabo or Cabo+Pmab group. Based on a threshold ORR of 1.6% response rate and an expected efficacy of 30%, the planned sample size was 14 patients with one-sided alpha of 1.25% and power of 80% in each arm, Cabo and Cabo+Pmab. A tumor response of at least 3 out of 14 patients would warrant further investigation of these treatments. Results: A total of 35 patients were enrolled (6 in phase I and 29 in phase II, 28 for the primary analysis; 13 in Cabo and 15 in Cabo+Pmab). In phase I, no DLTs were observed. This allowed researchers to set the maximum tolerated dose and recommend a dosage of 60 mg/day of cabozantinib in combination with panitumumab for phase II. Of 28 pts for the primary analysis, ORR was 7.7% (1/13; 95%CI 0.2-36%) in Cabo group and 0% (0/15; 95%CI 0-21.8%) in Cabo+Pmab group, median progression-free survival was 3.1 months in both groups, and cumulative proportion of pts with grade ≥3 treatment-related adverse events was 38.5% (including hypertension [23.1%]) in Cabo and 60% (including hypomagnesaemia [20%]) in Cabo+Pmab group. Conclusions: The combination of cabozantinib 60 mg plus panitumumab had manageable safety profile. However, this treatment did not demonstrate significant clinical benefit in patients with MET-amplified mCRC. Further investigation is warranted to explore alternative therapeutic strategies for this patient population. Clinical trial information: jRCT1080224637 .

Proto-oncogene HRAS transcript level and overall survival in stage II and III colorectal cancer.

231 Background: Mutational landscape is prognostic in colorectal cancer (CRC). Driver mutations in the RAS proto-oncogenes such as KRAS and NRAS portend poor survival outcomes, whereas HRAS mutations are extremely rare and their prognostic value remains uncertain. The prognostic implication of RAS gene activity at the transcript level is also obscure. Here, we retrospectively review stage II and III CRC tumor RNA-Seq data and demonstrate that high transcript levels of HRAS are associated with superior overall survival (OS). Methods: Tumor RNA-Seq of 734 stage II and III CRC cases and their associated clinical data were retrieved from the ORIEN AVATAR database (Aster Insights). Transcript level was determined by batch-corrected TPM (transcripts per million) of each gene, and cohort median was used as a reference to determine “high” versus “low” in subgroup analyses. The p-value and hazard ratio (HR) derived from Kaplan-Meier survival analysis are log-rank. Results: The 4-year HR for death in patients with “very high” HRAS transcript level (top 5%) was 0.15 (95% CI 0.07-0.34, p=0.03) compared to the rest, and this superior OS was independent from TNM stage or peri-operative 5-FU treatment history. In subgroup analyses, “high” HRAS expression was associated with superior OS only in patients with concomitant “low” KRAS expression in the absence of pathologic KRAS mutations in codons 12, 13 and 61 – the 5-year HR in “low” KRAS group was 0.42 (95% CI 0.18-0.96, p=0.03) compared to “high” KRAS group. NRAS transcript level did not influence OS. When further sub-grouped based on primary disease location, this superior OS was present only in the right-sided primary disease group with 5-year HR of “low” KRAS group at 0.17 (95% CI 0.03-0.99, p=0.06) compared “high” KRAS group. Conclusions: Contrary to the notion that RAS family genes are proto-oncogenic, we demonstrate that high HRAS transcript levels are associated with superior OS in stage II and III CRC. The high HRAS-associated OS benefit was most pronounced in patients with right-sided primary expressing low KRAS transcript levels in the absence of pathologic KRAS mutations. We speculate that when expressed at high levels, HRAS may counteract proto-oncogene KRAS but not oncogene KRAS at the transcript level. The potential of HRAS as a prognostic biomarker should be explored further.

Resilience and charge-dependent fibrillation of functional amyloid: Interactions of Pseudomonas biofilm-associated FapB and FapC amyloids

PK/PD analyses of circulating tumor DNA (ctDNA) in patients with metastatic colorectal cancer (mCRC) treated with telisotuzumab adizutecan (ABBV-400).

233 Background: Telisotuzumab adizutecan (ABBV-400) is an antibody drug conjugate (ADC) consisting of a c-Met targeting antibody telisotuzumab conjugated to a potent topoisomerase 1 inhibitor payload adizutecan. The ongoing first in human phase 1 trial (Study M21-404; NCT05029882) shows that ABBV-400 has encouraging radiographic response and ctDNA molecular response (MR) as monotherapy in patients with advanced solid tumors, including mCRC. Herein, correlation between ABBV-400 exposures and % change in ctDNA from baseline and PK/PD analyses using MR are presented for mCRC patients. Impact of c-MET expression and MET amplification ( MET -amp) status on exposures was also evaluated. Methods: Analyses utilized preliminary data in mCRC patients (N=122) from study M21-404 where subjects were treated with ABBV-400 (1.6 – 6.0 mg/kg Q3W). Serial PK samples were collected in cycles 1 (C1) and 3 (C3) and sparse samples across other cycles. C1 exposure metrics (C max , C avg , and C trough ) for both ABBV-400 conjugate and unconjugated payload were obtained by non-compartmental PK analysis. Baseline and C3 day 1 plasma samples were collected and analyzed using the Guardant INFINITY assay for biomarker analysis. ctDNA (circulating tumor fraction [cTF]) was estimated based on 1) variant allele frequency of somatic mutations in a 74 gene panel and 2) methylation signals across targeted regions of the Guardant INFINITY methylation panel. MR was defined as a 50% decrease in cTF from baseline. PK/PD correlations with % change in cTF at C3 and MR at C3 were evaluated. c-Met protein expression was assessed by IHC (VENTANA MET SP44 RxDx Assay) and MET -amp status was based on available local testing results and retrospective ctDNA testing. Results: Higher exposures of ABBV-400 conjugate and payload (primarily C avg for both analytes and C max for conjugate) correlated with greater decrease in % change in cTF at C3 from baseline, as assessed by the 74 gene panel (N =66) or methylation panel (N=74). PK/PD analysis showed that higher exposure was strongly correlated with higher probability of MR (n=66-74, nominal p &lt; 0.05). ABBV-400 conjugate and payload exposures were comparable across c-Met expression H-score (range 9 – 295), cut-offs (≥90% with 1+ intensity, ≥50% with 2+, ≥10% with 3+, ≥25% with 3+, and ≥50% with 3+), and MET -amp status. Conclusions: Exposure-response analyses have previously shown correlation between ABBV-400 conjugate exposures and probability of efficacy (objective response rate) as well as safety in mCRC subjects. The current PK/PD analyses demonstrate that higher ABBV-400 conjugate and payload exposures are also correlated with liquid biopsy data, i.e., ctDNA and MR based on ctDNA. c-MET expression and MET-amp did not have impact on ABBV-400 exposures. Clinical trial information: NCT05029882 .

The use of liquid biopsy comprehensive genomic profiling to identify the molecular landscape of patients with metastatic colorectal cancer who are candidates for anti-EGFR rechallange therapy: Findings from the CAVE-2 GOIM trial.

221 Background: In the era of precision medicine, biomarker guided therapies are necessary for patients with chemorefractory metastatic colorectal cancer (mCRC). Circulating tumor DNA (ctDNA) comprehensive genomic profiling (CGP) may contribute to the development of more effective treatments. Methods: CAVE-2 GOIM trial (ClinicalTrials.gov ID: NCT05291156) is the first randomized phase II study to assess the efficacy of avelumab plus cetuximab compared to cetuximab alone as rechallenge strategy in pre-treated plasma ctDNA RAS, BRAF WT mCRC patients. Before being enrolled in the trial, patients were selected by baseline plasma ctDNA analysis by Foundation One Liquid CDx (F1L CDx) 324 genes to identify ctDNA RAS/BRAF WT cases. Results: As of July 31th 2024, 229 (out of approximately 310) patients have been screened. A total of 1562 pathogenic variants (PV) were detected, with TP53 (86.0%), APC (84.2%), DNMT3A (30.5%) representing the most common altered genes. In these anti-EGFR pretreated patients different acquired mechanisms of resistance were observed. In particular, 72/229 (31.4%) patients had RAS or BRAF V600E PV (102 KRAS , 21 NRAS and 8 BRAF V600E mutations, respectively). Additionally, in these 72 patients, multiple RAS/BRAF V600E gene alterations (median of 1 PV, range 1-7) were observed in 41.6% cases. MAPK, RTK , and PI3K/AKT/mTOR PV were detected in 43.2%, 24.5% and 24.5% patients, respectively. Of note, the variant allele frequency of resistant PV was lower than other gene alterations, suggesting a high tumor heterogeneity as a consequence of the development and/or expansion of EGFR-inhibitor resistant cancer cell sub-clones. All patients were assessed for tumor mutational burden (TMB). Median TMB was 6 (IQR 4-10) mut/Mb, with 29.6% cases showing a TMB ≥10 mut/Mb. Finally, a total of 258 actionable genomic alterations were detected in 52,4% of patients according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT). Eighty-one tier I alterations were detected in 32.3% patients, which included TMB high (29,7%), BRAF V600E (3,5%), KRAS G12C (6,5%), and RET fusions (0,4%). Conclusions: These findings support liquid biopsy-based GCP for individualized therapeutic choices in chemorefractory mCRC. Up-dated final analyses of the entire screened patient population of the CAVE-2 GOIM trial will be presented. Clinical trial information: NCT05291156 .