For decades, doctors have consistently noticed men seem more likely to develop a range of cancers compared to women. This sex-based difference in cancer risk has often been waved away as a result of an assortment of lifestyle factors, from smoking and diet to occupational exposures.
But more recently, researchers have begun to identify some crucial biological factors that could be making men more susceptible to the development of some cancers. In 2016, for example, a landmark study from Harvard and MIT researchers homed in on a specific genetic factor that could account for some of the sex-based difference in cancer risk.
A new study has now offered the most robust investigation to date into the sex-based differences for cancer risk. Health records were analyzed from nearly 300,000 participants taking part in a long-term diet and cancer study.
“In the current study, we estimated sex differences in the risk of 21 solid tumors at shared anatomic sites, with a particular emphasis on quantifying the degree to which differences in risk behaviors (smoking and alcohol use), anthropometrics (body mass index and height), lifestyle factors (physical activity, diet, medication use), and medical and family history explained the higher cancer risk in men,” the researchers explained in the new study.
Overall, the study found non-biological factors could account for between 11.2% and 49.5% of the increased cancer risk in men, depending on the individual types of cancer being studied. In terms of shared non-anatomic cancer risks, women were found at higher risk than men for only two cancers: thyroid and gallbladder.
For some cancers, such as lung cancer, the research found nearly 50% of the increased risk for men could be attributed to lifestyle factors. But other cancers, such as esophageal, non-biological factors could only explain around 10% of the increased risk.
“Our results show that there are differences in cancer incidence that are not explained by environmental exposures alone,” explained lead author on the new study, Sarah Jackson. “This suggests that there are intrinsic biological differences between men and women that affect susceptibility to cancer.”
Of course, establishing the existence of intrinsic biological differences that can influence cancer risk between men and women is just the very first step of a long research path. Exactly what those mechanisms are can only be hypothesized at this point, and it’s likely they vary depending on the specific type of cancer being investigated.
Sex steroid hormones certainly account for some sex-based differences. High testosterone levels, for example, have been associated with higher risk of skin and liver cancer in men. While hormones such as progesterone and estrogen may be linked to lower rates of colon cancer in women.
“Immunologically, stronger innate and adaptive (particularly Th2) immune responses in women could reduce susceptibility to cancer,” the researchers speculated in the new study. “For example, women mount a more robust immune response to oncogenic infections, such as hepatitis B and C viruses and human papillomavirus, which, in turn, could mediate a lower risk of liver and oropharyngeal cancers, respectively.”
In general, researchers are increasingly trying to account for sex-based biological differences in clinical studies. A historical under-representation of women in clinical trials has recently been cited as a major problem, with 86 FDA-recommended drug dosages found to be unsatisfactory in women.
Other recent studies have looked at sex-based differences in everything from COVID-19 diagnoses to Alzheimer’s disease risk. By investigating the ways these diseases affect men versus women, researchers can better understand the mechanisms that lead to more severe clinical outcomes.
An editorial from two cancer researchers accompanying the new study called for sex-differences to be taken into account across all stages of cancer patient management. Jingqin Luo and Graham Colditz suggested it is becoming clear sex plays a significant role in the trajectory of the disease so it must be considered in both research and clinical contexts.
“Strategically including sex as a biological variable should be enforced along the whole cancer continuum from risk prediction and cancer primary prevention, cancer screening and secondary prevention, to cancer treatment and patient management,” explained Luo and Colditz. “Examining and addressing sex disparities in cancer and other diseases is an ongoing quest. Bench to bedside translational studies which effectively transform the existing research findings into clinical practice is a scalable means within easy reach to achieve precision medicine and will mitigate – and may ultimately eradicate – sex disparities in cancer.”
The new study was published in the journal Cancer.