Sex as a Predictor of Response to Immunotherapy in Advanced Cutaneous Squamous Cell Carcinoma

SIMPLE SUMMARY: Cutaneous squamous cell carcinomas (CSCC) are the second most common skin cancer amongst Caucasians, accounting for up to 20–25% of skin cancers. Whilst a majority of CSCCs can be cured with surgery alone, approximately 3–5% of patients develop advanced CSCC, which encompass locally advanced tumours or tumours with distant metastatic spread. As CSCCs are highly immunogenic, there is a strong rationale for treatment with immunotherapy. Several phase II clinical trials have demonstrated the benefit of immunotherapy in patients with advanced CSCC. However, only half of patients with advanced CSCC respond to immunotherapy, and thus there is a need to identify predictors of response. In this study, we demonstrated inferior clinical outcomes in female patients with advanced CSCC treated with immunotherapy compared to their male counterparts. This clinical finding is supported with translational assays on pre-treatment biopsies, demonstrating the presence of fewer anti-tumour immune cells in the tumours of female patients. ABSTRACT: Approximately 3–5% of patients with cutaneous squamous cell carcinoma (CSCC) develop advanced disease, accounting for roughly 1% of all cancer deaths in Australia. Immunotherapy has demonstrated significant clinical benefit in advanced CSCC in several key phase II studies; however, there are limited data for patients treated outside of clinical trials. This is particularly relevant in advanced CSCC, which is most often seen in elderly patients with significant comorbidities. Thus, we aim to describe our experience with immunotherapy in a cohort of patients with advanced CSCC in Australia. We retrospectively reviewed all advanced CSCC patients treated with immunotherapy within the Illawarra and Shoalhaven Local Health District. Among the 51 patients treated with immunotherapy, there was an objective response rate (ORR) of 53% and disease control rate (DCR) of 67%. Our most significant predictor of response was sex, with male patients more likely to have better responses compared to female patients (DCR 85% vs. 41%, p < 0.0001), as well as improved progression-free survival (HR 4.6, 95%CI 1.9–10.8, p = 0.0007) and overall survival (HR 3.0, 95%CI 1.3–7.1, p = 0.006). Differential expression analysis of 770 immune-related genes demonstrated an impaired CD8 T-cell response in female patients. Our observed ORR of 53% is similar to that described in current literature with durable responses seen in the majority of patients.