Toward Understanding the Etiology of Male Breast Cancer: An Ongoing Research Challenge

Male breast cancer is rare and accounts for less than 1% of all breast cancers, with an estimated 2650 new cases in the United States in 2021, compared with 281 550 cases for women (1). Despite increasing male breast cancer incidence rates worldwide over the past 3 decades (2), the etiology, prognosis, and treatment of male breast cancer is not well understood, as there are limited population-based studies and clinical trials focused on male breast cancer. Moreover, most treatment and clinical management guidelines for male breast cancer are based on studies of female breast cancer, even though men with breast cancer are older at diagnosis, are primarily diagnosed with hormone receptor–positive tumors, and have different hormonal profiles than females (3). Unlike female breast cancer risk factors that have been extensively studied, elucidating the role of different hormonal, genetic, and lifestyle factors for male breast cancer has been challenging, because of the rarity of the disease. Obesity has been of particular interest in male breast cancer given its association with high estrogen levels, the hormonal activity of adipose tissue, and the established association of obesity with elevated risk of female postmenopausal breast cancer (4,5). Moreover, there is evidence that the rising rates of male obesity and increasing incidence of male breast cancer show parallel trends (6), although it is unclear if the two are linked. In female breast cancer, there is strong evidence that higher body mass index (BMI) and greater central adiposity are associated with increased risk of postmenopausal breast cancer, with heterogeneity by breast cancer subtype and underlying familial risk (5,7-9). In contrast, the evidence for obesity and male breast cancer is very limited but, based on smaller studies that examined BMI, not central adiposity or the associations by tumor subtype. In this issue of the Journal, Swerdlow and colleagues (10) present evidence based on 1998 male breast cancer cases and 1597 controls that greater BMI and abdominal obesity are associated with increased risk of breast cancer in men. Considering the sparse evidence highlighted above, these are important and novel findings that leverage data from a large British population-based case-control study over a 12-year period, representing one of the largest and most detailed studies examining this association to date. The authors report a statistically significant elevated risk of male breast cancer for increasing BMI at ages 20, 40, and 60 years (odds ratio [OR] 1⁄4 1.07, 1.11, and 1.14 per 2-unit increase, respectively). They also report an association with increasing waist-to-height ratio at 5 years before interview (OR per 0.02-unit increase 1⁄4 1.12, 95% confidence interval [CI] 1⁄4 1.08 to 1.15). Notably, no previous study has examined the association of central obesity and male breast cancer. Overall, Swerdlow et al. (10) make a unique contribution to the literature with this analysis by examining the associations with BMI and central obesity at different ages. The findings of the study are novel; however, some of the analyses are not easy to interpret. For example, the authors did not use World Health Organization BMI categories, which they suggest is because of small sample size in some categories in their study. Moreover, including recent BMI (ie, measured close to the diagnosis) would have been valuable for comparing against the only other large study examining this association, the Male Breast Cancer Pooling Project, which includes 2405 cases of male breast cancer and 52 013 controls from 11 case-control studies and 10 cohorts, and found that recent rather than distant BMI was a strong predictor (4). The pooling project reported a 19% increased risk per 5-unit increase in BMI (OR 1⁄4 1.19, 95% CI 1⁄4 1.1 to 1.3) and a 35% statistically significantly increased risk for obese men (BMI 30 kg/m) compared with normal weight men (BMI 1⁄4 18.5-24.9 kg/m) (4). Generally consistent with this information, Swerdlow et al. (10) found that recent waist-to-height ratio was a stronger risk factor than that at age 20 years. It should be noted that, although the study by Swerdlow and colleagues (10) was one of the largest studies examining these associations to date, their study population was primarily comprised of White men (94% of cases and 98% of controls). As such, these findings may not be generalizable to other racial and ethnic groups, which may have different rates of obesity and other social and environmental factors that may be associated with cancer risk as well as different patterns of breast cancer subtypes. Considerably higher incidence rates have been reported in