Introduction

‘Precision medicine’ is defined as ‘a healthcare approach with the primary aim of identifying which interventions are likely to be of most benefit to which patients based upon the features of the individual and their disease’ [1]. Careful consideration of sex differences is a fundamental step towards precision medicine that will promote equality and equity in healthcare [2].

The terms ‘sex’ and ‘gender’ are not interchangeable. ‘Sex’ refers to the biological differences between males and females, and encompasses sex organs, endogenous hormones and chromosomes [3]. ‘Gender’, however, is a sociocultural construction that encompasses the roles, norms and behaviours expected for males and females in society, which may or may not correspond to their sex [3, 4]. Each individual’s health is determined by both their biological sex and gender expression [3] because access to healthcare and interactions with healthcare professionals can be influenced by sex and/or gender due to social or economic inequalities, power imbalances or discrimination [4, 5].

Oncology research has mainly focussed on the genomic profile of a cancer to personalise treatment, and current approaches to precision medicine in oncology generally do not include factors such as sex or gender in therapeutic decisions [6]. It is of increasing concern that sex and gender influence cancer susceptibility, progression, survival and response to different treatments; as such, there is growing recognition that a patient’s sex and gender also need to be considered in the formulation of an optimal treatment approach [7].

There is evidence to suggest that women do not receive the same treatment for cancer as men [8, 9]. This is unsurprising because women have been historically excluded from clinical trials for various reasons, resulting in research and medical attention focussed on male physiology; indeed, the diagnosis, treatment, and prevention of disease originates from studies carried out mainly on male cells, male mice and men [10]. The Sociedad Española de Oncología Médica (SEOM) in Spain has created a Women’s Task Force, named Oncogenyx, to analyse the impact of sex and gender on the diagnosis, treatment and outcomes of cancer patients. The aim is to improve the quality of care for cancer patients in Spain by implementing appropriate measures to address sex/gender disparities. One of the first initiatives of Oncogenyx was to carry out a survey among SEOM members to assess the awareness of Spanish oncologists with regard to sex differences in the diagnosis, treatment and prognosis of patients with cancer. Participation in the survey was not very high, which indicates the dire need to inform and educate oncologists on these sex differences. This article describes the rationale for the SEOM Task Force by discussing how sex differences impact the diagnosis, treatment and outcomes of cancer, with a focus on data from Spain.

Sex differences in cancer incidence and mortality

Disparities occur in cancer incidence and mortality based on a patient’s sex [11]. Although women in Europe tend to report worse general health than men, the probability of somatic tumour development is higher and the prognosis is worse in men (Fig. 1) [12]. Overall, the age-standardised incidence and mortality rates of patients with cancer are higher in men than in women, both globally [13] and in Spain [14, 15]. The major exceptions (excluding cancers specifically related to reproductive organs, such as breast cancer or prostate cancer) are thyroid and gallbladder cancer (Fig. 1), both of which occur at higher rates in women than in men [12,13,14].

Fig. 1
figure 1

Sexual dimorphism in the incidence of different cancer types unrelated to reproductive functions representing the percentages of new diagnosed cancer cases in 2020 among men and women. The percentage values have been calculated using data retrieved from the Global Cancer Observatory GLOBOCAN 2020 [68]. The data have been extracted from Cardano M [12]. Created using Biorender

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In Spain, the incidence of lung cancer is lower in women than in men [16,17,18], but the difference between the sexes is becoming less marked as a result of changes in smoking habits in men and women [16, 17]. Consequently, the incidence of lung cancer has somewhat stabilised in men, while it continues to increase in women [16]. Spanish women also show lower age-adjusted rates of mortality compared with Spanish men across a range of cancers, including colorectal cancer [19, 20], cancer of the lip, oral cavity or pharynx [21], lung cancer [22,23,24], non-melanoma skin cancer [25], oesophageal cancer [26] and pancreatic cancer [27, 28].

With regard to sex-specific tumours, the leading causes of premature mortality among women and men are breast cancer and prostate cancer, respectively [29].

Potential reasons for sex differences

Cancer occurs as a result of a complex interplay between genetic and environmental factors, which differs between the sexes.

Genetic factors

The Cancer Genome Atlas (TCGA) analysed the molecular profiles of a range of cancers in males and females and identified those with strong or weak sex-related differences (Table 1) [30]. The tumour mutational burden tends to be lower in females than males in various cancers [31, 32]; this may affect the antigenicity of the tumour and therefore the efficacy of immune checkpoint inhibitor (ICI) therapy [33]. In addition, the X and Y chromosomes themselves may play a role in determining cancer biology [11, 34]. Tumour suppressor genes may be present on the inactive X chromosome (** severe AEs was 34% higher than men, specifically in the treatment domains of chemotherapy (74% vs 68%), immunotherapy (57% vs 49%) and targeted therapy (50% vs 45%) [63].

Sex disparities in clinical research

Historically, biomedical research has focussed on male physiology, at all levels: basic, preclinical and clinical [65]. Biomedical research in some medical specialities, such as cardiology, already reflects the importance of sex differences as modulators of disease biology [53]. However, in oncology, the importance of these difference is underestimated. For example, there is evidence that women are under-represented in clinical trials of treatments for many different types of cancer. As a result, drugs are being approved based on research that was conducted principally in men [66], with the results of this research, including drug toxicity or efficacy, extrapolated to all patients, assuming similar biological behaviour. There is a risk that negative results of clinical studies conducted mainly in men may lead to a discontinuation of drug development for treatments that may be effective and well tolerated in women [65]. Moreover, female researchers are under-represented in oncology publications [67].

Conclusion

There is growing evidence that sex differences influence cancer prevention, susceptibility, progression, survival and response to different treatments. The impact of biological sex on the aetiology of cancer has not been fully elucidated, but there is clear evidence that the disease is not the same in men and women. Sex differences in cancer biology and treatment deserve more attention and systematic research that is equally representative of women and men. Interventional clinical trials evaluating sex-specific dosing regimens are needed to improve the balance between efficacy and toxicity of anticancer drugs. Clinicians’ increased awareness of sex differences in the epidemiology, pathophysiology, clinical manifestations, psychological effects, disease progression and response to treatment is essential to the success of oncological care and translational science. The SEOM has created a Task Force group to address sex differences in cancer biology and treatment, and to raise awareness of these differences among oncology professionals. The SEOM considers that the inclusion of a sex perspective is a necessary and fundamental step towards precision medicine that will benefit all individuals equally and equitably.