BRIEF COMMUNICATION

Risk of Subsequent Cancer Following Breast Cancer in Men

Anssi Auvinen, Rochelle E. Curtis, Elaine Ron

Affiliation of authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.

Correspondence to: Rochelle Curtis, M.A., Radiation Epidemiology Branch, National Cancer Institute, Executive Plaza South, Rm. 7042, Bethesda, MD 20892–7362 (e-mail: rcurtis{at}mail.nih.gov).

ABSTRACT

The etiology of breast cancer in men is not well understood. We assessed the risk of subsequent cancers among all 1788 men diagnosed with a first primary breast cancer from 1973 through 1996 who were registered with the Surveillance, Epidemiology, and End Results (SEER) Program. Although the overall subsequent cancer risk in men was not increased (standardized incidence ratio [SIR] = 0.99, 95% confidence interval [CI] = 0.86 to 1.1), the risk of contralateral second breast cancer was strongly elevated (12 cases; SIR = 30, 95% CI = 15 to 52). The risk was higher for men diagnosed with their first breast cancer before age 50 years than for older men. There were no major differences in the risk of contralateral breast cancer associated with different treatments received for the first breast cancer. The relative risk of second breast cancer was substantially higher among men than among women with breast cancer, but the absolute excess risk was lower. We conclude that men diagnosed with breast cancer are at high risk of contralateral breast cancer.


Breast cancer among men is relatively rare, with an age-standardized incidence rate of about 1 per 100 000 person-years in most countries and approximately 1% of the incidence rate among women (1). Geographic and temporal variation in the rates is modest, suggesting limited environmental and life-style influence (2). However, international comparisons have shown some association in breast cancer rates between men and women (3,4). Although the etiology of breast cancer in men is not well understood, hormonal and genetic factors both appear to play a role. Similar to that of breast cancer in women, an increased risk of breast cancer in men has been associated with a family history of breast cancer (5,6). Additional known or suspected risk factors include hormonal abnormalities, such as Klinefelter's syndrome, gynecomastia, testicular disease, liver cirrhosis, and treatment with exogenous estrogens (7,8). To gain insight regarding the etiology of breast cancer in men, we conducted a follow-up study of the risk of subsequent cancers among men with breast cancer.

We evaluated the risk of a subsequent cancer among 2-month survivors who were diagnosed with a first primary cancer from 1973 through 1996 and reported to the nine Surveillance, Epidemiology, and End Results (SEER)1 Program cancer registries. SEER registry incidence files were searched for a second primary cancer that developed at least 2 months after the diagnosis of a first primary cancer. For each patient, person-years at risk (PYR) were accrued 2 months after the first primary breast cancer diagnosis (to avoid detection bias due to staging procedures) until the date of death, date of last follow-up, date of diagnosis of subsequent primary cancer, or study end, whichever came first. Age-specific, sex-specific, and calendar-specific incidence rates for all cancers combined and for specific cancer sites were multiplied by the appropriate person-years to compute the expected number of cancers. Two-sided tests for statistical significance of the standardized incidence ratios (SIRs, ratio of the observed-to-expected number of subsequent cancers) and exact 95% confidence intervals (CIs) were calculated assuming that the observed number of second cancers followed a Poisson distribution, as described (9). Absolute excess risks (AERs) were calculated as observed minus expected numbers of cancers divided by the PYR and were expressed as the number of excess cases per 10 000 PYR.

Of the cancers identified from 848 863 male patients, 96% of the first and 95% of the second primary cancers (99% and 97% of breast cancers from men, respectively) were histologically confirmed. The cohort included 1788 men with a first primary breast cancer, none of whom had bilateral disease. The mean age at diagnosis was 65 years for all men with a first primary cancer and 66 years for men with breast cancer (the medians were 67 and 66 years, respectively). Overall, men with a first primary cancer were followed for a mean of 3.9 years (3 277 970 PYR), whereas men with breast cancer were followed for a mean of 5.6 years (10 033 PYR).

Among men with breast cancer, overall subsequent cancer risk was not increased (SIR = 0.99, 95% CI = 0.86 to 1.13) (Table 1Go). However, the risk of developing a contralateral second breast cancer was strongly elevated (SIR = 29.64, 95% CI = 15.48 to 52.41; AER = 12 per 10 000 PYR) (Table 1Go). All second breast cancers were histologically confirmed. Men with breast cancer also had an increased risk of skin melanoma (SIR = 2.41, 95% CI = 1.15 to 4.43) and a slightly decreased risk of lung cancer (SIR = 0.73, 95% CI = 0.49 to 1.06).


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Table 1. Observed and expected second cancers among 1788 men with a first primary breast cancer who were registered with SEER from 1973 through 1996*
 
Men aged less than 50 years at the time of first breast cancer diagnosis had the highest relative risk of a contralateral second breast cancer (SIR = 110.29, 95% CI = 13.33 to 401.32) (Table 1Go). There were no major differences in the risk of second breast cancers associated with treatment modality received for the first breast cancer, with similar risks between men who received radiation (SIR = 37, 95% CI = 7.6 to 110) and those who did not (SIR = 28, 95% CI = 13 to 53). The 121 men who received both radiotherapy and chemotherapy had a statistically significantly elevated risk of second breast cancer (SIR = 212, 95% CI = 43 to 621); however, the SIR is based on only three case patients and has wide CIs. Laterality, time since first diagnosis, or calendar year period did not statistically significantly modify the risk of a second breast cancer.

The relative risk of second breast cancer was substantially higher among men (SIR = 29.6, 95% CI = 15 to 52) than among 263 370 women with first primary breast cancer (SIR = 1.8, 95% CI = 1.7 to 1.8; 9635 second cancers). However, the overall incidence (observed/PYR) of second breast cancer among women (58 per 10 000 PYR) far exceeded that among men (12 per 10 000 PYR). The risk of a contralateral second breast cancer was higher among women aged 50 years or younger at the time of diagnosis (SIR = 3.18, 95% CI = 3.06 to 3.30) than among older women (SIR = 1.51, 95% CI = 1.47 to 1.54).

Among men with a primary cancer other than breast cancer, there was no increased risk of subsequent breast cancer (SIR = 1.13, 95% CI = 0.95 to 1.33) (Table 2Go). In fact, for men with any specific primary cancer other than breast cancer, there was no increased risk of subsequent breast cancer (Table 2Go). Although not statistically significant, there was a twofold increased risk for subsequent breast cancer among men with melanoma (SIR = 2.00, 95% CI = 0.86 to 3.94). Among 151 men who developed breast cancer as a second malignancy (after any first malignancy), two were diagnosed with a contralateral breast cancer, i.e., a third primary cancer, indicating an especially high risk (SIR = 77.10, 95% CI = 9.23 to 277.84).


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Table 2. Observed and expected second breast cancers following selected first primary cancers among men who were registered with SEER from 1973 through 1996*
 
Our results indicate that men with breast cancer have a 30-fold increased risk of contralateral breast cancer, much greater than the two- to fourfold risk among women with breast cancer (10,11). However, the absolute risk of contralateral breast cancer among men with breast cancer was much lower (0.1% per year) than among women (0.6% per year) (10,11). The risk of subsequent contralateral breast cancer was highest for men aged less than 50 years at the time of the first cancer diagnosis, which is consistent with studies of women with breast cancer (11–13).

Because information on family history or other risk factors is not available from the SEER database, we could not directly study etiology. However, our results, indicating an increased risk of contralateral breast cancer but not of other malignancies, suggest an influence of a factor or factors specific to breast cancer. Previous investigators have indicated that family history is one of the strongest risk factors for breast cancer among men and women (4–6,8,14). An increased risk of breast cancer in men has been demonstrated among families with a history of breast cancer in women, and the risk increases with the number of affected female relatives (5,6,14). In addition, an increased risk of breast cancer among female offspring of men with breast cancer has been reported (15–17). These findings are consistent with the frequently detected germline BRCA2 mutations in men with breast cancer (18–20) or other constitutional factors (i.e., inherited or intrinsic features, such as a chromosomal anomaly or gene polymorphism) affecting androgen metabolism, such as Klinefelter's syndrome (8).

Our findings of the association between breast cancer and melanoma of the skin (seen in both directions) in men cannot be readily explained because the only recognized risk factors shared by these two cancers is high socioeconomic status (21,22). A similar relationship between breast cancer and melanoma of the skin has also been found in women (23–25). In men, no association was detected between breast cancer and prostate cancer, suggesting different etiologies for these two hormone-dependent cancers.

The strengths of our study include the relatively large number of cases, given the rarity of breast cancer in men, and that 97% of the subsequent cancers (including all 12 contralateral breast cancers) were histologically confirmed invasive cancers. Thus, it is unlikely that these cancers were misdiagnosed metastases. By contrast, the limitations of our registry-based analyses include imprecise data on treatments received, lack of information on potential confounding factors, and the potential for a detection bias in ascertainment of subsequent cancers. Moreover, because SEER patients who migrate outside SEER areas are not followed for subsequent cancer incidence, our findings are likely to be conservative.

In summary, our findings demonstrate that although the relative risk of contralateral breast cancer following breast cancer in men is substantial, especially among early onset cases, the AER is small. Indeed, less than 1% of the 1788 patients studied developed a contralateral breast cancer.

NOTES

Present address: A. Auvinen, School of Public Health, University of Tampere, Finland.

1 Editor's note: The Surveillance, Epidemiology, and End Results (SEER) Program is a set of geographically defined, population-based tumor registries in the United States, operated by local nonprofit organizations under contract to the National Cancer Institute (NCI). Each registry annually submits its cases to the NCI on a computer tape. These computer tapes are then edited by the NCI and made available for analysis. The SEER Program records all treatment given for the first course of therapy in broad categories, i.e., surgery, radiotherapy, chemotherapy, and hormonal therapy; therapy given subsequent to the first course is not recorded. Back

REFERENCES

1 Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J, editors. Cancer incidence in five continents. Vol 7. Lyon (France): IARC; 1997.

2 La Vecchia C, Levi F, Lucchini F. Descriptive epidemiology of male breast cancer in Europe. Int J Cancer 1992;51:62–6.[Medline]

3 Ewertz M, Holmberg L, Karjalainen S, Tretli S, Adami HO. Incidence of male breast cancer in Scandinavia, 1943–1982. Int J Cancer 1989;43:27–31.[Medline]

4 Thomas DB. Breast cancer in men. Epidemiol Rev 1993;15:220–31.[Medline]

5 Lenfant-Pejovic MH, Mlika-Cabanne N, Bouchardy C, Auquier A. Risk factors for male breast cancer: a Franco-Swiss case-control study. Int J Cancer 1990;45:661–5.[Medline]

6 Rosenblatt KA, Thomas DB, McTiernan A, Austin MA, Stalsberg H, Stemhagen A, et al. Breast cancer in men: aspects of familial aggregation. J Natl Cancer Inst 1991;83:849–54.[Abstract]

7 Thomas DB, Jimenez LM, McTiernan A, Rosenblatt K, Stalsberg H, Stemhagen A, et al. Breast cancer in men: risk factors with hormonal implications. Am J Epidemiol 1992;135:734–48.[Abstract]

8 Sasco AJ, Lowenfels AB, Pasker-de Jong P. Review article: epidemiology of male breast cancer. A meta-analysis of published case-control studies and discussion of selected aetiological factors. Int J Cancer 1993;53:538–49.[Medline]

9 Curtis RE, Boice JD Jr, Shriner DA, Hankey BF, Fraumeni JF Jr. Second cancers after adjuvant tamoxifen for breast cancer. J Natl Cancer Inst 1996;88:832–5.[Free Full Text]

10 Brenner H, Siegle S, Stagmeier C, Ziegler H. Second primary neoplasms following breast cancer in Saarland, Germany, 1968–1987. Eur J Cancer 1993;29A:1410–4.

11 Broet P, de la Rochefordiere A, Scholl SM, Fourquet A, Mosseri V, Durand JC, et al. Contralateral breast cancer: annual incidence and risk parameters. J Clin Oncol 1995;13:1578–83.[Abstract]

12 Bernstein JL, Thompson WD, Risch N, Holford TR. Risk factors predicting the incidence of second primary breast cancer among women diagnosed with a first primary breast cancer. Am J Epidemiol 1992;136:925–36.[Abstract]

13 Cook LS, White E, Schwartz SM, McKnight B, Daling JR, Weiss NS. A population-based study of contralateral breast cancer following a first primary breast cancer (Washington, United States). Cancer Causes Control 1996;7:382–90.[Medline]

14 D'Avanzo B, La Vecchia C. Risk factors for male breast cancer. Br J Cancer 1995;71:1359–62.[Medline]

15 Anderson D, Badzioch M. Breast cancer risks in relatives of male breast cancer patients. J Natl Cancer Inst 1992;84:1114–7.[Abstract]

16 Storm HH, Olsen J. Risk of breast cancer in offspring of male breast cancer patients. Lancet 1999;353:209.

17 Hemminki K, Vaittinen P. Male breast cancer: risk to daughters. Lancet 1999;353:1186–7.[Medline]

18 Couch FJ, Farid LM, DeShano ML, Tavtigian SV, Calzone K, Campeau L, et al. BRCA2 germline mutations in male breast cancer cases and breast cancer families. Nature Genet 1996;13:123–5.[Medline]

19 Haraldsson K, Loman N, Zhang QX, Johansson O, Olsson H, Borg A. BRCA2 germline mutations are frequent in male breast cancer patients without a family history of the disease. Cancer Res 1998;58:1367–71.[Abstract]

20 Struewing JP, Coriaty ZM, Ron E, Livoff A, Konichezky M, Cohen P, et al. Founder BRCA1/2 mutations among male patients with breast cancer in Israel. Am J Hum Genet 1999;65:1800–2.[Medline]

21 Elwood JM, Whitehead SM, Davison J, Stewart M, Galt M. Malignant melanoma in England: risks associated with naevi, freckles, social class, hair colour, and sunburn. Int J Epidemiol 1990;19:801–10.[Abstract]

22 Kirkpatrick CS, Lee JA, White E. Melanoma risk by age and socio-economic status. Int J Cancer 1990;46:1–4.[Medline]

23 Harvey EB, Brinton LA. Second cancer following cancer of the breast in Connecticut, 1935–82. Natl Cancer Inst Monogr 1985;68:99–112.[Medline]

24 Volk N, Pompe-Kirn V. Second primary cancers in breast cancer patients in Slovenia. Cancer Causes Control 1997;8:764–70.[Medline]

25 Rubino C, de Vathaire F, Diallo I, Shamsaldin A, Le MG. Increased risk of second cancers following breast cancer: role of initial treatment. Breast Cancer Res Treat 2000;61:183–95.[Medline]

Manuscript received October 30, 2001; revised June 24, 2002; accepted July 2, 2002.


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