Introduction:

Epidermal growth factor receptor (EGFR) is one of the most widely activated oncogenes associated with the development and progression of several types of cancer. We recently identified a previously unrecognized aberrant EGFR splice variant (EGFR-20-CTF) with specific expression in patients with clear cell renal cell carcinoma (ccRCC). The purpose of this study was to evaluate EGFR-20-CTF expression with response to immunotherapy.

Methods:

We identified 88 patients with ccRCC in a prospective cohort hospital registry between 2004 and 2018 whose tumors had undergone RNA sequencing and characterization of the EGFR-20-CTF splice variant. In this cohort, 19 patients had received immunotherapy (IL-2 or checkpoint inhibitors). We divided the cohort into three tertiles based on levels of EGFR-20-CTF expression and measured time to death (months) following first immunotherapy treatment. A log-rank test was used to compare survival between the groups.

Results:

EGFR-20-CTF expression was identified in 76.1% (n=67/88) of ccRCC tumors. Patients with the highest expression of the EFR-20-CTF splice variant had a significantly lower survival at 48 months following immunotherapy compared to patients with the lowest expression of EGFR-20-CTF (p = 0.036). The average survival in patients with high EGFR-20-CTF expression was < 16 months.   

Conclusion:

This pilot study shows that the aberrant EGFR-20-CTF splice variant occurs frequently in patients with ccRCC and is enriched in patients who had a poor response to immunotherapy. This previously unrecognized splice variant presents a possible molecular marker of resistance and will need prospective validation.

Funding: This work was supported in part by the Urology Care Foundation Research Scholar Award Program and Society for Urologic Oncology. The content is solely the responsibility of the authors and does not necessarily represent the official views of the American Urological Association (AUA) or the Urology Care Foundation.