, according to new research funded by the charity Breast Cancer Now and published in Breast Cancer Research. The study is one of the largest ever into male breast cancer, enabling the team to show a highly statistically significant association.
A link with infertility had been suspected, since parity markedly reduces the risk of female breast cancer; there are known genetic links in both sexes, and a high risk of both breast cancer and infertility among men with Klinefelter syndrome, suggesting some sex hormone-related involvement. However, the rarity of breast cancer in men – with an annual incidence of about 370 cases and 80 deaths per year in the United Kingdom – meant that past studies were necessarily small and yielded mixed results.
“Compared with previous studies, our study of male breast cancer is large,” said study coauthor Michael Jones, PhD, of the division of genetics and epidemiology at the Institute of Cancer Research (ICR) in London. “It was carried out nationwide across England and Wales and was set in motion more than 15 years ago. Because of how rare male breast cancer is, it took us over 12 years to identify and interview the nearly 2,000 men with breast cancer who were part of this study.”
The latest research is part of the wider Breast Cancer Now Male Breast Cancer Study, launched by the charity in 2007. For the new study, the ICR team interviewed 1,998 males living in England and Wales who had been diagnosed with breast cancer between 2005 and 2017. All were aged under 80 but most 60 or older at diagnosis; 92% of their tumors were invasive, and almost all were estrogen receptor positive (98.5% of those with known status).
Their responses were compared with those of a control group of 1,597 men without breast cancer, matched by age at diagnosis and geographic region, recruited from male non-blood relatives of cases and from husbands of women participating in the Generations cohort study of breast cancer etiology.
Raised risk with history of male infertility
Overall, 112 cases (5.6%) and 80 controls (5.0%) reported that they had had infertility problems for which they or their partner had consulted a doctor or infertility clinic. This represented a raised odds ratio of 1.29 (95% confidence interval, 0.94-1.77), which was statistically not significant. However, when analyzed by outcome of the infertility consultation, there was a significant and more than doubled risk of breast cancer among men who were diagnosed as the source of the couple’s infertility (OR = 2.03 [1.18-3.49]), whereas this was not the case among men whose partner was the source (OR = 0.86 [0.51-1.45]) or for whom no source was identified (OR = 1.26 [0.71-2.24]).
In addition, proportionately fewer cases (1,615, or 80.8%) compared with controls (1,423, or 89.1%) had fathered any children, also giving a statistically significantly raised risk of breast cancer for men with no biological children (OR = 1.50 [1.21-1.86], P < .001), “congruent with infertility as a risk factor,” the authors said. The risk was statistically significant for invasive tumors but not for the much smaller number of in situ tumors.
Analysis by number of children showed a decreasing risk with increasing numbers of children, with a highly significant (P < .001) inverse trend where zero was included as a value, but a borderline significant trend (P = .04) if it was not. The team noted that number of children beyond one is difficult to interpret as an indicator of male fertility, since it may more reflect social and cultural factors than fertility per se.
Baseline demographic factors were adjusted for in the risk analyses, and results were not materially changed by sensitivity analyses adjusting additionally for alcohol consumption, smoking, liver disease, and family history of breast cancer. The association also largely remained after exclusion of patients with other preexisting potential confounders including severe obesity and testicular abnormalities, and was consistent irrespective of HER-2 status (there were too few ER-negative tumors to analyze results by ER status).