Heinz-Josef Lenz, MD, is a professor in the Departments of Medicine and Preventive Medicine in Keck School of Medicine’s oncology division. He is the associate director of clinical research of the USC Norris Comprehensive Cancer Center, is chair of the GI Oncology Program and is the co-director of the Colorectal Center. He also serves as the scientific director of the Cancer Genetics Unit. In this video, he speaks about the ASCO 2022 Abstract Predictive value of MAOB gene expression for targeted therapy in patients (pts) with metastatic colorectal cancer (mCRC) enrolled in CALGB (Alliance)/SWOG 80405.
Origins:
Monoamine oxidases (MAOs), which include MAOA and MAOB, are mitochondrial enzymes that catalyze monoamine oxidation. MAOs were discovered to be overexpressed in numerous cancer types, and having a high MAOB was related with a worse disease stage and a lower chance of survival in CRC. MAOB expression has been found to have both positive and negative relationships with gene expression of the mesenchymal and epithelial types. As a result, we evaluated whether MAOB expression predicts response to targeted treatments in mCRC.
Methodology:
In the CALGB/SWOG 80405 experiment, 430 mCRC patients were treated with either bevacizumab (BEV, n = 224) or cetuximab (CET, n = 206) in conjunction with first-line chemotherapy.
MAOB RNA was extracted from FFPE tumor tissues and sequenced using a HiSeq 2500. (Illumina). Overall survival (OS) and progression-free survival (PFS) were compared across groups of patients classified by MAOB expression tertiles into high (H), medium (M), and low (L) (L). Hazard ratios (HR) and 95 percent confidence intervals (CI) were calculated using a multivariate Cox proportional hazards model that controlled for age, gender, location, number of metastases, KRAS, MSI status, and FOLFOX or FOLFIRI therapy. After stratifying by gender, sensitivity analyses were performed. Logrank P-values describe differences without taking patient variables into account.
Outcomes:
When compared to MAOB-M and MAOB-H, MAOB-L had significantly longer OS (median 39.2 vs 30.9 vs 15.9 months, logrank P = 4.7E-05, L versus H (as reference) adjusted HR 0.42, 95 percent 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 When MAOB expression was evaluated as a continuous variable, similar findings were obtained. When comparing MAOB expression tertiles in BEV-treated patients, no significant changes were identified; however, when analyzing MAOB as a continuous variable, patients with lower MAOB expression had significantly improved OS but not PFS (Cox LRT P = 0.015, covariate adjusted). The effect of MAOB expression was seen in male but not female pts in CET-treated 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 When males and females were pooled, there was a significant interaction between MAOB expression and OS treatment (P = 0.010), but only in males (P = 0.018) when stratified by sex.
Inferences:
Our findings indicate that patients with MAOB-L cancers may benefit more from CET-based treatment, and that targeting MAOB may be a promising technique for improving patient outcomes. Further validation studies are needed to establish a fresh tailored approach in mCRC patients based on MAOB expression. NCT00265850 is the clinical trial number.