Clinical Characteristics and Responses to Immune Checkpoint Inhibitors in RET-Aberrant Digestive Tract Tumours

Background: RET plays an oncogenic role, and its aberrations are potentially actionable. However, they have seldom been reported in tumours other than lung or thyroid cancers. The correlation of RET aberrations with clinical characteristics, co-occurring aberrations, and responses to immune checkpoint inhibitors (ICPi) have not been explored in digestive tract tumours. Objectives: The aim of the study was to elucidate the clinical characteristics, frequently co-altered genes, and treatment responses in RET-aberrant digestive tract tumours. Patients and Methods: We retrospectively evaluated patients with digestive tract cancers for RET-aberrant tumours via FoundationOne CDx tumour-based selected genome sequencing from Jan 2016 to Jan 2021. Results: In a median follow-up time of 51 months, a total of 453 patients were analysed. RET-aberrant tumours accounted for 4.4% in the studied population (n = 20), and 1.1% had an oncogenic fusion (n = 5). APC, KRAS, TP53, MSH6 and STK11 were the differentially co-altered genes (all false discovery rates <0.05). The presence of RET aberrations alone was not a significant prognostic factor. Eleven patients with RET-aberrant tumours received ICPi-based treatment and none achieved an objective response. In contrast, 47 patients with non-aberrant tumours received ICPi treatment and had an objective response rate of 27.7% and a significantly longer treatment duration (6.2 vs 2.8 months, p = 0.0008). Conclusions: Albeit rarely, RET aberrations can be found in digestive tract tumours. Patients with RET-aberrant tumours have a blunted response to ICPi and a comparable prognosis as compared with RET-wild type tumours. Together, these results provide insights into this rare but potentially actionable target in digestive tract tumours.