The present study includes 1,926 males aged 85 years or less diagnosed with first primary breast cancer between 1 January 1988 and 31 October 2003, registered at the CCR. A second primary cancer was defined in this study as a malignant metachronous tumor that developed at least two months after first primary male breast cancer diagnosis. There were 221 (11.5%) second primaries diagnosed in this cohort of men during the study period. Synchronous tumors occurring less than two months from first primary breast cancer were excluded in order to control for detection bias due to diagnostic methodology and also to be consistent with prior research conducted in the same geographic region [5]. Ninety-three percent of the cohort received surgery. In addition, 25% underwent adjuvant hormone therapy, 24% chemotherapy, and 20%, radiation therapy, while 19% of the cohort had some combination therapy. No men were excluded from the analysis due to missing data as information regarding second malignancy, date of diagnosis and date of last contact or death were available for all patients.

For the purposes of rate adjustment, five-year age groups, resulting in 18 age categories, were used in calculating the expected number of cases. Race/ethnicity was categorized into five mutually exclusive groups: non-Hispanic white, Black, Hispanic, Asian/Pacific Islander, and other/unknown. To calculate the expected number of cancers for the other/unknown group, we used the incidence rates of all others combined. The calendar period was classified in five-year categories of diagnosis: 1988 to 1992, 1993 to 1997, and 1998 to 2003. Tumor site codes in accordance with SEER definitions for breast, prostate, colorectal, lung and bronchus, bladder, melanoma, and stomach cancer were obtained from the CCR [7]. The unit of analysis in our study was person/days at risk in order to maximize use of fractions of years if applicable. Person-years of observation were calculated two months from the date of breast cancer diagnosis up to and including age 85, the date of the second primary cancer, date of last contact or death, or study end (31 December 2003), whichever came first.

The overall SIRs for second malignancy by tumor site, controlling for age, race and calendar period, are shown in Table ​Table22 for sites where at least ten cases were recorded. The observed number of second primary malignancies was 221 compared to 190.42 expected, thereby producing an SIR of 1.16 (95% CI = 1.01–1.32), which shows an excess risk of 16%. The excess risk of subsequent cancer decreased to 5% when second breast cancer was excluded and the result is not statistically significant. Overall, a significant excess of second primary was noted for breast cancer (SIR = 52.12, 95% CI = 31.83–80.49), cutaneous melanoma (SIR = 2.98, 95% CI = 1.63–5.00), and stomach cancer (SIR = 2.11, 95% CI = 1.01–3.88).

The effect of diagnostic age on risk of subsequent cancer is presented in Table ​Table3.3. The SIR or risk ratio for all malignancies combined (breast included and breast excluded) was highest in the younger population. A similar pattern was also observed for second breast cancer with higher excess risks starting in the <60 years age group and decreasing with increasing age. A significant excess of skin melanoma (SIR = 3.18, 95% CI = 1.17–6.93) was noted among men 70 years or older. In patients diagnosed between 60 and 69 years, a 2-fold increased risk of colorectal cancer was observed. Patients 70 years or older experienced a lower risk of lung and bronchus cancer (SIR = 0.47, 95% CI = 0.19–0.97).

The effect of race on subsequent cancer risk, controlling for age and calendar period, is shown in Table ​Table4.4. The 39 observed second primaries in the 'other' race/ethnic category comprise 15 black, 17 Hispanic and 7 Asian/Pacific Island men. Overall, non-Hispanic whites (SIR = 1.19, 95% CI = 1.02–1.38) showed a significant excess of subsequent cancers. When breast was excluded, the excess of second primaries was no longer observed. Second breast cancer is elevated in both racial/ethnic categories. However, the excess risk was more prominent in the 'other' ethnic background compared to non-Hispanic whites. The increased risk of second primary breast cancer among the 'other' racial/ethnic category is largely due to the risk among blacks. The risk of melanoma among non-Hispanic white men was three-fold that expected. A significant excess in stomach cancer was observed in non-Hispanic white males (SIR = 2.53, 95% CI = 1.09–4.99).

The SIRs for second malignancy by length of time after breast cancer diagnosis, controlling for age, race and calendar period, is shown in Table ​Table5.5. The risk of all malignancies combined was significantly lower than expected in the first year of follow-up (SIR = 0.74, 95% CI = 0.53–0.99) and higher than expected after 5 years of follow-up (SIR = 1.63, 95% CI = 1.31–2.00). When breast cancer was excluded, the risk was 21% lower than expected in the first 5 years after diagnosis, but later increased to 45% after 5 years of follow-up. Second breast cancer was higher in each follow-up category, with the highest risk after five years of follow-up. A higher SIR was observed after 5 years from diagnosis for bladder cancer (SIR = 2.89, 95% CI = 1.49–5.05). Melanoma was in excess for 2 follow-up periods: 1 to 5 years (SIR = 2.68, 95% CI = 1.08–5.53) and >5 years (SIR = 4.15, 95% CI = 1.52–9.02). Lung and bronchus cancer was protective in the first five years after diagnosis. We also analyzed the data stratified by treatment type and subsequent cancer risk. We did not find any statistical associations with the risk of second cancers.

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 [3,9].

Male tumors related to BRCA1 and BRCA2 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 [10,11]. 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 [13,14]. 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 [5,6]. Obesity is one of the main risk factors for gastric cancer [15,16] and MBC [17-21] 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].