Breast cancer is being diagnosed earlier and treated more effectively. Although this has improved survival following diagnosis of breast cancer, it has also placed an increasing number of women at risk for developing a second primary breast tumor. Even so, the incidence rate of second primary breast cancer is not well documented. A 1999 comprehensive review of second primary breast cancer1 identified 16 cohort studies, with the most recent published in 1993. Three reports are dated from the 1980s, and five are from between 1964 and 1978. Only three of the reports were population-based and nine were reported from the United States. The 1993 study was based on a clinical series of 1624 women.2 Unfortunately, most studies of second primary breast cancer are similarly based on a small series of patients that lack statistical power to examine subgroups of interest, or they are based on a limited subsample that may not be representative of the U.S. population.
This study describes the epidemiology of second primary breast cancer among a large population-based cohort of U.S. women using current data on incidence of breast cancer collected by the National Surveillance, Epidemiology and End Results (SEER) Program. The three main objectives were as follows: to describe the age-specific incidence rates of contralateral breast cancer; to examine whether the rates vary according to year of diagnosis, demographic factors, and tumor characteristics of the first primary; and to contrast these rates to the overall rates of breast cancer. The large number of events in the database provided adequate power to calculate age- and risk factor-specific incidence rates for second primaries as well as for the overall rates. The long follow-up period allowed us to determine whether the rates of second primary breast cancer change as a function of time since the first primary.
We derived information on breast cancer patients from the SEER Cancer Incidence Public-Use Database, 1973–1998.3 This database includes nine population-based tumor registries across the United States, covering approximately 10% of the population. It is representative of the total U.S. population for African-Americans and whites.
For the years 1973 through the end of 1998, we calculated overall age-specific incidence rates of ductal or invasive breast cancer among women 20 years of age or older. There were 374,215 such tumors reported for 352,413 women. For consistency with previous studies, we considered an incident in situ or invasive breast cancer diagnosed in the contralateral breast at least 6 months after a ductal or invasive tumor to be a second primary. We excluded cases with a diagnosis before 6 months (N = 27,172), an unspecified prior tumor (N = 13,299), ambiguous laterality (N = 4,934) or unknown month of diagnosis (N = 1,475), leaving 305,533 cases at risk for a second primary.
We calculated age-specific incidence rates for overall and second primary breast cancer by dividing the number of incident cases by the number of person-years at risk. A woman was considered to be at risk from 6 months after the first primary until the diagnosis of a second primary, loss to follow-up, death, or end of the study period (December 31, 1998). We present overall incidence rates for breast cancer, rather than incidence of first primary breast cancer, to be consistent with other published reports and because in a substantial number of cases it could not be determined whether the tumor was a first or subsequent breast cancer (5.7%). In contrast to the overall rates, all in situ tumors were included in the calculation of rates for the second primary breast cancers. However, as the number of non-DCIS in situ tumors was low, the impact on the comparability between the rates is minimal. Race was categorized into “white”, “African-American” and “other” for comparability with the population figures provided by SEER. Age-specific (rather than age-standardized) rates are presented because the age distribution for the population at risk for a second primary differed so markedly from the overall population that adjusted rates were considered uninformative.
Of the 305,533 women with first primary breast cancer, 13,320 (4.3%) developed a second primary breast cancer in the contralateral breast. The rate of second primary was higher than the overall rate across all age categories—most markedly so for women in the younger age groups (Fig. 1). Among those 20 to 29 years of age, the incidence of second primary was more than 100 times greater than the rate of breast cancer overall (Table 1). In all tables, the rates for the second primary are stratified by the age at the time of the second primary.
The overall age-specific incidence rates steadily increased from the period 1973–1978 through 1994–1998 for all three age groups, whereas the rates of second primary breast cancer declined for women under 60 years of age (Table 2). Because data on first primaries prior to 1973 was unavailable and women were not considered to be at risk for a second primary until 6 months or more after the first, the rates of second primary during the years 1973–1978 are based on relatively few person-years of follow-up and should be interpreted cautiously.
Compared with white women, overall age-specific incidence rates for African-American women were lower among older women but the rates of second primary breast cancer were higher at all ages (Table 2). The rate of second primary breast cancer among African-American women 20 to 44 years of age was 25 times greater than the overall rate and more than 50% greater than that for white women.
Table 3 shows age-specific incident rates by stage and morphology of the first primary. In this table, the incidence rates for second primary breast cancer are stratified by characteristics of the first primary. The highest rates of second primaries among young women were observed following a late stage first tumor, whereas the highest rates for women over age 60 were after an early stage first tumor. Across all ages, the overall rates are lowest for medullary and lobular tumors and the highest are ductal invasive tumors. The rate for a tumor with lobular histology doubles after age 60. Compared with women who had a first primary breast cancer with ductal histology, those with medullary morphology have a 60% higher rate of second primary.
SEER collects information on intended course of treatment. We found no relation between radiation treatment of the first primary and incidence of second primary breast cancer (data not shown).
Age-specific rates of second primary breast cancer by the length of time between diagnoses, and stage and histology of the second primary are shown in Table 4. There was no consistent relationship between the rates of second primary as a function of months since the first primary. Very few second primaries are detected with distant metastases or in situ. Stage at diagnosis seems to be unrelated to age at diagnosis. Rates of ductal and medullary invasive tumors were elevated among young women.
Our observation that 4.3% of the at-risk population developed a second primary falls within the range of 1-15% observed in smaller studies of second primary breast cancer.4-9 In this study, rates of second primary breast cancer were consistently greater than the overall rates, but the magnitude of this excess risk was not uniform across all age groups. Younger women had a much greater ratio of rates than older women, which is consistent with previous studies reporting a higher risk for developing a second primary than a first primary4,7,10-13and with studies demonstrating an age-related effect.2,4,10,14-22 Our finding that tumor characteristics and risk factors associated with incidence of second primary vary by age also suggests differences in tumor biology for second primary breast cancers diagnosed earlier rather than later in life. Previous studies demonstrating familial aggregation of early onset breast cancers have concluded that young women with breast cancer are more likely than older patients to represent gene carriers especially predisposed to second primary breast cancer.23-28
A major strength of this study was the large number of cases that allowed us to examine, with precision, the incidence of second primary breast cancer over time. In addition, the population-based nature of the SEER registries ensured that the cases included here were not selected for factors that might influence the observed incidence rates. Unfortunately, SEER registry data do not include several pertinent risk factors such as family history of cancer or information on treatment modalities14,15,29-31 Our conclusions are thus limited to demographic factors (age and race) and information on tumor characteristics, and are generalizable only to populations covered by SEER.32,33 Further, the higher rates of second primary may be explained in part by an increased surveillance of women who have already had a first primary—an issue that we are unable to explore further. Lastly, although the contralateral breast is a rare site for a metastasis without histologic confirmation, there may be some misclassification of the first primary16 and variation in reporting registry.
Having a first primary breast cancer diagnosed with lobular carcinoma is one of the most consistently reported risk factors for developing second primary breast cancer,2,5,7,8,12-14,21,26,34 although the association with age is inconsistent.27,28 When the first primary had lobular or medullary histology the overall age-specific rates were low, however, the risk of developing a second primary breast cancer was high. An elevated risk of developing a second primary breast cancer, given a first primary with medullary histology, has not been previously reported. However, although ductal carcinomas account for approximately 75% of all breast tumors, medullary tumors account for only 2%27 and the small number of cases diagnosed before age 40 results in low power. Nevertheless, other studies have demonstrated that women with medullary cancer are diagnosed at younger ages,27 and experience a longer projected survival period following diagnosis of the first primary,6 thus having more time to develop a second primary breast cancer. Further, a study demonstrating an association between BRCA1 gene mutations and medullary histology among young women35 suggests a genetic predisposition to developing breast cancer. Because BRCA1 mutations have been associated with both younger age-at-onset cancers and with contralateral breast cancer, our finding is biologically plausible. Whether DCIS is actually a cancer or a precancerous lesion is uncertain.36 Our results show no consistent pattern of increased or decreased rates of second primary following a first primary with DCIS.
The incidence of unilateral breast cancer is lower among African-American women than among white women.7 Some previous studies show an increased risk of second primary breast cancer among African-American women7,37 whereas others do not.14 In this large population-based study, we found an increased risk of second primary breast cancer across all age groups, although the greatest was among young women.
In summary, our study demonstrates the importance of age at onset, histology of the first primary, and race in the development of second primary breast cancer. The large number of women included in this study and the long period of follow-up enabled us to examine trends over time in diagnosis of second primary breast cancer and to make comparisons with overall rates by histology, race, and age. With the growing number of women at risk for developing a second primary breast cancer, more specific public health education geared at early detection is warranted.
We thank Ira Bleiweiss for his insightful comments on the manuscript and Anitha Chetty and Monica Katyal for their editorial assistance.
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