# Frequency of Common and Uncommon BRAF Alterations among Colorectal and Non-Colorectal Gastrointestinal Malignancies

## TL;DR

This study shows that BRAF gene changes are more common in certain non-colorectal GI cancers, like bile duct and small intestine cancers, and suggests they could be important for treatment.

## Contribution

The study reveals a distinct BRAF alteration profile in non-colorectal GI cancers, highlighting the higher frequency of BRAF fusions and amplifications compared to colorectal cancer.

## Key findings

- BRAF alterations are most common in bile duct and small intestinal cancers among non-CRC GI malignancies.
- BRAF fusions and amplifications are more frequent in non-CRC GI cancers than in CRC.
- Non-CRC GI cancers show a higher prevalence of class II and III BRAF alterations compared to CRC.

## Abstract

The combination of dabrafenib plus trametinib received tumor-agnostic approval for patients with BRAF V600E mutations. BRAF alterations are well characterized in patients with colorectal cancer (CRC) but their role in other gastrointestinal (GI) cancers is not known. This study demonstrates that amongst non-CRC GI cancers, BRAF alterations are most commonly present in bile duct cancers and small intestinal cancers. BRAF amplifications and BRAF fusions are more commonly observed in non-CRC GI cancers than in CRC and can potentially be an attractive therapeutic target. The prognostic impact of BRAF alterations in non-CRC GI cancers needs to be further investigated.

Background: The predictive and prognostic role of BRAF alterations has been evaluated in colorectal cancer (CRC); however, BRAF alterations have not been fully characterized in non-CRC gastrointestinal (GI) malignancies. In the present study, we report the frequency and spectrum of BRAF alterations among patients with non-CRC GI malignancies. Methods: Patients with CRC and non-CRC GI malignancies who underwent somatic tumor profiling via a tissue-based or liquid-based assay were included in this study. Gain-of-function BRAF alterations were defined as pathogenic/likely pathogenic somatic short variants (SVs), copy number amplifications ≥8, or fusions (RNA or DNA). Results: Among 51,560 patients with somatic profiling, 40% had CRC and 60% had non-CRC GI malignancies. BRAF GOF alterations were seen more frequently in CRC (8.9%) compared to non-CRC GI malignancies (2.2%) (p < 0.001). Non-CRC GI malignancies with the highest prevalence of BRAF GOF alterations were bile duct cancers (4.1%) and small intestine cancers (4.0%). Among BRAF GOF alterations, class II (28% vs. 6.8%, p < 0.001) and class III (23% vs. 14%, p < 0.001) were more common in non-CRC GI malignancies. Among class II alterations, rates of BRAF amplifications (3.1% vs. 0.3%, p < 0.001) and BRAF fusions (12% vs. 2.2%, p < 0.001) were higher in non-CRC GI malignancies compared to CRC. Conclusions: Non-CRC GI malignancies demonstrate a distinct BRAF alteration profile compared to CRC, with a higher frequency of class II and III mutations, and more specifically, a higher incidence of BRAF fusions. Future studies should evaluate clinical implications for the management of non-CRC GI patients with BRAF alterations, especially BRAF fusions.