Association between gender difference in outcomes and immune checkpoint inhibitors in colorectal cancer and esophagogastric cancer

Background: Immunity, encompassing both cellular and humoral responses, is significantly influenced by sex. Factors such as genetic differences, hormonal variations, environmental influences, and the composition of the commensal microbiome all contribute to these differences. Although numerous studies have examined the relationship between gender and the effectiveness of immunotherapy, the results have often been inconsistent. This study aimed to explore whether an association exists between gender and the therapeutic effect of immune checkpoint inhibitors (ICIs) in Colorectal Cancer (CRC) and Esophagogastric Cancer. Methods: We conducted a cohort study using data from the cBioPortal database, focusing on patients with CRC and esophagogastric cancer who received ICIs. Patients included in the study had been treated with ICIs such as atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab, pembrolizumab, or tremelimumab, either as monotherapy or in combination. We excluded other cancer types from our analysis. Overall survival (OS) was measured from the date of first ICI treatment to time of death or most recent follow-up, with a median follow-up period of 19 months. To assess gender differences in OS, we calculated median OS separately for male and female patients. Survival analysis was performed using the Kaplan–Meier method, and we calculated pooled 95CIs) to determine the reliability and precision of our findings. The log-rank P-value was used to assess differences in OS between genders. Results: In cohort study of a total of 1,661 patients, we focused on 110 (6.6 CRC patients and 126 (7.6 patients with esophagogastric cancer. Among the CRC patients, 62 (56.4 were male and 48 (43.6 were female. In the esophagogastric cancer patients 98 (77 males and 28 (22 females. The most common genetic mutations identified in CRC patients were APC 80 (72, KRAS 57 (51, and TP53 56 (50. Among esophagogastric cancer patients, TP53 mutations were found in 92 (72 patients, and CDKN2A mutations were present in 20 (15 patients. Out of these, 99 (90 of CRC patients and 93(73 of esophagogastric cancer patients received PD-1/PD-L1 inhibitors and the remaining patients received either anti-CTLA-4 or combination of anti-CTLA-4 and anti-PD-1/PD-L1 therapies, as part of their treatment. In studies measuring median OS for CRC patients treated with ICIs, male patients had a median OS of 31 months (95 13.00–NA), compared to 12 months (95 8.00–NA) for female patients (p=0.03). For esophagogastric cancer patients, the median OS was 13 months (95 7.00–21.00) for male patients, while for female patients, it was 20 months (95 10.00–NA) (p=0.32). Conclusion: Our study highlighted that ICI therapy improves survival outcomes, with males showing greater benefit as, indicated by a longer OS, compared to females in CRC, while the opposite result was observed in esophagogastric cancer.Citation Format: Ebtesam Al-Najjar, Bayan Khasawneh, Raed Zaidan, Abdullah Esmail, Maen Abdelrahim. Association between gender difference in outcomes and immune checkpoint inhibitors in colorectal cancer and esophagogastric cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A046.