Lenz, Heinz‐Josef

Abstract Endocytosis regulates receptor trafficking and signaling, yet its role in colorectal cancer (CRC) remains unclear. We analyzed transcriptomic data from 15,025 CRC tumors to evaluate gene expression in clathrin-mediated endocytosis (CME) and the endosomal sorting complexes required for transport (ESCRT) pathway. Pathway-level signatures were compared across consensus molecular subtypes (CMS) and examined in relation to oncogenic signaling programs, while individual endocytosis-related genes were evaluated for associations with clinical outcomes in an independent randomized trial cohort. Expression of CME and ESCRT pathways varied by CMS, with the highest expression in CMS4 and the lowest in CMS3. Endocytosis signatures correlated with multiple oncogenic signaling pathways, including MAPK, TGF-β, WNT, PI3K, NOTCH, and angiogenesis, suggesting broad links between endocytic activity and tumor biology. In the randomized phase III CALGB/SWOG 80405 trial, low expression of AP2M1 —a core adaptor in the CME complex—was significantly associated with longer overall survival and progression-free survival in patients treated with anti-EGFR agents, but not in those receiving anti-VEGF agents. These findings suggest that endocytic trafficking may be associated with oncogenic signaling and differential therapeutic benefit in patients with metastatic CRC. The endocytosis pathway reflects biologically relevant heterogeneity in CRC and may help guide therapeutic stratification.

3593 Background: CUB domain-containing protein 1 (CDCP1) is a transmembrane protein shown to be over-expressed in colorectal cancer (CRC), with an important role in tumor initiation, growth and metastasis. Through interactions with EGFR, CDCP1 promotes nuclear translocation of the key regulators of Wnt signaling, β-catenin and E-cadherin. High CDCP1 expression has been associated with poor survival outcomes in multiple solid tumors but data in CRC remains limited. We investigated associations between CDCP1 level and survival outcomes in patients with metastatic CRC (mCRC) in the phase III clinical trial CALGB/SWOG 80405 (Alliance). Methods: Data from 433 mCRC patients in the CALGB/SWOG 80405 (Alliance) trial were analyzed. Patients received bevacizumab (n = 226) or cetuximab (n = 207) plus chemotherapy as 1st-line treatment. Tumor RNA was extracted from FFPE samples and processed through the HiSeq 2500 (Illumina) platform. Overall survival (OS) and progression free survival (PFS) curves were evaluated in all treatment subgroups and stratified according to high or low CDCP1 expression. Likelihood ratio tests, hazard ratios (HRs), and 95% confidence intervals (CIs) were calculated using Cox proportional hazards multivariate models, adjusting for age, sex, ECOG performance status, tumor location, number of metastatic sites, KRAS status, consensus molecular subtypes, and treatment arm. Results: Overall, low CDCP1 expression was associated with better OS compared to high expression (HR = 1.38; 95% CI 1.07-1.77; 35.8 vs 25.0 months, p = 0.045). Subgroup analysis re-demonstrated this pattern in males (HR = 1.64; 95% CI 1.64-2.28; 35.9 vs 23.6 months, p = 0.01), patients with MSS tumors (HR = 1.56; 95% CI 1.17-2.08; 36.7 vs 25.1 months, p = 0.0094), and patients treated with cetuximab+FOLFOX (HR = 1.79; 95% CI 1.16-2.77; 40.8 vs 24.0 months, p = 0.03). The effect of CDCP1 expression on PFS was less pronounced. Relative to high expression, low expression was associated with better PFS in males (HR = 1.49; 95% CI 1.10-2.03; 13.1 vs 9.8 months, p = 0.027) and left-sided tumors (HR = 1.50; 95% CI 1.10-2.04; 14.4 vs 10.1 months, p = 0.034). Conclusions: Our findings represent real-world data of the predictive role of CDCP1 in patients with mCRC undergoing anti-EGFR or anti-VEGF treatment. Consistent with studies of other cancers, we show that low CDCP1 expression is predictive of better survival outcomes, with subgroup analysis revealing associations in males, MSS tumors, and left-sided tumors. Among treatment groups, low CDCP1 expression is predictive of better OS in cetuximab+FOLFOX-treated patients, a key finding given CDCP1’s close mechanistic ties to EGFR. Further studies should explore whether these associations are seen in other treatment modalities and whether CDCP1 blockade could represent a viable strategy in patients with high expression.

3510 Background: Patients with RAS-mutated mCRC have limited treatment options. Chemotherapy in combination with bevacizumab (Bev) has been the standard first-line treatment for the past two decades, yet the prognosis for these patients remains poor. Onvansertib (Onv), a selective PLK1 inhibitor, has previously demonstrated synergy with chemotherapy in the second line setting. The Phase 2 randomized CRDF-004 trial evaluated onvansertib plus standard-of-care (SoC; FOLFIRI or FOLFOX with Bev) in as first-line RAS-mutated mCRC. Methods: Patients with first-line KRAS or NRAS mutant mCRC were randomized to SoC alone or SoC plus onvansertib (20 mg or 30 mg). The primary endpoint was objective response rate (ORR) as determined by a blinded-independent central review (BICR) using RECIST v1.1. Key secondary endpoints included progression-free survival (PFS), duration of response, and safety. PFS was assessed by BICR and investigator assessments combined. Results are presented in the intent-to-treat population (ITT). Results: At the data cutoff of 22 Jan 2026,110 patients were randomized with a median follow up of approximately 10 months. Baseline characteristics were relatively balanced across arms. Onv 30 mg + FOLFIRI + Bev demonstrated numerically higher ORR (n = 13/18, 72.2%, 95% CI: 46.5, 90.3) compared with the FOLFIRI + Bev control arm (n = 8/19, 42.1%, 95% CI: 20.3, 66.5), the FOLFOX + Bev control arm (n = 8/18, 44.4%, 95% CI: 21.5, 69.2) and the combined control arms (SoC: n = 16/37, 43.2%, 95% CI: 27.1-60.5). Onv 30mg + FOLFIRI + Bev demonstrated a p-value of 0.051 for confirmed ORR vs. SoC; and a p-value of 0.045 for the 6-month ORR compared to FOLFIRI + Bev (n = 10/18, 55.6%, 95% CI: 30.8-78.5 vs. n = 4/19, 21.1%, 95% CI: 6.1-45.6, respectively). The median PFS for the control arms was 10.97 months (95% CI: 7.52, NR) for FOLFIRI + Bev, 9.89 months (95% CI: 9.43, NR) for FOLFOX + Bev and 10.97 months (95% CI: 9.43-15.44) for the combined SoC arms. The median PFS in the Onv 30mg+ FOLFIRI + Bev arm was not reached (95% CI: 9.72-NR). The PFS HR of 30mg + Onv +FOLFIRI + Bev vs FOLFIRI + Bev was 0.38 (95% CI: 0.12-1.17) and vs SoC was 0.37 (95% CI: 0.13-1.02, p = 0.048). The clinical benefit from Onv treatment was further evidenced by the 12-month PFS rates, 61.9% (95% CI: 40.1, 95.8) in the Onv 30 mg + FOLFIRI + Bev arm vs. 28.4% (95% CI: 9.3, 86.9) in the FOLFIRI + Bev arm, and 30.1% (95% CI: 13.8-65.7) in the SoC. Onvansertib was well tolerated, with no unexpected toxicities observed; the most common grade ≥3 adverse event was neutropenia. PK data support moving forward with the onvansertib 30mg dose with FOLFIRI + Bev. Conclusions: Onvansertib plus FOLFIRI and bevacizumab demonstrated improved antitumor activity and manageable safety in first-line RAS-mutated mCRC. These results support further clinical and support planned confirmatory Phase 3 evaluation. Clinical trial information: NCT06106308 .

Abstract Introduction: Fibroblast growth factor receptor 2 and 3 (FGFR2 and FGFR3) are metabolic genes overexpressed in malignant epithelia. In colorectal cancer (CRC), intimate crosstalk between FGFR2/3 and epidermal growth factor receptor (EGFR) pathways has been suggested but is not fully elucidated. As a result, this study investigated associations between FGFR2/3 expression levels and clinical outcomes in patients with metastatic CRC (mCRC) enrolled in the phase III clinical trial CALGB /SWOG 80405. Methods: Data from 433 patients with mCRC enrolled in the CALGB/SWOG 80405 trial were analyzed. Patients received either bevacizumab (bev, n = 226) or cetuximab (cet, n = 207) plus chemotherapy as first-line treatment. Tumor RNA was extracted from FFPE samples and processed through the HiSeq 2500 (Ilumina) platform. Median overall survival (OS) and progression-free survival (PFS) curves were evaluated in all treatment subgroups and stratified according to high (H), medium (M), and low (L) FGFR 2 and 3 gene expression levels. Likelihood ratio tests, hazard ratios (HRs), and 95% confidence intervals (CIs) were calculated using Cox proportional hazards multivariate models, adjusting for age, sex, ECOG performance status, tumor location, number of metastatic sites, KRAS status, consensus molecular subtypes, and treatment arm. Results: Both FGFR2 and FGFR3 expression levels were associated with outcomes in patients treated with cetuximab. FGFR2-L tumors showed significantly longer OS compared to the M (HR = 1.04; 95%CI 0.71-1.51) and H (HR = 1.56; 95%CI 1.06-2.28) expression groups (35.7 vs. 31.2 vs. 23.7 months, p = 0.017). In contrast, FGFR3-L tumors were associated with shorter OS compared to the M (HR = 0.63; 95%CI 0.44-0.92) and H (HR = 0.59; 95%CI 0.41-0.85) expression groups (24.7 vs 32.4 vs 37.1 months, p = 0.0009). Significant differences in PFS were not observed. A nominally significant interaction was found between treatment and FGFR3 expression for both PFS (p = 0.02) and OS (p = 0.0003), but no interaction with FGFR2 expression. No significant associations were detected in patients treated with bev. Neither FGFR2 nor FGFR3 suggested to be prognostic markers after multivariate adjustment analyses. Conclusions: Our findings suggest a predictive role of FGFR3 in patients with mCRC undergoing anti-EGFR treatment. Differences in survival within the cet subgroup suggest that EGFR inhibitor efficacy may be modulated by FGFR2/3 signaling activity. Interestingly, FGFR2 and FGFR3 expressions were inversely and positively correlated with improved OS. The findings suggest that FGFR2 signaling minimizes the specific effects of cetuximab, while FGFR3 signaling amplifies its therapeutic effects. Further studies should determine whether these associations are seen in other anti-EGFR inhibitors and detail the mechanistic interaction between FGFR and EGFR pathways. Citation Format: Steve Soto Trujillo, Yan Yang, Michela Bartolini, Shivani Soni, Pooja Mittal, Fang-Shu Ou, Lesly Torres-Gonzalez, Unnati Hemant Shah, Jae Ho Lo, Yitzhar Goretsky, Wu Zhang, Alan Venook, Sandra Algaze, Joshua Millstein, Heinz-Josef Lenz. Differences in survival outcomes among metastatic colorectal cancer patients across fibroblast growth factor receptor 2 and 3 expression levels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6751.

Abstract Background. Mitophagy plays a crucial role in removing dysfunctional mitochondria to maintain cellular homeostasis but also has been implicated in cancer tumorigenesis. Previously, we showed that genetic variation in mitophagy pathway genes holds a predictive value in metastatic CRC (mCRC) patients (pts) treated with bevacizumab-based chemotherapy. In this study, we analyzed the correlation between tumor expression profiles of genes associated with PINK1/Parkin and BNIP3/NIX/FUNDC1 mitophagy pathways with clinical outcome in a large phase III randomized clinical trial CALGB SWOG 80405. Method. We analyzed 433 pts with mCRC treated with first-line chemotherapy in combination with the targeted agents bevacizumab (Bev, n = 226) or cetuximab (Cet, n = 207). Tumor RNA isolated from FFPE samples was sequenced using the HiSeq 2500 platform (Illumina). Median Overall survival (mOS) and median progression-free survival (mPFS) were compared across pts groups divided into high, medium, and low tertiles based on mitophagy-related gene (BNIP3, BNIP3L, PINK1, PRKN) expression levels. Likelihood ratio tests, hazard ratios (HRs), and 95% confidence intervals (CIs) were calculated using multivariable Cox proportional hazards models, adjusting for age, sex, ECOG performance status, tumor location, number of metastatic sites, KRAS status, Consensus Molecular Subtypes, and treatment arm. Results: Overall, BNIP3L demonstrated significant prognostic value for both PFS and OS after adjustment for multiple testing (false discovery rate [FDR] < 0.05). Tumors with low BNIP3L expression showed longer PFS and OS compared to those with medium or high expression levels (mPFS 14.8 vs. 10.0 vs. 9.2 months, HR 1.16, 95% CI 1.04 - 1.29p = 0.0182; mOS: 37.4 vs. 30.2 vs. 24.4 months, HR 1.22, 95% CI 1.09 - 1.38, p = 0.0036), independent of treatment. In pts treated with Cet, high PRKN expression was associated with improved PFS and OS (mPFS: 8.9 vs. 10.3 vs. 14.6 months, HR 0.79; 95% CI 0.69 - 0.91, p = 7.3e-05; mOS: 21.2 vs. 27.7 vs. 41.1 months, HR 0.87; 95% CI 0.75 - 1.01, p = 0.00084), whereas low PINK1 expression was significantly associated with longer OS (mOS: 24.9 vs. 30.9 vs. 39.2 months, HR 1.23; 95% CI 1.04 -1.46, p = 0.013). No significant associations were observed in Bev-treated patients for PRKN or PINK1. No significant results were found for BNIP3 expression analysis. Conclusion. Mitophagy is a crucial player in CRC biology due to its tumor-intrinsic (mitochondrial bioenergetics) and microenvironment (interacts with immune components) effects. Our study highlights the prognostic value of BNIP3L and predictive potential of PINK1 and PRKN, suggesting a potential combinatorial therapeutic approach using mitochondrial targeting drugs and targeted agents e.g Cet, which warrants further investigation. Support: Genentech; Clinicaltrials.gov Identifier: NCT00265850 Citation Format: Shivani Soni, Yan Yang, Michela Bartolini, Pooja Mittal, Fang-Shu Ou, Lesly Torres-Gonzalez, Unnati Hemant Shah, Jae Ho Lo, Steve Soto Trujillo, Yitzhar Goretsky, Wu Zhang, Alan P. Venook, Sandra Algaze, Joshua Millstein, Heinz-Josef Lenz. Correlation of mitophagy related genes expression and clinical outcome in metastatic colorectal cancer patients enrolled in CALGB (Alliance)/SWOG 80405 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1011.

Background Cysteine–cysteine chemokine receptors 2 (CCR2) and 5 (CCR5) contribute to immune suppression in tumor microenvironments. CCR2 and CCR5 antagonists have demonstrated antitumor activity in pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC), respectively. This phase 1b/2, open-label study evaluated BMS-813160, a CCR2/5 dual antagonist, in combination with chemotherapy±nivolumab in advanced PDAC or metastatic CRC. Methods Part 1 included patients with metastatic untreated (first-line (1L)) PDAC, 1L CRC, or previously treated (second or third line (2/3L)) microsatellite stable (MSS) CRC. Patients received 2 weeks of BMS-813160 monotherapy (300 mg two times a day, 600 mg once daily, 300 mg once daily, or 150 mg once daily) and then BMS-813160+chemotherapy (gemcitabine+nab-paclitaxel (gem/nabP; 1L PDAC), 5-fluorouracil+leucovorin+irinotecan (FOLFIRI; 1L CRC)), or nivolumab (2/3L MSS CRC). Part 2 included patients with metastatic 1L PDAC or 2L CRC. Patients received BMS-813160 300 mg two times a day+gem/nabP±nivolumab (1L PDAC), BMS-813160 300 mg two times a day or 150 mg once daily+FOLFIRI (2L CRC), or chemotherapy alone. Primary endpoints were safety and pharmacodynamics (Part 1) and efficacy (Part 2). Results In Part 1, 22 of 75 (29%) and 54 of 72 (72%) patients experienced a treatment-related adverse event during monotherapy lead-in and overall, respectively. Two dose-limiting toxicities (rash and pericardial effusion with pericarditis, both grade 3) occurred. In Part 2, patients with 1L PDAC who received BMS-813160 300 mg two times a day+gem/nabP+nivolumab achieved an overall response rate (ORR) of 37% (13/35); the median duration of response (DOR) was 45 weeks (95% CI 26.1 to not evaluable). ORRs with BMS-813160 300 mg two times a day+gem/nabP and gem/nabP alone were 26% (9/35) and 28% (9/32), respectively; median DORs were 121 and 31 weeks, respectively. Progression-free survival rates at 24 weeks were 56% (BMS-813160 300 mg two times a day+gem/nabP+nivolumab), 56% (BMS-813160 300 mg two times a day+gem/nabP), and 50% (gem/nabP). ORRs in 2L CRC were 19% (6/32; BMS-813160 300 mg two times a day+FOLFIRI), 13% (4/32; BMS-813160 150 mg once daily+FOLFIRI), and 27% (7/26; FOLFIRI). Conclusions In 1L PDAC, BMS-813160 300 two times a day+gem/nabP±nivolumab demonstrated durable antitumor response and was well tolerated. BMS-813160 combination regimens were tolerable in other cohorts, but clinical efficacy was not demonstrated. Trial registration number NCT03184870 .

198 Background: The Hedgehog (Hh) signaling pathway regulates tissue patterning, growth and differentiation, including within gastrointestinal tract. Mammalian homologs include Sonic (SHH), Indian (IHH) and Desert (DHH) Hedgehog, which signal through PTCH and SMO and the GLI transcription factors. In the digestive tract, both SHH and IHH are expressed, but the functional role of Hh signaling in mCRC remains incompletely defined. Methods: We analyzed 433 mCRC patients treated with either bevacizumab (bev = 226) or cetuximab (cet = 207) plus first line chemotherapy in CALGB/SWOG 80405 (NCT00265850). RNA expression (Illumina HiSeq 2500) of 9 Hh pathway genes (SHH, IHH, DHH, PTCH1, PTCH2, SMO, GLI1, GLI2, GLI3) was evaluated. Median overall survival (mOS) and progression free survival (mPFS) in months (mo) were compared across expression tertiles (low [L], medium [M], high [H]). Likelihood ratio tests, hazard ratios and 95% confidence intervals were computed from multivariable Cox proportional hazards models, adjusting for age, sex, ethnicity, ECOG PS, tumor location, number of metastatic sites, KRAS , microsatellites instability status and treatment. Prognostic effects were modeled as marginal terms; predictive effects were modeled as multiplicative interactions. Results: Overall, IHH and GLI2 demonstrated prognostic value for OS after adjusting for multiple testing (Benjamini-Hochberg False Discovery Rate (FDR) < 0.05). High IHH expression (H group, n = 143) correlated with improved mOS (H: 36.0 mo vs M: 32.8 mo vs L: 23.5 mo; p= 0.031), whereas low GLI2 expression (L group, n = 145) was associated with longer mOS (H: 25.6 mo vs M: 33.9 mo vs L: 33.7 mo; p= 0.0016). Moreover, IHH showed predictive value for cet benefit in both OS (mOS H: 38.1 mo vs M: 34.0 mo vs L: 18.4 mo; p= 0.0032) and PFS (mPFS H: 12.6 mo vs M: 12.9 mo vs L: 8.8 mo; p= 0.0025) with significant treatment interaction for OS and PFS (p= 0.0046 and p= 0.0049, respectively; FDR< 0.05). No significant associations were found in bev treated pts. No other Hh genes showed significant prognostic or predictive effects after FDR correction. Conclusions: These results highlight a dual role of Hh pathway in mCRC. Consistent with prior preclinical evidence, reduced IHH expression appears to mark poor prognosis, likely reflecting the loss of IHH-mediated restraint on Wnt signaling, which drives proliferation and dedifferentiation. Conversely, low GLI2, a downstream transcription factor, was linked with favorable outcomes, underscoring context-specific effects of Hh signaling. The strong predictive association of IHH with cet efficacy supports its potential as a biomarker in RAS wild type mCRC. These results suggest that Hh pathway modulation, particularly IHH signaling, may influence disease biology and treatment response. Validation in independent cohorts and mechanistic studies is warranted to clarify implications.

179 Background: Neuroligins are a family of postsynaptic cell adhesion molecules that play a crucial role in synapse formation and function. Recent studies suggest Neuroligin family genes (NLGN1,2,3,4X) may promote cancer cell growth and metastasis in various cancers, including colorectal cancer. Here, we investigated the association between neuroligin family gene expression and first-line treatment outcomes in mCRC. Methods: We evaluated the expression of 4 genes in the neuroligin family (NLGN1, NLGN2, NLGN3 and NLGN4X) on treatment outcomes of 433 pts with mCRC treated with either bevacizumab (Bev, n = 226) or cetuximab (Cet, n = 207) in combination with first-line chemotherapy within the CALGB/SWOG 80405 trial. mRNA was isolated from FFPE tumor samples and sequenced on the HiSeq 2500 (Illumina). Overall survival (OS) and progression-free survival (PFS) were compared between groups of pts categorized by low expression (Q1) (≤25 percentile), medium expression (Q2-3) (25th-75th percentile) and high expression (Q4)(>75th percentile) of NLGN family genes. The associations between gene expression and clinical outcomes were assessed via the multivariable Cox model and plotted with Kaplan-Meier curve. Treatment-gene interactions were evaluated using the likelihood ratio test. False discovery rate (FDR) was controlled through the Benjamini-Hochberg procedure. Results: High NLGN2 expression was associated with shorter PFS (median 10.0 mos, 95% CI (8.3, 11.3)) and OS (median 25.2mos, 95%CI (20.9, 30.0)) compared to low NLGN2 expression (PFS: median 11.2mos, 95% CI (9.8,14.3))(HR 1.41, 95% CI (1.06, 1.89)), P = 0.029). (OS: (median 31.8mos, 95%CI (26.8, 37.5)( HR 1.49, 95% CI (1.10, 2.01) P =0.0095) in multivariate analysis. Patients treated in the cetuximab arm(n=207), high HLGN2 expression significantly associated with shorter PFS (median 8.0 vs 13.4, HR 2.02, 95% CI (1.35, 3.03), P = 0.0021) and OS (median19.6 vs 36.3, HR 2.30, 95% CI (1.50, 3.53), P =8.3e-05). High NLGN3 expression was associated with shorter OS (23.9 vs 36.0 mos, P =0.0083) in cetuximab treatment arms, no significance found in PFS. We found significant treatment interaction for OS with NLGN2 and NLGN3 favoring cetuximab. In pts treated with cetuximab, High NLGN2 expression was significantly associated with shorter OS (median 29.1vs 36.3) (p=0.024) compared to pts treated with bevacizumab. For NLGN3, pts treated with cetuximab, high NLGN3 expression was significantly associated with shorter OS (median 25.0 vs 36.0) (p=0.018) compared to pts treated with bevacizumab. No significant association was found in NLGN1 and NLGN4X. Conclusions: Our results suggest NLGN2/3 gene expression may predict mCRC treatment outcomes. Potential therapeutic drug target NLGN in combination with anti-EGFR treatment in mCRC is warranted.

PURPOSE Colorectal cancer (CRC) incidence and mortality have decreased since the 1970s, but the incidence in young adults (<50 years, named early-onset CRC [eoCRC]) has been increasing. PATIENTS AND METHODS Individual patient data on 13,365 patients with metastatic CRC enrolled between 2000 and 2012 in 17 first-line randomized trials in the Aide et Recherche en Cancérologie Digestive database were pooled. The distribution of demographics, clinicopathologic features, biomarkers, and outcome data were summarized and compared by age groups. Progression-free survival (PFS) and overall survival (OS) were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for potential confounders. Predictive value of age group on clinical outcomes was evaluated by testing interaction effect between treatment and age variables. RESULTS Overall, 2,045 patients with eoCRC (median age, 42.5) and 11,320 patients with average-onset CRC (aoCRC; median age, 63.8) were included in this analysis. Within the eoCRC population, treatment with bevacizumab in addition to chemotherapy improved PFS (9.9 v 6.8 months; hazard ratio [HR], 0.66 [95% CI, 0.54 to 0.80]; P < .0001), which was similar to the findings in aoCRC population (9.4 v 7.3 months; HR, 0.73 [95% CI, 0.67 to 0.80]; P < .001; interaction P = .5415). However, epithelial growth factor receptor inhibitor (EGFRi) did not improve PFS in RAS wild-type (WT) patients with eoCRC who had left-sided primary tumors (8.3 v 8.9 months; HR, 1.20 [95% CI, 0.81 to 1.77]; P = .36), whereas EGFRi significantly improved PFS in the aoCRC population (9.9 v 8.5 months; HR, 0.74 [95% CI, 0.64 to 0.86]; P < .0001; interaction P = .083). CONCLUSION Treatment-naïve patients with metastatic eoCRC appear to derive similar benefit from bevacizumab as patients with aoCRC. However, patients with eoCRC with left-sided RAS/RAF WT tumors did not appear to derive benefit from first-line EGFRi.

3145 Background: SnoRNAs are non-coding RNAs that primarily guide the chemical modification of ribosomal RNA. Emerging evidence suggests snoRNAs play critical roles in cancer, including CRC, by regulating cell proliferation, apoptosis and tumor progression. Aberrant snoRNA expression has been linked to CRC development and poor prognosis, offering potential as diagnostic biomarkers and therapeutic targets. We investigated whether the tumor expression levels of 3 types of snoRNAs (SCARNA, SNORA, SNORD) affect treatment response in pts enrolled in CALGB/SWOG 80405 (NCT00265850). Methods: 433 mCRC pts treated with bevacizumab (bev, n = 226) or cetuximab (cet, n = 207) in combination with first-line chemotherapy were analyzed. RNA was isolated from FFPE tumor samples and sequenced on the HiSeq 2500 (Illumina). 422 snoRNAs were evaluated (23 SCARNA, 140 SNORA, 259 SNORD). Overall survival (OS) and progression-free survival (PFS) were compared across tertiles of gene expression (high [H], medium [M], low [L]) by multivariable Cox proportional hazards models adjusted for age, sex, ECOG performance status, tumor side, number of metastatic sites, KRAS , CMS subtypes, and treatment. Interaction tests for the predictive effect (bev vs cet) were performed. P -values were corrected for multiple testing using the Benjamini-Hochberg approach ( q < 0.05). Results: Only SCARNA21 achieved statistical significance for OS after false discovery rate (FDR) adjustment. Tumors with H levels of SCARNA21 had shorter survival compared to tumors with M or L expression (median OS 24.4 vs 32.4 vs 33.9 months, respectively; P = 0.0015, q = 0.033), independent of treatment. No snoRNAs achieved FDR significance for PFS. However, several snoRNAs showed significant treatment interactions with biologic agents. SCARNA6-H and SCARNA5-H tumors had longer PFS and OS when treated with cet, but shorter PFS and OS when treated with bev, compared to the M and L expression groups (PFS interaction q = 0.0067 and 0.045, respectively; OS interaction q = 0.022 and 0.034, respectively). SCARNA7 also showed significant treatment interaction for OS, favoring cet in the H expression group ( q = 0.018); the opposite was observed for SNORA63B, SNORA63D, SNORA35B, and SNORA36C ( q = 0.027, 0.027, 0.027 and 0.047, respectively). No significant results were observed for any of the tested SNORDs. Conclusions: SnoRNAs dysregulation affects key pathways such as cell cycle control and immune evasion, making them promising players in CRC biology. Our study highlights the prognostic and predictive potential of specific snoRNAs in mCRC. Notably, high SCARNA21 expression was linked to shorter OS, while SCARNA5 and 6 showed predictive value for treatment response, indicating their potential for guiding treatment decisions. Further validation is needed to confirm these findings, and mechanistic studies are warranted.