Men at Higher Risk Than Women for Many Cancers: Why?

Men have a significantly increased risk than women of developing 11 different cancers, and the risk is three times greater for men for certain cancers, including those of the esophagus, larynx, gastric cardia, and bladder.

But why? A new analysis finds that the difference can only partly be explained by risky behaviors and carcinogenic exposure.

“There are differences in cancer incidence that are not explained by environmental exposures alone,” commented lead author Sarah S. Jackson, PhD, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.

“This suggests that there are intrinsic biological differences between men and women that affect susceptibility to cancer,” she added in a statement.

The study was published online August 8 in the journal Cancer.

“Understanding the sex-related biologic mechanisms that lead to the male predominance of cancer at shared anatomic sites could have important implications for etiology and prevention,” the researchers suggest.

In an interview, Jackson said that the results “do not support changes to existing cancer prevention protocol” to address the disparities in cancer rates between men and women.

“More research is needed before any recommendations can be made,” she told Medscape Medical News. “For example, we need more research on the female immune response. If we can discover the mechanisms by which females have an immune advantage, we may be able to develop therapeutics to bolster the immune system to prevent and treat cancer.

“We also should start reporting our findings on cancer incidence, screening, and survival by sex to ensure that we are not missing important sex-specific associations.”

Comprehensive Analyses

The researchers “should be applauded” for their “thorough and comprehensive analyses,” say the authors of an accompanying editorial, Jingqin R. Luo, PhD, and Graham A. Colditz, MD, DrPH, both from Washington University School of Medicine, St Louis, Missouri.

This study “has furthered our understanding on sex disparities in cancer, particularly in terms of the contributions of risk factors.”

However, as it included a largely elderly population and omitted comorbidities such as hypertension, hypercholesterolemia, and cardiovascular disease, the study has some “pertinent” limitations, they comment.

The contribution of risk factors to sex disparities is “likely by means of complex interactions,” and the editorialists wonder if the statistical modeling used in the study was “over-stringent.” Other aspects that need to be considered include race as well as socioeconomic determinants of health, they suggest.

Nevertheless, they point out that sex disparities have been “observed in nearly every aspect of the cancer continuum,” and a “multifaceted approach” is needed to address them.

“Strategically including sex as a biologic 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,” Luo and Colditz conclude.

Details of the Analysis 

In their paper, Jackson and colleagues point out that the lifetime probability of developing cancer is “approximately equal” in men and women, at 40% vs 39%.

However, the burden of cancer at shared anatomic sites is “significantly higher” in men, with the relative risk more than twofold higher than in women.

Some previous studies have pointed to differences in smoking, alcohol use, diet, access to and use of healthcare, and cancer screening between men and women, to explain the sex disparity, the researchers note, but few have used individual-level data.

They therefore examined records from the prospective National Institutes of Health-AARP Diet and Health Study. This was launched in 1995 with a baseline questionnaire sent to 3.5 million members of AARP aged 50-71 years and living in six US states. At the time, 617,119 returned the baseline questionnaire (17.6% response rate).

The current study focused on 334,905 participants who also completed a follow-up questionnaire between 1996 and 1997, which included more detailed information on diet and other lifestyle factors.

After excluding those who had already had a cancer diagnosis, self-reported poor health, extremely high or low caloric intake, or conflicting gender information, the researchers focused on 294,100 individuals (58% men, 42% women, median age 63.5 years).

After more than a decade of follow up (mean of 11.5 person-years for men and 12.4 person-years for women), the team found 26,693 incident cancers at 21 shared anatomical cancer sites. Of those, 17,951 were in men and 8742 in women.

The five most common cancers were nearly the same: the top three were lung, colon, and skin cancer in both men and women, and the fifth most common was kidney cancer in both. No. 4 for men was bladder cancer and for women it was pancreatic cancer.

After adjusting for demographic, lifestyle, and dietary covariates, the researchers found that the cancers with the highest male-to-female hazard ratios were esophageal adenocarcinoma, at 10.80, larynx cancer, at 3.53, gastric cardia cancer, at 3.49, and bladder cancer, at 3.33.

In contrast, men had a reduced risk of thyroid cancer, at a hazard ratio vs women of 0.55, and gallbladder cancer, at a hazard ratio of 0.33.

The team says that, overall, the increased relative risk among men was retained after adjusting for covariates for 11 cancers, but the relationship was no longer significant for many others, including lung, pancreas, small intestine, colon, oral cavity, esophagus-squamous cell carcinoma, and other head and neck cancers.

Cox proportional hazards regression modeling using the Peters−Belson method indicated that sex differences in risk factors explained at least some of the observed differences between men and women for seven cancer sites.

These were lung, colon, rectum, other biliary tract, skin, bladder, and esophageal adenocarcinoma, with 11.2% of the variance explained by risk factor differences for esophageal adenocarcinoma, rising to 49.4% for lung cancer.

Interestingly, there were no significant interactions between cancer rates at any of the anatomic sites and alcohol use, smoking status, body mass index, and age group.

Jackson told Medscape Medical News that sex differences in cancer outcomes “represents a very promising area of research” and the team “absolutely want to examine these associations further.”

“The dataset we used consists largely of non-Hispanic White adults. We’d like to see if the same sex bias is present in other ethnic groups, which would provide more evidence for a biological basis for these differences.”

“We’d also like to explore the contribution of sex hormones and genetics to cancer incidence in future research,” Jackson added.

The study was funded by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. Morgan A. Marks, PhD, performed this work as a postdoctoral fellow at the Division of Cancer Epidemiology and Genetics, National Cancer Institute. Marks reports relationships with Merck & Co outside the submitted work.

The editorial was supported in part by a National Cancer Institute Cancer Center Support Grant. Luo reports grants from the National Institutes of Health outside the submitted work. Colditz reports grants from the Breast Cancer Research Foundation and the National Cancer Institute outside the submitted work.

No other relevant financial relationships declared.

Cancer. Published online August 8, 2022. Abstract, Editorial

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