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

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.

Ex vivo therapeutic screening of metastatic cSCC: A review of methodological considerations for clinical implementation

“…Given distinct differences in the molecular alterations and TME characteristics of tumours of immunocompromised compared to immunocompetent patients, comprehensive screening of both cohorts is critical 46,47 . Further, none are derived from a female; while males are more predominately affected by metastatic cSCC, there is increasing suggestion of a sex‐related influence on disease progression requiring greater preclinical representation 48,49 . These limitations are compounded by the time to establish these cell lines by clonal outgrowth, followed by a minimum of four but usually beyond 10 passages 13,14 .…”

“…46,47 Further, none are derived from a female; while males are more predominately affected by metastatic cSCC, there is increasing suggestion of a sex-related influence on disease progression requiring greater preclinical representation. 48,49 These limitations are compounded by the time to establish these cell lines by clonal outgrowth, followed by a minimum of four but usually beyond 10 passages. 13,14 This is notwithstanding the laborious efforts to comprehensively validate the cell lines to facilitate meaningful correlations between tumour properties and therapeutic sensitivity for responder stratification.…”

PIK Your Poison: The Effects of Combining PI3K and CDK Inhibitors against Metastatic Cutaneous Squamous Cell Carcinoma In Vitro

“…Loco−regional and distant metastases are associated with a worse prognosis due to limited effective therapeutic options compared with other cancers [2]. The immune checkpoint inhibitor cemilipimab has made remarkable strides in the treatment of multiple cancers, with up to 47% response rate in locally advanced and metastatic cSCC [3][4][5][6][7]. However, immunotherapy is contraindicated in immunocompromised patients, and approximately 50% of non−immunosuppressed patients do not benefit [8].…”