EVEN BEFORE Joshua Rubin began to study sex differences in cancer, the pediatric neuro-oncologist noticed the majority of his brain cancer patients were boys.

The higher number of boys in his practice couldn’t be attributed to sex hormones since his patients hadn’t yet reached puberty, he reasoned. He couldn’t blame high-risk behaviors such as smoking, says Rubin, who practices at St. Louis Children’s Hospital in Missouri. Moreover, as he delved further into sex differences across a range of cancers, Rubin learned that males of all ages have a higher risk of getting many cancers.

“It’s true around the world. It’s true regardless of genetic ancestry, which suggests it’s not just about environmental and lifestyle exposures,” he says. For decades, epidemiological studies have documented greater male vulnerability to many cancers that generally occur in both men and women. Excluding cancers of sex-specific organs and the breast (a cancer that is typically found in women but can affect men), studies have shown that males are more likely to develop most malignancies shared by men and women, and are more likely to die from them.

“For almost every single nonreproductive cancer you see, men have a higher incidence that is usually two to three times higher than women,” says Sarah Jackson, a research fellow at the National Cancer Institute (NCI), who studies sex differences in cancer incidence and risk.

Behavioral choices or other risk factors remain critically important in cancer development and prognosis. For example, about four out of five lung cancer deaths are linked to smoking. Higher risk for developing at least 13 cancers, including kidney, colorectal and liver, is associated with being overweight or having obesity.

But lifestyle factors don’t fully explain why men carry a disproportionate burden, Jackson says. “I think that what happened is that people just kind of dismissed it as, ‘Well, women don’t smoke as much, women don’t drink as much. Women are more likely to go to the doctor when they have an issue. They eat healthier. They engage in more physical activity,’” says Jackson.

In recent years, researchers have been examining biological mechanisms, including sex-based differences in genetics and the immune system, that could be driving this disparity between men and women. Although there is plenty of evidence of a link between biological sex and cancer risk, researchers are still trying to understand the connection, says Justin Lathia, a researcher who studies sex differences in brain cancer at the Cleveland Clinic.

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Looking at cancer through the prism of biological sex could yield better insights into drug treatments, he says. As one example, Lathia cites a study published May 1, 2022, in the Journal of Clinical Oncology, which found that women are more likely to experience severe side effects to a range of drug treatments, particularly to immunotherapies.

Those recent findings may prove to be the tip of the proverbial iceberg, Lathia says. He proposes that researchers should make a greater effort to look at the findings from drug treatment studies to determine if there are notable differences in the benefits for males and females.

“There may be a chance, if sex is a biological variable and taken into account, that maybe some drugs that were considered to not be effective were actually effective in one sex versus the other,” he says. (In describing sex differences, researchers often use the terms male and female to refer to differences rooted in genetics and biology, rather than identifying as a man or a woman.)

A Heightened Risk

Cancer isn’t the only disease that disproportionately impacts men, Jackson says. “I honestly think that COVID kind of put sex disparities on the map,” she says, noting that men are also more likely than women to die from COVID-19.

The assumption that poorer behaviors could fully account for men’s higher cancer risk “didn’t sit right with me,” Jackson says. She and colleagues analyzed data from nearly 300,000 U.S. adults between 50 and 71 years of age who participated in a national study on the influence of diet in health outcomes. Researchers documented 26,693 cancer diagnoses in shared anatomical sites from the mid-1990s until 2011. They found that men are between 1.3 times and 10.8 times more likely than women to be diagnosed with a cancer, depending upon the type, according to the findings, published Oct. 1, 2022, in Cancer. Only thyroid and gallbladder cancers are more common in women.

The researchers adjusted for factors associated with risk, such as body mass index, physical activity, diet, smoking status and alcohol use. The goal was to find out if accounting for those differences in health behaviors “actually changes the male predominance,” Jackson says.

The researchers discovered that a relatively small proportion of the higher cancer risk in males can be linked to smoking and other behaviors, indicating that biological differences exert a considerable effect. For lung cancer, where smoking does significantly boost risk, half of the higher risk in males can be tied to behaviors, they found. But at the other end of the range, just 11% of the higher risk of esophageal cancer has a behavioral association.

This field of study focuses on cancers that can emerge from somatic mutations, genetic alterations that develop over the course of someone’s life rather than being inherited. For example, a mutation in the tumor suppressor gene p53 is involved in half of all cancers, says Sue Haupt, a cancer biologist and honorary senior research fellow at the Peter MacCallum Cancer Centre in Melbourne, Australia. One study published in 2016 analyzed cancer-related mutations in a large tumor database called the Cancer Genome Atlas, Haupt says. Researchers looked for sex- and age-based differences in mutational burden in tumor samples from 20 cancer types.

Behaviors That Matter

Changing some behaviors can lower your risk for cancer.

“What they found for at least 50% of the cancer types—and again it’s cancers that are not related to the reproductive system—[was] that there were higher levels of damage around 10 years earlier in males than females,” she says, noting that the pattern corresponds to an earlier onset of cancer in males than females.

Some of that earlier mutational burden may be related to lifestyle choices and cancer-causing exposures, Haupt says, but she and other researchers have identified other differences embedded in biology.

Genetic Differences

The evolution of DNA sequencing has further elucidated the influence of biology, says Paul Boutros, a cancer data scientist at UCLA’s David Geffen School of Medicine. The “really clear evidence that there were genetic differences is about a decade old,” coinciding with the emergence of better sequencing techniques, says Boutros, who has published research on sex differences in somatic mutations that drive cancer.

Cancers in males and females can have distinct mutational patterns, Boutros says. For example, some types of leukemia show substantial sex differences while others do not, he says. Meanwhile, colorectal tumors exhibit few to no sex differences, while lung cancers demonstrate more variability between males and females after controlling for lifestyle and epidemiological differences.

“And I think that’s almost the biggest mystery of sex differences in cancer, is why are they so [cancer] site specific,” Boutros says. “That variability even within a single organ, and then of course broader across organs, is a real mystery.”

In guarding against cancer, females appear to enjoy benefits from their sex chromosomes, Haupt says. She notes that while females inherit two X chromosomes, one from each parent, males inherit an X from their mother and a Y chromosome from their father.

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Thus, if a gene on the male’s X chromosome is damaged, there’s no backup, including for X-linked tumor suppressor genes, Haupt says. “If it’s out of action, it’s out of action,” she says. “For the females, even if one of them is out of action, you’ve got a potential spare.”

In addition, while the female’s second X chromosome is largely inactive, recent findings have shown that about 15% of genes on that second X chromosome escape that inactivation. Some of those genes have cancer-protective functions including tumor suppression and immunity, Haupt says.

Haupt and Rubin are among the researchers studying another biological tool in combating cancer—the body’s ability to repair cellular damage. The p53 gene is a key player because it controls cell division and cell death. For instance, if ultraviolet radiation begins to damage cells on the surface of the skin, the p53 gene is primed to thwart that very early damage, Haupt says.

But in a 2019 analysis looking at a dozen nonreproductive cancers in U.S. adults, published in Nature Communications, Haupt and colleagues found that the p53 gene is more often mutated in males than in females. “It means that there is a difference in the capacity of males and females to fight cancer even on the basis of that one gene,” she says. Males with a mutated p53 gene, she says, “are at a disadvantage in regard to repairing any damage that occurs.”

Researchers have also postulated that the stronger female immune response can help protect against cancer. Women often build up higher levels of antibodies in response to viral and bacterial vaccines, including against influenza. Broadly speaking, Lathia says, “If you have a more active immune system, there’s a better chance that you’ll be able to detect and eliminate a tumor cell compared to a male.”

That stronger response doesn’t always benefit females, Lathia adds, pointing out that women are more vulnerable to autoimmune diseases like multiple sclerosis or rheumatoid arthritis. Also, it’s likely their higher risk of severe side effects to some cancer drugs, such as immunotherapies, is “rooted in [sex] differences in the immune system,” he says.

Biology and Behaviors

While biological sex comprises one of the largest differences across species, it wasn’t included in all phases of federally funded research until relatively recently. Starting in 2015, the National Institutes of Health (NIH) required that all NIH-funded scientists take steps to factor in biological sex in the design and results of studies involving not just humans, but animals as well. Strong justification must be provided to study only one sex, for example, research into a sex-specific condition involving the prostate.

Lathia notes that, prior to this requirement, his research on a type of brain cancer called glioblastoma had only involved female mice, as they were less aggressive and easier to house together, he says. The NIH requirement helped to refocus the lens for researchers. “I think that really forced a lot of researchers to say, ‘Look, is there actually a [sex] difference?’ And the more people that looked, the more differences that seem to emerge,” Lathia says.

But this increased focus on sex differences has produced more questions than answers for researchers, says Jackson, of the NCI. For instance, it’s not known whether certain behaviors carry more of a cancer risk in men than women, as studies to date haven’t typically broken down findings based on sex, she says. “We’re not at a place where we can say, ‘Smoking is more dangerous for men than it is for women.’”

But the influence of biology on cancer’s development has been hiding in plain sight for years in epidemiological studies, Rubin says. Research conducted in the wake of large radiation exposures, such as that generated by the atomic bombs dropped in 1945 on Hiroshima and Nagasaki in Japan, found higher rates of non-sex-specific solid tumors in male survivors, even though both sexes were exposed to the same levels of radiation, Rubin says. “This probably relates back to sex differences in DNA repair and overall mutational burden that reaches high levels in males earlier in life than in females.” 

While radiation is an environmental exposure, a similar correlation may be found between risky behaviors and other types of nonreproductive cancers, Rubin says. Potentially, if you’re engaging in something that results in DNA damage and you’re male, you’re more likely to get cancer from the exposure than if you’re a female who has had similar exposure, he says.

But biological sex does not translate into destiny, Boutros stresses, noting that refraining from smoking, eating a healthy diet and exercising regularly significantly reduce a person’s chance of developing cancer, whether male or female.

“It is important to understand this [sex differences], and it really will improve the way in which we’re able to treat and eventually cure cancers,” Boutros says. “But on a day-to-day basis, we each make decisions that are far more important than what we were born as in terms of our sex chromosomes.”

Charlotte Huff is a Texas-based journalist who writes about medicine, psychology and health policy.