The landscape of MAP3K1/MAP2K4 alterations in gastrointestinal (GI) malignancies.

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4113 Background: Inactivating alterations in MAP3K1/MAP2K4 occur in various solid tumors, sensitize cancer models to MEK inhibitors, and have co-mutation partners which may enable therapeutic targeting. Methods: We retrospectively reviewed 20290 GI malignancy patients (pts), comprised of 9986 colorectal carcinoma (CRC) and 10304 non-CRC, whose tumors were profiled with Caris Life Sciences from 2015-2019. Profiling included immunohistochemistry (IHC) with programmed death ligand-1 (PD-L1), next-generation sequencing (NGS), tumor mutational burden (TMB) and deficient mismatch repair or microsatellite instability-high status (dMMR/MSI-H). Results: MAP3K1/MAP2K4-alteration ( MAP3K1/MAP2K4-MT) was more frequent in CRC than non-CRC pts (2.0% v. 1.2%, p<0.0001), with truncating mutations representing the majority of lesions along both genes. While MAP3K1/MAP2K4-MT CRC pts were similar in age and gender to wild-type (WT), mutated non-CRC pts were older (median age 69 v. 65 years) and more likely female (51% v. 42%) compared to WT (both p<0.05). MAP3K1/MAP2K4-MT CRC (25% v. 7%) and non-CRC (30% v. 3%) were more frequently dMMR/MSI-H than WT pts (both p<0.0001). MAP3K1/MAP2K4-MT CRC cases were affiliated with higher TMB and similar rate of PD-L1 expression compared to WT. A higher rate of MAP3K1/MAP2K4-MT CRC pts were right-sided (36% v. 22%, p<0.0001) and transverse (8% v. 4%, p<0.05) compared to WT, whereas a higher frequency of WT cases were left-sided (20% v. 28%, p<0.05) and rectal (15% v 23%, p<0.05). Of microsatellite stable (MSS) CRC pts, those with MAP3K1/MAP2K4-MT were more likely PIK3CA (26% v. 17%) and APC (85% v. 78%) and less-likely TP53 (64% v. 77%) co-mutated versus WT MSS pts (all p<0.05); no difference was seen in BRAF V600E, ERBB2/ ERBB3 or KRAS co-mutation rate in MSS pts. In both all-comers and MSS CRC, MAP3K1/MAP2K4-MT pts were more frequently co-mutated than WT with ARID1A, POLE, ATM, BRCA2 and PIK3R1 (all ≥7% of MAP3K1/MAP2K4-MT pts, p<0.0001). A higher frequency of all-comer non-CRC GI malignancy pts with MAP3K1/MAP2K4-MT were co-mutated with PIK3CA (13% v. 6%), ERBB2/ERBB3 (8% v. 3%) or APC (13% v. 5%) compared to WT (all p<0.01). For MSS non-CRC GI cases, ARID1A (50% v. 30%) and SMAD4 (21% v. 12%) were more frequently co-mutated in MAP3K1/MAP2K4-MT versus WT pts (all p<0.05). Conclusions: Truncating MAP3K1/MAP2K4 alterations occur in nearly 2% of GI malignancy pts and are more commonly associated with dMMR/MSI-H than WT. Potentially targetable co-mutation partners implicated in MAPK and PI3K pathways as well as POLE, BRCA2 and ATM warrant further evaluation.