Association of non–gain-of-function alterations in exportin-1 with improved overall survival in colorectal cancer

Abstract

Background

Upregulation of nuclear export protein exportin-1 (coded by gene XPO1) has been previously demonstrated in multiple cancer subtypes, contributing to pharmacotherapy resistance and increased recurrence rates. This study aimed to explore the effect of non–gain-of-function (GOF) XPO1 alterations in patients with colorectal cancer (CRC).

Methods

Patients with colon/rectal/colorectal adenocarcinoma were identified from the Memorial Sloan Kettering Clinicogenomic, Harmonized Oncologic Real-World Dataset using cBioPortal. A subpopulation with alterations in XPO1 was identified. Patients with known amplifications and GOF E571K and R749Q alterations were excluded, as were patients with in situ and stage IV disease. Survival analysis was performed via Kaplan-Meier and Cox proportional hazards analyses, adjusted for patient age and disease stage.

Results

Among 5543 patients with CRC, 83 (1.5%) had alterations in the XPO1 locus, and 5460 patients (98.5%) did not. Of patients with XPO1 alteration, 66 (79.5%) had non-GOF alterations, and 17 (21.5%) had GOF point mutations or amplifications. Patients with non-GOF XPO1 alteration had a mortality hazard ratio of 0.601 (95% CI, 0.463–0.805; P =.011). When adjusted for patient age and disease stage, XPO1 co-alteration was associated with improved overall survival (OS) in patients with alterations in TP53, APC, FBXW7, SMAD4, and BRAF genes (all P <.01).

Conclusion

XPO1 alterations were associated with improved OS in patients with CRC. Associated survival benefits persisted when co-alterations were present, particularly in co-alterations with intranuclear tumor suppressor proteins.