Impact of GABA pathway genes expression on first-line treatment outcomes in patients (pts) with metastatic colorectal cancer (mCRC): Data from CALGB/SWOG 80405 (Alliance).
Authors: Battaglin Francesca , Yang Yan , Millstein Joshua , Soni Shivani , Algaze Sandra , Ashouri Karam , Mittal Pooja , Jayachandran Priya , Wong Alexandra , Lo Jae Ho , Torres-Gonzalez Lesly , Zhang Wu , Mulkerin Daniel L , Ou Fang-Shu , Venook Alan P. , Innocenti Federico , Mumenthaler Shannon M. , Lenz Heinz-Josef 
Published: June 2024

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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