Does cancer immunotherapy work better in men than women?

Italian researchers have proposed that a patient's sex might impact on the efficacy of immunotherapy in cancer treatment, following meta-analysis of 20 randomised trials featuring over 11,000 patients with advanced cancer.

Cancer immunotherapy represents one of the most important advances in cancer treatment in the past decade. It is the standard treatment for some types of cancers, including melanoma and non-small-cell lung cancer, and trials are ongoing into its effectiveness in the treatment of other cancers.

Previous studies have shown that men have an almost two-times higher risk of mortality from all cancers than women, likely as a result of behavioural and biological factors. In this study, researchers led by Dr Fabio Conforti looked specifically at the differences in survival for patients treated with immunotherapy. The results were presented in The Lancet Oncology.

The team combined data from 20 previously published randomised trials including 11,351 patients who had received immune checkpoint inhibitors (ipilimumab, tremelimumab, nivolumab or pembrolizumab) for advanced or metastatic cancers. These included melanoma, renal cell carcinoma, urothelial cancer, head and neck cancer, and lung cancer. 3632 (32%) of 11,351 patients had melanoma and 3482 (31%) had non-small-cell lung cancer. Of those included in the analysis, 7646 (67%) were male and 3705 (33%) were female.

For both men and women, immunotherapy was more effective than the control — whether this was a placebo or another type of cancer drug. But there was a higher survival benefit for men compared to women, regardless of the type of cancer and the type of drug administered. On average, the relative survival gain was double the size for men compared to women.

But why is this the case? According to Dr Conforti, who is based at the European Institute of Oncology, “Both sex and gender can potentially affect the strength of the body’s immune response. On average, women mount stronger immune responses than do men, which results in more rapid clearance of pathogens, explaining the lower severity and prevalence of many infections in women, and their greater response to vaccination than men.

“On the other hand, women account for roughly 80% of all patients with systemic autoimmune diseases worldwide. Therefore, it’s possible that differences in the immune system of women and men could be relevant to the natural course of chronic inflammatory conditions such as cancer, and potentially how they respond to drugs.”

The study authors add that sex differences in the immune system at the cellular level have also been reported, likely as a result of complex interactions between genes, hormones, the environment and microbiome composition. Immune checkpoint inhibitor (CTLA-4 and PD-1) pathways play an important part in tumour-induced immunosuppression, and animal studies have suggested that sex hormones may modulate some of these pathways. Similarly, female and male mice show different responses to anti-PD-L1 monoclonal antibodies.

“Despite the available evidence on the potential role played by sex in influencing how drugs work, trials testing new therapies rarely take sex into account,” said Dr Conforti. “Immune checkpoint inhibitors have revolutionised cancer treatment, showing higher efficacy than standard therapies in several cancers. As we seek to improve immunotherapy further by identifying predictive biomarkers of response, sex differences should be further investigated.”

The authors do note several limitations, including that the meta-analysis relies on published results rather than on individual patients’ data. The authors also note that EGFR-mutated non-small-cell lung cancers are less sensitive to immune checkpoint inhibitors than are EGFR wild-type non-small-cell lung cancer tumours, and are more common in female patients than in male patients. However, most (94%) non-small-cell lung cancers included in the meta-analysis were wild-type, indicating that sex-dependent differences in the efficacy of immune checkpoint inhibitors were not exclusively related to mutation status.

Dr Conforti emphasised that treatment for women should not altered based on the study’s findings. “Rather,” he said, “we need to understand more about the mechanisms to ensure that these novel treatments can be optimised for both men and women.” The researchers also acknowledge that the underrepresentation of female patients in clinical trials is a widely recognised problem, with women comprising less than one-third of the total population in half of the trials in their study. This means that individual trials likely cannot reliably show the interaction between sex and treatment efficacy.

The findings from the meta-analysis thus highlight the need for sex-specific analyses to avoid erroneously extending to women results that are obtained mainly in male patients, which may lead to poorer care and potentially harm.

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