Why we need to investigate sex differences in cancer research

An innovative approach

Sex- and gender-sensitive medicine postulates that differences in biological sex, gender identity, role and relations all impact health and disease, and may have implications for prevention, screening, diagnosis and treatment. Its goal is to learn from these differences to improve care and treatment for men and women.

There is a growing body of evidence to suggest that patients’ sex can have an impact on the biology and evolution of cancer. However, it is not possible to generalise – there may be no differences in some cancers and large differences in others. With our growing understanding of tumour biology, we can better appreciate such potential differences.

But therein lies the crux, we can only do this if we are actively looking for differences. According to Goethe, “One only sees what one looks for. One only looks for what one knows.” The consequence of assuming that non-sex-related cancers and their treatments are the same, is that inter-sex differences in cancer biology and response to treatment have often escaped our attention.

It is clear that some differences in cancer epidemiology and/or outcomes between men and women can be attributed to differences in past behaviour. For example, in melanoma, differences in the site of tumour development broadly reflect gender behaviour in exposing different areas of the body to the sun – the legs in women and the trunk in men. However, when human melanoma cells are injected into mice, those from men lead to the development of a more aggressive disease than those from women, indicating the involvement of a biological sex effect.

Sex- and gender-sensitive medicine has been taken into consideration by the cardiovascular community for many years but it is relatively new to oncology. I began working in the field around five years ago, quite by chance. I came across young women in my clinical practice with a type of treatment-resistant diffuse gastric cancer that I had not seen in men. In addition, I had the impression that the toxicity of the chemotherapies I was using for gastrointestinal cancers was more pronounced in women. Hoping to find out more about the influence of sex on the development and treatment of cancer, I conducted a systematic literature review about the impact of the patient’s sex on chemotherapy toxicity and was astonished to find that it generated only around 40 relevant articles. This made me realise that the area was indeed insufficiently studied, and that we would have to conduct our own research to get answers to our questions.

Further research confirmed my initial clinical suspicions. In younger patients with non-hereditary gastric cancer, women suffer more often from poorly cohesive adenocarcinomas (Ann Surg Oncol. 2016 Dec;23(13):4344–4351), which have a very aggressive evolution. This has been observed in different geographical regions (Acta Oncol. 2017 Jan;56(1):39–45). Others have now confirmed that sporadic diffuse gastric cancer has a distinct molecular profile in young women (Gastroenterology. 2017 Aug;153(2):536–549.e26). Another disease subtype, for which patient sex significantly affects the epidemiology – having a significantly higher incidence in males – is adenocarcinoma of the lower oesophagus or gastro-oesophageal junction.

Precision medicine is a much-talked-about goal in cancer management. Patient age, sex and race are fundamental biological variables and while the impact of age on cancer and its treatment have been investigated extensively, the effects of sex and race remain unclear. If we truly want to tailor therapy, we need to challenge the long-held tradition of treating men and women as if they are biologically identical. They are not.

For example, men have a higher metabolically active fat-free body mass than women, which is why some chemotherapy agents have higher elimination rates and lower plasma levels in men compared with women. In view of this, we should be questioning if men are receiving sufficiently high doses for optimum efficacy. A trial in elderly men with lymphoma demonstrated that increasing the dose of rituximab – to counterbalance the higher elimination rate – led to an increase in progression-free survival without an increase in toxicity (Br J Haematol. 2017 Nov;179(3):410–420). Another issue of particular interest is that while inter-sex differences in the immune system are well recognised, little has been done to investigate if these differences affect the relative efficacies of cancer immunotherapy in men and women.

The challenge for oncology today is to look for patterns of how sex and gender affect treatment by investigating potential differences between men and women in cancer epidemiology and outcomes, as well as the pharmacology of cancer therapies and the treatment effects. If such differences are observed, we need to try to understand the biological basis for these differences and what can be done to improve treatment outcomes.

It is difficult to power studies to look at inter-sex differences, as their type and magnitude is unknown. What is key is that we analyse the efficacy and toxicity of treatments according to sex, in both the control and experimental arms of existing clinical trials and, crucially, publish these results. Rather than assuming upfront that differences between sexes are due to statistical errors, it should be considered that they may be the result of true biological differences. Medicine targets, but also the optimal dose necessary to hit a medicine target with an acceptable level of toxicity, may be different for men and women (JAMA Oncol. 2018 Jul 1;4(7):1003–1006). Generally, in early studies, patient numbers are too small, and data from large trials or pooled analyses are necessary to understand if inter-sex differences exist, and if they do, to what magnitude.

The ESMO workshop held in 2018 – ‘Gender medicine meets oncology’ – was the first organised discussion about gender medicine in oncology. Featuring some top names in cancer on its faculty, the event was judged a great success by participants and faculty members and we truly hope that it helps to raise awareness among oncologists about the importance of this field. The proceedings are due to be published soon.

Going forward, we need to have broad collaborations, to continue to raise awareness and to increase the involvement of societies if we are to make progress in sex- and gender-sensitive medicine. I personally am very hopeful that a sex-based approach to treatment will improve patient outcomes. And, after a slow start, I am delighted about the current level of interest in the topic – this year, I was invited to present talks on the subject at the Royal Society of Medicine in London, at the ESMO World Congress on Gastrointestinal Cancer and at the International Society of Gender Medicine. All in all, I think that the outlook is very promising for an area that is still very much in its infancy in oncology.


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