Sex disparities matter in cancer development and therapy

Abstract

Curing cancer through precision medicine is the paramount aim of the new wave of molecular and genomic therapies. Currently, whether patients with non-reproductive cancers are male or female according to their sex chromosomes is not adequately considered in patient standard of care. This is a matter of consequence because there is growing evidence that these cancer types generally initiate earlier and are associated with higher overall incidence and rates of death in males compared with females. Gender, in contrast to sex, refers to a chosen sexual identity. Hazardous lifestyle choices (notably tobacco smoking) differ in prevalence between genders, aligned with disproportionate cancer risk. These add to underlying genetic predisposition and influences of sex steroid hormones. Together, these factors affect metabolism, immunity and inflammation, and ultimately the fidelity of the genetic code. To accurately understand how human defences against cancer erode, it is crucial to establish the influence of sex. Our Perspective highlights evidence from basic and translational research indicating that including genetic sex considerations in treatments for patients with cancer will improve outcomes. It is now time to adopt the challenge of overhauling cancer medicine based on optimized treatment strategies for females and males.

Fig. 1 |. Non-reproductive cancers per 100,000 males and females.

a | Aged-adjusted cancer incidence and mortality per 100,000 people for all non-reproductive cancers for males versus females. b,c | Age-adjusted data for individual cancers that occur at higher rates in males than females for incidence (part b) and mortality (part c). Data taken from the US 2017 Surveillance, Epidemiology, and End Results (SEER) programme.

Fig. 2 |. Gene expression from the sex chromosomes differs between males and females.

a | Males inherit their X chromosomes from their mothers and Y chromosomes from their fathers. Females inherit one X chromosome (hereafter X) from each parent but only completely express one chromosome, which is termed the active X chromosome (Xa). Long non-coding RNA X-inactive specific transcript (XIST; marked in yellow) silences one X of each pair at random during early development. The silenced chromosome is the inactive X chromosome (Xi). As the X chromosome inactivation (XCI) process in females is normally random, cells within females have a mosaic expression of either the maternal or paternal X. b | A somatic gene mutation in a male X is a disease risk due to mono-allelic expression. Females will express a mutation on the Xa, but this will remain unexpressed if on the Xi (except for the special case of the escapers; not shown). c | XCI leads to overestimation of female X-methylation levels when compared with males. Promoters of the Xi are methylated to maintain the silencing initiated by XIST. Methylation may either occur on the promoter where it silences genes or in the gene body where it may promote transcription. The levels of promoter methylation on the Xa are at risk of overestimation in females due to the inability to distinguish between DNA promoter methylation levels of the Xa and the Xi alleles.

Fig. 3 |. Gene pathways are enriched on the X chromosome.

We conducted over-representation analysis (ORA) of the protein coding X chromosome genes to identify enrichment of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. ORA was applied using the R package gprofiler2 (v0.1.8). P values were adjusted for false discovery rate (FDR). Significant gene sets were inferred, using an FDR < 0.05 significance level. The pathway enrichment visualization was created using the R package ggplot2 (v3.3.0). Pathways with their associated genes are listed in Supplementary Table 1. JAK, Janus kinase; NF-κB, nuclear factor-κB; STAT, signal transducer and activator of transcription.

Fig. 4 |. Sex disparity in cancer therapy benefits in humans.

Females have greater overall survival outcomes from surgery for lung cancer and less sepsis than males. Radiotherapy offers survival advantage to females at the expense of toxicity, as evident in patients with oesophageal squamous cell carcinoma (ESCC). Chemotherapies advantage female survival in responses to: combined treatment with an alkylating platinum agent, the antimetabolite pyrimidine and an anthracycline antibiotic in oesophagogastric cancer; the antimitotic paclitaxel in non-small cell lung cancer (NSCLC); and the alkylating agent temozolomide in glioblastoma (with surgery and radiotherapy). Targeted therapies show greater efficacy in females for an epidermal growth factor receptor inhibitor (EGFRi) in NSCLC. Immune checkpoint inhibitors (ICIs; anti-PD1 or anti-PDL1) trend to greater individual female survival benefit in NSCLC, whereas male outcomes are better for colorectal cancer.

Fig. 5 |. Sex differences in cancer metabolic pathways and immune response contribute to cancer sex disparity.

a | Glucose metabolism may proceed through different pathways in male and female cancers. Glucose metabolism may differ in cancer cells in males and females. In male cancer cells, energy (ATP) is frequently generated from the breakdown of glucose through the glycolysis pathway (Warburg effect), feeding pyruvate into the TCA cycle and then oxidative phosphorylation. Cancer cells tend to divert pyruvate to lactate that can circulate in the bloodstream and enter other cancer cells. These processes are more prevalent in male cancers than female (for example, in non-small cell lung cancer (NSCLC)) due to higher expression levels of glucose transporter 1 (GLUT1 (REF.)), the lactate–pyruvate converting enzyme (lactate dehydrogenase (LDH), for which the LDHB subunit is higher in male gliomas) and the lactate transporter (monocarboxylic acid transporter 4 (MCT4), which is higher in male melanoma). By contrast, in females, intermediates of glucose metabolism may preferentially be diverted to the less energy-efficient pentose phosphate pathway (PPP; as in right-sided colon cancer (RCC)) that produces antioxidant NADPH and metabolic building blocks. b | Immunity differs between the sexes. Females have greater adaptive and innate immune responses than males. These confer greater antiviral T cell immunity and anticancer response. A more efficient resolution of inflammation in females protects them from chronic inflammation-associated cancers^–. Additionally, female microbiota improve responses to anticancer immune therapies. On the other hand, males have higher risk of infection from pathogenic agents and, consequently, are at greater risk of infection-associated cancers.