Millstein, Joshua

269 Background: Sirtuins (SIRT1-7) are class III histone deacetylases with different roles in CRC as tumor suppressive and oncogenic, mainly influencing proliferation, migration, invasion, DNA damage and chemoresistance. In the present study, we explored the association between tumor gene expression of sirtuins and first-line treatment outcomes in mCRC pts. Methods: We evaluated the impact of the tumor gene expression of sirtuin genes ( SIRT1 -7) on treatment outcomes (overall survival: OS; progression free survival: PFS) in 433 pts enrolled in the randomized, phase III CALGB/SWOG 80405 (NCT00265850) trial. RNA extracted from FFPE tumor samples was sequenced using the HiSeq 2500 (Illumina). Subgroup analyses were based on treatment (bevacizumab [bev] (N = 226) vs. cetuximab [cet] (N = 207)). For each gene, expression was divided into tertiles of high, medium and low. The associations between tumor gene expression and outcomes (PFS and OS) were assessed using log-rank test in univariate analysis. Multivariable Cox proportional hazards regression model was used to compute hazard ratios (HR) and 95% confidence intervals while adjusting for baseline characteristics. Treatment-gene interactions were analyzed using the likelihood ratio test. Results: Of the seven genes analyzed, SIRT3 high was associated with both longer PFS (HR: 0.59 [95% CI: 0.46-0.74], P < 0.001) and OS (HR:0.64 [95% CI: 0.50-0.83], P = 0.002) overall. Treatment-gene interaction testing found significant interactions for SIRT1 and SIRT5 with PFS ( P values: 0.021 and 0.016, respectively) and OS ( P values: 0.038 and 0.014, respectively) with targeted therapies (bev vs. cet). Multivariate analysis showed SIRT1 high associated with longer PFS (HR: 0.62 [95% CI: 0.42-0.89], P = 0.014) and OS (HR: 0.59 [95% CI: 0.40-0.89], P = 0.036) in cet-treated pts; in contrast with shorter observed PFS (HR: 1.38 [95% CI: 0.96-1.99], P = 0.22) and OS (HR: 1.31 [95% CI: 0.90-1.93], P = 0.23) in bev-treated pts. SIRT5 high showed similar results and associated with longer PFS (HR: 0.64 [95% CI: 0.45-0.91], P = 0.039) and OS (HR: 0.57 [95% CI: 0.39-0.83], P = 0.013) in cet-treated pts, with no similar associations in bev-treated pts. Conclusions: Our results highlight a potential role for SIRT3 as prognostic and, SIRT1 and SIRT5 as predictive biomarkers for first-line treatment in mCRC, with differential effects based on targeted agents. Significant interaction favored cet treatment in SIRT1 high and SIRT5 high tumors. However, previous reports suggest an opposite role of SIRT5 that has been linked to chemotherapy and/or cet resistance in CRC via the inactivation of succinate dehydrogenase complex subunit A. Therefore, further studies are warranted to dissect the mechanism behind the interaction of SIRT5 with cetuximab activity and establish the potential of targeting SIRT1/5 in CRC.

254 Background: SLFN11 was recently identified as a dominant determinant of response to DNA-damaging anticancer agents. Several studies showed SLFN11 expression led to better sensitivity to topoisomerase inhibitors and PARP inhibitors. However, clinical evidence in mCRC has been lacking. Methods: Two independent cohorts (CALGB/SWOG 80405 trial and a real-world patient [Caris CODEai] cohort) were included in this study. Patients were stratified into SLFN11 -high and -low groups based on the median SLFN11 gene expression levels. Survival outcomes were compared between SLFN11 -high and SLFN11 -low in irinotecan-treated and oxaliplatin-treated patients. Median time was estimated using Kaplan-Meier method and Cox models were used for covariate adjustment. Endpoints of interest were progression-free survival (PFS) and overall survival (OS). Results: In the CALGB/SWOG 80405 trial cohort, 433 patients were included (110 treated with FOLFIRI-based chemotherapy and 323 treated with FOLFOX-based chemotherapy). In patients treated with FOLFIRI-based chemotherapy, SLFN11 -low patients exhibited numerically better PFS (median PFS, 13.4 vs 11.2 months, log-rank p = 0.03, adjusted hazard ratio [HR] = 0.86, 95% confidence interval [CI] 0.55-1.39, p = 0.50) and OS (median OS, 39.6 vs 30.3 months, log-rank p = 0.02, adjusted HR = 0.73, 95% CI 0.46-1.16, p = 0.19) compared to SLFN11 -high patients. In patients treated with FOLFOX-based chemotherapy, SLFN11 -low patients exhibited numerically better PFS (median PFS 11.2 vs 9.8 months, log-rank p = 0.03, adjusted HR = 0.83, 95% CI 0.65-1.05, p = 0.12) and OS (31.1 vs 26.1 months, log-rank p = 0.07, adjusted HR = 0.84, 95% CI 0.65-1.08, p = 0.16) compared to SLFN11 -high patients. No significant interaction was observed between treatment and SLFN11 expression in terms of PFS ( p = 0.69) and OS ( p = 0.44). In the Caris CODEai cohort, a better OS in SLFN11 -low patients than in SLFN11 -high patients was observed in irinotecan-treated patients ( N = 2906) (median OS, 25.5 vs 21.7 months, HR = 0.90, 95% CI 0.82-1.00, p = 0.048). However, no significant difference in OS between SLFN11 -low and SLFN11-high was observed in oxaliplatin-treated patients ( N = 4428) (median OS, 39.5 vs 35.8 months, HR = 0.98, 95% CI 0.90-1.06, p = 0.56). Conclusions: Low SLFN11 expression showed a potential for better prognosis in mCRC patients receiving irinotecan- and oxaliplatin-containing chemotherapies. These findings are not consistently aligned with preclinical data and clinical evidence in other cancer types previously reported. Further investigation is warranted to better understand the biological role and clinical implication of SLFN11 in mCRC.

285 Background: Immune checkpoint inhibitors (ICIs) have shown limited efficacy in colorectal cancer (CRC) outside of mismatch repair (MMR) deficient/microsatellite instability-high (MSI-H) tumors. Most CRC cases are MMR proficient /microsatellite stable and demonstrate resistance to ICIs, attributed to the tumor microenvironment. Colony Stimulating Factor 1 Receptor (CSF1R), a regulator of tumor-associated macrophages, has emerged as a potential target due to its association with poor prognosis in CRC. Methods: Data from 433 metastatic CRC (mCRC) patients in the CALGB/SWOG 80405 trial were analyzed. CSF1R RNA was extracted from formalin-fixed, paraffin-embedded tumor samples and sequenced. Patients were divided into tertiles of CSF1R expression (high, medium, low). Progression-free survival (PFS) and overall survival (OS) were compared using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. Subgroup analyses were conducted based on liver metastases, treatment type (Bevacizumab, Cetuximab, FOLFOX, FOLFIRI), and MSI status. Results: Low CSF1R expression (CSF1R-L) was associated with significantly better survival outcomes. Median PFS was 12.9 months for CSF1R-L, compared to 11.2 and 9.2 months for CSF1R-M and CSF1R-H (p = 0.003). Median OS was 35.8 months for CSF1R-L versus 32.5 and 24.4 months for CSF1R-M and CSF1R-H (p = 0.00086). Stratification by liver metastases showed that CSF1R-L remained a strong prognostic factor only in patients with liver metastases. There were no significant survival differences based on CSF1R expression in bevacizumab-treated patients. However, in cetuximab-treated patients, CSF1R-L tumors had significantly longer PFS (12.9 vs 8.8 months, p = 0.037) and OS (35.8 vs 21.4 months, p = 0.002) than CSF1R-H tumors. Similarly, in FOLFOX-treated patients, CSF1R-L tumors showed longer PFS and OS (p = 0.018 and p = 0.013, respectively), and in FOLFIRI-treated patients, OS was significantly longer for CSF1R-L tumors (42.2 vs 24.7 months, p = 0.022) than CSF1R-H tumors. Conclusions: Our data suggests that CSF1R expression may serve as a prognostic biomarker in CRC, with lower expression potentially linked to improved survival, particularly in patients with liver metastases. These findings warrant further investigation of CSF1R as a possible prognostic and predictive biomarker, as well as a potential therapeutic target in CRC. Clinical trial information: NCT00265850 .

3588 Background: The brain-gut axis, a bidirectional network between the central and enteric nervous systems, plays a critical role in modulating the gastrointestinal tract function. Increasing evidence suggests that neuronal signaling molecules can promote gastrointestinal cancers; however, the mechanisms remain unclear. Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter and dysregulated GABA signaling has been found in CRC, affecting both tumor and tumor microenvironment. Here, we investigated the association between tumor GABA pathway gene expression and first-line treatment outcomes in mCRC. Methods: We evaluated the impact of the expression of 25 genes in the GABA pathway ( GABBR1, GABBR2, GABRA1, GABRA2, GABRA4, GABRA5, GABRA6, GABRB1, GABRB3, GABRD, GABRE, GABRG1, GABRG2, GABRG3, GABRQ, GABRR1, GABRR2, ABAT, ALDH5A1, GAD1, GAD2, SLC6A1, SLC6A13, SLC6A11, SLC6A12) on treatment outcomes (overall survival: OS; progression free survival: PFS) of 433 pts enrolled in the randomized, phase III CALGB/SWOG 80405 trial. RNA extracted from FFPE tumor samples was sequenced using the HiSeq 2500 (Illumina). The associations between gene expression (continuous, per standard deviation increase) and outcomes were assessed via the multivariable Cox proportional framework, with hazard ratios (HR) and 95% confidence intervals (CI) computed. The likelihood ratio test was used for interaction tests. False discovery rate (FDR) was controlled at 5% with the Benjamini-Hochberg method. Results: Overall, low GAD1 (encoding for glutamate decarboxylase 1, the enzyme responsible for catalyzing the production of GABA from L-glutamic acid) was associated with longer PFS (HR: 1.26, 95% CI [1.13, 1.41], P = 3.2E-05) and OS (HR 1.27 [1.13, 1.43], P = 5.9E-05) across all treatment arms. High ABAT (encoding for the aminotransferase responsible for GABA catabolism) was also associated with longer OS (HR 0.81 [0.72, 0.91], P = 6E-04). To evaluate the predictive value, interactions with targeted therapies bevacizumab (n = 226) vs cetuximab (n = 207) were tested. We found significant interactions for PFS with ABAT ( P= 0.0017) and OS with SLC6A13 ( P= 0.0014 ).In pts treated with cetuximab, high ABAT expression was significantly associated with longer PFS (HR 0.73 [0.61, 0.87], P = 2.8E-04), and high SLC6A13 was marginally associated with worse OS (HR 1.18 [1.00, 1.39], P = 0.052). We did not observe similar associations in pts treated with bevacizumab. Conclusions: Our results highlight a potential role for GABA signaling in affecting mCRC treatment outcomes, suggesting that GABA pathway genes may be promising novel predictive and prognostic biomarkers and supporting the rationale to investigate GABA as a target for drug development. ClinicalTrials.gov Identifier: NCT00265850

3144 Background: Longitudinal brain structure changes across the lifespan are associated with neurodegenerative disorders. We previously showed that genetic variants in dopamine and Parkinson’s disease genes are predictive and prognostic in mCRC. Indeed, the brain-gut axis is emerging as a critical player in CRC biology. Hence, we investigated whether the tumor gene expression of 3 metabolic genes involved in brain development and aging could affect treatment response in patients enrolled in the CALGB/SWOG 80405 trial. Methods: 433 mCRC pts treated with either bevacizumab (bev, n = 226) or cetuximab (cet, n = 207) in combination with first-line chemotherapy were included in the analysis. RNA 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 tertiles of expression of 3 genes: APOE, DACH1, and GPR139. Likelihood ratio tests, hazard ratios and 95% confidence intervals were computed from multivariate Cox proportional hazards models, adjusting for age, sex, ethnicity, ECOG PS, tumor location, number of metastatic sites, KRAS, MSI status, and treatment. Logrank P-values describe differences without adjustment for patient characteristics. Results: Both APOE and DACH1 (but not GPR139) met the 0.05 false discovery rate threshold for association with both PFS ( P = .00085, P = .015) and OS ( P = .021, P = .021, respectively) in the full Cox models. In cet-treated pts, APOE-high (H) showed significantly shorter PFS (median 9.2 vs 11.8 vs 13.0 months (mo), high vs low (as reference) logrank P = .0021) and OS (median 21.9 vs 35.8 vs 34.6 mo; logrank P = .0017) compared to APOE-median and -low, respectively. Opposite results were observed for DACH1, where DACH1-H tumors had longer PFS (median 14.5 vs 10.6 vs 8.07 mo; logrank P = .0011) and OS (median 39.4 vs 30.9 vs 21.5 mo; logrank P = .0021) when treated with cet. In bev-treated pts, similar results were observed with APOE-H showing shorter OS (median 25.8 vs 26.3 vs 37.5 mo; logrank P = .0016) and DACH1-H longer OS (median 36.5 vs 28.3 vs 22.4 mo; logrank P = .0017). No significant gene-treatment interaction was observed for either gene for PFS and OS. Conclusions: The tumor expression of metabolic genes associated with changes in the brain structure was prognostic in mCRC pts treated with first-line therapy. Notably, APOE and DACH1 have been recently reported to play a role in CRC where APOE overexpression has been associated with aggressive biological behavior whereas DACH1 has been shown to suppress CRC cell growth and invasion. Our results support this evidence and suggest that further investigation into the role of APOE and DACH1 in CRC biology and into their potential as targets for drug development is warranted. Trial Identifier: NCT00265850.

3523 Background: Evidence suggests neurotransmitter signaling may play a crucial role in tumorigenesis of gastrointestinal (GI) cancers, including migration, proliferation, and apoptosis, as well as angiogenesis and the microenvironment. We developed and applied a strategy to identify upstream regulators of neurotransmitters and their associations with patient outcomes. Methods: Prior literature yielded 85 neurotransmitter signaling genes mapped to RNA-seq gene expression in tumor tissue from 545 patients with mCRC enrolled in the phase III CALGB/SWOG 80405 trial. These samples were also sequenced by FoundationOne CDx for DNA damage. Using Cox proportional hazards regression, we identified a subset of CDx genes associated with overall survival (OS) or progression-free survival (PFS). We extended the Causal Inference Test (CIT) for time-to-event data and identified a subset of the 85 signaling genes consistent with mediation of DNA mutation effects on OS and PFS. Another CIT analysis identified potential upstream neurotransmitter regulators, gene expression mediators of mutation effects on the signaling genes. Top genes were then assessed in whole-transcriptome sequencing (WTS) expression data with Caris MI profile collected from 398 patients with advanced CRC enrolled in the MONSTAR-SCREEN-2 trial. Results: At the 0.05 alpha level, we identified 20 signaling genes with gene expression associated with PFS and/or OS, and 68 genes with evidence of DNA mutations associated with PFS and/or OS. False discovery rate (FDR) < 0.05 was applied to filter the 56,674 expression features on PFS and OS associations, yielding 173 unique genes as possible mediators. The CIT yielded 53 putative mediators at FDR < 0.05, suggesting upstream regulation of neurotransmitter signaling. Five genes were identified as targeting at least 8 signaling genes each, PIGU, ANO9, LY6G6D, and GPR160, and FSCN1, where the first 4 are favorable and only FSCN1 is a poorer prognostic. Following up on these 5 genes in MONSTAR-SCREEN-2 by dichotomizing at the median value of WTS expression, 3 were nominally associated with OS, PIGU ( P = 0.050; HR, 0.59; 95%CI, 0.34-1.00), ANO9( P = 0.029; HR, 0.55; 95%CI, 0.32-0.95), LY6G6D( P = 0.0024; HR, 0.44; 95%CI, 0.25-0.76), and FSCN1 was suggestive ( P = 0.079; HR, 1.62; 95%CI, 0.94-2.77), with direction of effects in agreement with 80405 results for all four. Conclusions: Our novel approach identified previously unknown upstream regulators of neurotransmitter signaling associated with treatment outcomes in mCRC. PIGU, FSCN1, and LY6G6D have been suggested in prior literature as targets for CRC and ANO9 has been suggested as a target for GI cancer. These results bolster the strategy of using mediation analysis with large-scale molecular data to identify new therapeutic targets in CRC. NCT00265850.

Background The C-C motif chemokine receptor 5 (CCR5)/C-C motif chemokine ligand 5 (CCL5) axis plays a major role in colorectal cancer (CRC). We aimed to characterize the molecular features associated with CCR5 / CCL5 expression in CRC and to determine whether CCR5 / CCL5 levels could impact treatment outcomes. Methods 7604 CRCs tested with NextGen Sequencing on DNA and RNA were analyzed. Molecular features were evaluated according to CCR5 and CCL5 tumor gene expression quartiles. The impact on treatment outcomes was assessed in two cohorts, including 6341 real-world patients and 429 patients from the Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial. Results CCR5 / CCL5 expression was higher in right-sided versus left-sided tumors, and positively associated with consensus molecular subtypes 1 and 4. Higher CCR5 / CCL5 expression was associated with higher tumor mutational burden, deficiency in mismatch repair and programmed cell death ligand 1 (PD-L1) levels. Additionally, high CCR5 / CCL5 were associated with higher immune cell infiltration in the tumor microenvironment (TME) of MMR proficient tumors. Ingenuity pathway analysis revealed upregulation of the programmed cell death protein 1 (PD-1)/PD-L1 cancer immunotherapy pathway, phosphatase and tensin homolog (PTEN) and peroxisome proliferator-activated receptors (PPAR) signaling, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) signaling in cytotoxic T lymphocytes, whereas several inflammation-related pathways were downregulated. Low CCR5 / CCL5 expression was associated with increased benefit from cetuximab-FOLFOX treatment in the CALGB/SWOG 80405 trial, where significant treatment interaction was observed with biologic agents and chemotherapy backbone. Conclusions Our data show a strong association between CCR5/CCL5 gene expression and distinct molecular features, gene expression profiles, TME cell infiltration, and treatment benefit in CRC. Targeting the CCR5/CCL5 axis may have clinical applications in selected CRC subgroups and may play a key role in developing and deploying strategies to modulate the immune TME for CRC treatment.

AbstractBackgroundCyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo‐ovarian high‐grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large‐scale, histotype‐specific validation has been performed. The hypothesis was that high‐level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC.MethodsWithin the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated.ResultsHigh‐level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high‐level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08‐1.47, p = .034, and HR, 1.18; 95% CI, 1.05‐1.32, p = .015, respectively). This was also true for cases with combined high‐level amplification/overexpression (HR, 1.26; 95% CI, 1.09‐1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1‐SD increase; 95% CI, 0.94‐1.06; p = .58). CCNE1 high‐level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss.ConclusionThis study provides large‐scale validation that CCNE1 high‐level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

3586 Background: HSP90 mediated chaperoning is a well-conserved biological mechanism for stabilization and activation of kinases. More than 60% of human kinases including VEGFR, CRAF, CSF1R, and FGFR are target of HSP90 (client kinases), whereas EGFR is non-client. CDC37 is a specific co-chaperone determining selectivity of client kinases recognized by HSP90. We hypothesized that gene expression levels of CDC37 have predictive values for anti-angiogenic therapies in mCRC. Methods: The subjects of this study were mCRC patients treated with regorafenib (REGO, Japanese retrospective cohort) and those treated with bevacizumab (BEV) or cetuximab (CET) in combination with first-line chemotherapy (CALGB/SWOG 80405 trial cohort). CDC37 expression levels were measured using RNA isolated from FFPE samples by nCounter gene expression profiling (Nanostring) and HiSeq 2500 (Illumina) in the Japanese and CALGB/SWOG 80405 cohorts, respectively. Overall survival (OS) and progression-free survival (PFS) were compared between patients with high CDC37 expression ( CDC37-H) and those with low expression ( CDC37-L), grouped by median cutoff value in each cohort. Results: In total, 484 patients were included (50 treated with REGO, 227 treated with BEV, and 207 treated with CET). In REGO-treated patients, CDC37-H showed significantly better OS (median 11.3 vs 6.0 months, adjusted hazard ratio [HR] 0.24, 95% confidence interval [CI] 0.11-0.54, p <0.01) and PFS (median 3.5 vs 1.9 months, adjusted HR 0.51, 95% CI 0.28-0.94, p = 0.03) compared to CDC37-L. Similarly, in BEV-treated patients, CDC37-H showed significantly better PFS (median 13.5 vs 9.6 months, adjusted HR 0.59, 95% CI 0.43-0.79, p <0.01) and numerically better OS (median 34.1 vs 29.4 months, adjusted HR 0.81, 95% CI 0.60-1.11, p = 0.20) compared to CDC37-L. However, in CET-treated patients, CDC37-H and CDC37-L patients showed similar OS (median 33.7 vs 26.1 months, adjusted HR 1.00, 95% CI 0.73-1.38, p = 0.98) and PFS (median 11.3 vs 11.0 months, adjusted HR 1.08, 95% CI 0.81-1.45, p = 0.60). Significant interaction was observed between CDC37 expression and treatment in terms of PFS in the CALGB/SWOG 80405 cohort ( p = 0.01). Conclusions: Our results suggest patients with CDC37-dependent ( CDC37-H) tumors may derive more benefit from REGO and BEV both of which target HSP90 client kinases or signaling pathways, but not from CET which target HSP90 non-client kinase. Further validation studies are warranted to develop a novel personalized approach for targeted therapies based on CDC37 expression in mCRC patients. Support: U10CA180821, U10CA180888; Pfizer, Genentech; https://acknowledgments.alliancefound.org. ClinicalTrials.gov Identifier: NCT00265850.

3580 Background: Monoamine oxidases (MAOs), including MAOA and MAOB, are mitochondrial enzymes responsible for catalyzing monoamine oxidation. Increased expression of MAOs were found in several cancer types and high MAOB was associated with worse disease stage and poorer survival in CRC. Positive and negative correlations of MAOB expression with mesenchymal type and epithelial type gene expressions, respectively, have been reported. Hence, we investigated whether MAOB expression is predictive for targeted therapies in mCRC. Methods: 430 mCRC pts treated with either bevacizumab (BEV, n = 224) or cetuximab (CET, n = 206) in combination with first-line chemotherapy within the CALGB/SWOG 80405 trial were included in the analysis. MAOB RNA 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 tertiles of MAOB expression into high (H), medium (M) and low (L). Hazard ratios (HR) and 95% confidence intervals (CI) were computed from multivariable Cox proportional hazards model, adjusting for age, sex, location, number of metastases, KRAS, MSI status, and treatment with FOLFOX or FOLFIRI. Sensitivity analyses were conducted after stratifying by sex. Logrank P-values describe differences without adjustment for patient characteristics. Results: In CET-treated pts, MAOB-L showed significantly longer OS (median 39.2 vs 30.9 vs 15.9 months, logrank P = 4.7E-05, L vs H (as reference) adjusted HR 0.42, 95% CI [0.27, 0.65]) and PFS (median 13.2 vs 11.8 vs 7.6 months, logrank P = 0.006, L vs H adjusted HR 0.59 [0.40, 0.88]) compared to MAOB-M and MAOB-H, respectively. Similar results were observed when evaluating MAOB expression as a continuous variable. In BEV-treated pts, no significant differences were observed when comparing MAOB expression tertiles; however, pts with lower MAOB expression had significantly better OS, but not PFS, when evaluating MAOB as a continuous variable (Cox LRT P = 0.015, covariate adjusted). In CET-treated pts, the effect of MAOB expression was observed in male but not female pts (OS: median 40.3 vs 30.9 vs 16.1 months by MAOB-L, M, H, respectively, logrank P = 6.8E-05, L vs H adjusted HR 0.33 [0.19, 0.59]; PFS: median 13.8 vs 12.6 vs 7.9 months, logrank P = 0.001, L vs H adjusted HR 0.46 [0.28, 0.79]). A significant interaction was observed between MAOB expression and treatment for OS ( P = 0.010) in males and females combined, but only in males ( P = 0.018) when stratified by sex. Conclusions: Our results suggest that pts with MAOB-L tumors may have greater benefit from CET-based treatment and that targeting MAOB may be a promising strategy to improve patient outcomes. Further validation studies are warranted to develop a novel personalized approach based on MAOB expression in mCRC pts. Clinical trial information: NCT00265850.