Gender difference in side effects of immunotherapy: a possible clue to optimize cancer treatment

Topic: Sex, gender and health

Sex plays a role in cancer incidence and progression, response to therapy and chemotherapy adverse reactions. Accumulating evidences support the existence of sex-driven differences in immune responses as potential factors contributing to disease outcome and response to therapy. Increasing use of immune checkpoint inhibitors (ICI) is associated with immune-related adverse events (irAEs) caused by non-specific activation of the immune system. We will conduct a multicenter prospective observational study investigating sex differences in irAEs in relation to genetic, immunological and hormonal profiles. The study will include ICI treated patients with different tumor types. We hypothesize that sex specific profiles may explain differential incidence of irAEs, and aim at: estimating and comparing the irAEs incidence in F and M; estimating irAEs incidence according to different clinical features and gender dimension; identifying genetic/immunological/hormonal profiles associated with sex-related and menopausal status-related differences in irAES occurrence; developing irAEs predictive tools based on selected clinical characteristics, possibly complemented by genetic, immunological and hormonal features. The proposal represents a step towards a personalized-approach considering sex differences in irAEs occurrence to improve toxicity prevention and management. By focusing on biological F/M differences possibly affecting discrepant irAEs incidence, we explicitly address sex inequality, complemented by the exploration of association between gender dimension and irAEs development.

At the closing date 31st January 2023, the study has enrolled 256 patients. F more frequently developed adverse irAEs of any grade and, in particular, the patient-specific cumulative burden of irAEs was statistically significantly higher in F than M. Exploring irAEs incidence in relation to patients’ sex and gender determinants is of clinical relevance, and developing tools to identify irAEs high risk patients would be of help to optimize patients selection for ICI treatments minimizing toxicity.


Project coordinator

Rosalba Miceli, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy


Ireland, Italy, Norway, Sweden

Institutions involved

Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy (INT) ; Dept of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Sweden (Onk-Pat KI) ; Dublin City University, Dublin -St Vincent’s University Hospital, Ireland (DCU- SVUH) ; Oslo University Hospital – The Radium Hospital Norway (OUH)





Rosalba Miceli, project coordinator of the G-DEFINER project, gave a presentation of the research project at two meetings on Gender Medicine :