Our study shows that men diagnosed with a first primary breast cancer have a 16% increased risk of developing a new primary cancer in comparison with men in the general population. The prior US study, based on the geographic areas included in the SEER program, did not find an overall excess of second primary cancer [5
]. That study accounted for roughly 50% of California.
Breast cancers in men are characteristic of the BRCA2
phenotype, which accounts for approximately 15% of all MBC [8
]. Founder BRCA2
mutations contribute even higher prevalence rates of MBC in countries like Iceland, Sweden, Hungary, and also in Ashkenazi Jewish populations [8
]. The high risks for the presence of bilateral breast disease or multiple disease sites in one organ, especially among younger men, in the current investigation as well as in prior investigations are a likely indicator of a hereditary cancer syndrome [3
Male tumors related to BRCA1
include breast, melanoma, stomach, prostate, colon and pancreatic cancer [8
]. The risk is even more pronounced among carriers younger than 65 for melanoma, stomach, and prostate cancer [10
]. Although in MBC a second breast cancer has the strongest association, melanoma was in excess consistently throughout the analysis and also appears to have a high relative risk, confirmed by the prior US investigation [5
], but uncorroborated by Hemminki and colleagues [6
]. The excess risk of melanoma was more prominent among older men, in non-Hispanic whites, and after one year of follow-up. Epidemiological studies on malignant melanoma and breast cancer suggest the influence of steroid hormones on the etiology and development of these tumors. Melanoma and breast cancer are more common in women than men, implicating the role of female hormones and further strengthening the argument of a common etiological pathway between the two. A high socio-economic status is another shared risk factor [12
], but this may represent a proxy for race, as non-Hispanic whites have higher rates of both diseases. In regards to shared genetic susceptibility, both the CDKN2A
mutation and the BRCA2
mutation are linked. Families with the CDKN2A
mutation have an increased risk not only of multiple melanomas and pancreatic carcinoma but also of breast cancer [13
]. Further, an excess of melanoma has been reported in 173 BRCA2
families, particularly among carriers younger than 65 [10
We observed an overall excess of stomach cancer, a result inconsistent in the two prior investigations [5
]. Obesity is one of the main risk factors for gastric cancer [15
] and MBC [17
] and this common risk factor may, to some degree, explain the relationship between the two.
The risk of lung cancer was lower than expected for men ≥70 years of age during the first 5 years of follow-up after their breast cancer. The observed lower number of lung cancer cases may be an underestimate due to potential competing risk of dying due to other conditions.
We examined treatment effects (not shown) on risk of subsequent cancer. There was no statistical association of subsequent cancer risk with prior hormone therapy, radiation therapy, or chemotherapy on risk with the exception of second breast cancer. The increased SIR for second primary breast cancer in patients with and without prior hormone therapy and chemotherapy is more likely to be related to the rarity of breast cancer in men, which causes each observed case to contribute a substantial portion to the risk estimate. In addition, the increased risk of second primary breast cancer observed with a five year latency period may be attributable to advances in breast cancer diagnosis and treatment, which improve prognosis, and thus patients may live longer and are at a higher risk for second primary breast cancer.
The high rate of subsequent cancer among non-Hispanic whites may be due to better follow-up, better treatment or they may have a survival advantage to develop a second cancer. This is exemplified by the higher mean length of survival adjusted for age observed in non-Hispanic whites compared to other racial/ethnic groups. Based on time to death after breast cancer diagnosis, non-Hispanic whites experienced the highest mean survival of 4.49 years (n
= 1,454), followed by 4.38 for Asian/Pacific Islanders (n
= 107), 4.14 for blacks (n
= 157) and 3.86 for Hispanics (n
= 170) in this study. The excess of stomach cancer among non-Hispanic white males is unexpected as it is usually more prevalent in other racial/ethnic groups, particularly Asian/Pacific Islanders [22
The overall risk of subsequent malignancies other than breast cancer was not significantly elevated, confirming the observations reported by Hemminki and colleagues [6
]. The differences in risk estimates between investigations could be explained by several factors. First, there are important distinctions in racial/ethnic distribution between the Swedish populations (mostly Caucasian) and the diverse California population that may account for the discrepancy. Second, differences in screening practices, quality of healthcare, and access to and use of healthcare between the populations may also play a role. Thirdly, the variation of dietary, lifestyle and environment exposures, as well as genomic reactions to environmental exposures may play a role in the differences observed.