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Patient's sex might affect immunotherapy outcomes

Under-representation of women in clinical trials could influence development of therapies

Mark Gould

Thursday, 17 May 2018

A patient’s sex might impact on the efficacy of immunotherapy in cancer treatment, according to a new meta-analysis* of 20 randomised trials in over 11,000 patients with advanced cancer.

Writing in The Lancet Oncology the authors suggest that different immune responses between men and women, and potential interaction with hormones might impact how men and women benefit from immunotherapy drugs.

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 the authors, from the European Institute of Oncology in Milan, looked specifically at the differences in survival for patients treated with immunotherapy.

Overall, 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.

The trail combined data from 20 previously published randomised trials including 11,351 patients who had received an immune checkpoint inhibitors for advanced or metastatic cancers. These included melanoma, renal cell carcinoma, urothelial cancer, head and neck cancer, and lung cancer. 3,632 (32%) of 11,351 patients had melanoma and 3,482 (31%) had non-small-cell lung cancer. Of those included in the analysis, 7,646 (67%) were male and 3,705 (33%) were female.

“An individual’s prognosis will depend on multiple variables including type of cancer and the drugs used, and immunotherapies continue to be the standard treatment for several cancers, with survival often far better than other drugs. Treatment for women should not altered based on these findings, rather we need to understand more about the mechanisms to ensure that these novel treatments can be optimised for both men and women,” author Dr Fabio Conforti said.

While the findings do not imply a change in treatment guidelines for men or women, the authors say they should prompt further research to understand the mechanisms at play in order to improve treatments for all patients.

“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,” adds Dr Conforti.

The authors also note that under-representation of female patients in clinical trials is a widely recognised problem. Indeed, in half of the trials in this study, women comprised less than a third of the overall population, meaning that individual trials likely cannot reliably show the interaction between sex and treatment efficacy. The authors say their findings 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.

The 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.

“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. 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,” says Dr Conforti.

The authors note several limitations, including that the meta-analysis relies on published results rather than on individual patients’ data.


*Conforti, Fabio et al. Cancer immunotherapy efficacy and patients' sex: a systematic review and meta-analysis. Published: 16 May 2018, Elsevier Ltd. Doi:10.1016/S1470-2045(18)30261-4

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