Predictive value of MAOB gene expression for targeted therapy in patients (pts) with metastatic colorectal cancer (mCRC) enrolled in CALGB (Alliance)/SWOG 80405.
Authors: Zhang Wu , Millstein Joshua , Yang Yan , Ou Fang-Shu , Innocenti Federico , Arai Hiroyuki , Soni Shivani , Mumenthaler Shannon M. , Algaze Sandra , Jayachandran Priya , Bertagnolli Monica M. , Deming Dustin A. , Niedzwiecki Donna , Goldberg Richard M. , Mayer Robert J. , Blanke Charles David , Venook Alan P. , Kabbarah Omar , Battaglin Francesca , Lenz Heinz-Josef 
Published: June 2022

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.