Breast Cancer after Childhood Cancer: A Report from the Childhood Cancer Survivor Study

Context Adult survivors of childhood cancer are at risk for developing breast cancer and other secondary cancer. Knowing the risk factors for breast cancer in these women may help to formulate screening policies for them. Contribution Among 6068 women who survived childhood cancer, 95 developed breast cancer at a median age of 35 years. Childhood sarcoma, chest irradiation, family history of breast cancer, and personal history of thyroid disease increased the risk for breast cancer. Implications Women who survived childhood cancer and had sarcoma, chest irradiation, family history of breast cancer, or personal history of thyroid disease should consider early, vigilant screening for breast cancer. The Editors Women treated with chest radiation therapy for childhood and adolescent Hodgkin disease are at increased risk for developing breast cancer at a young age (1-12). However, case reports and preliminary studies indicate that survivors of childhood cancer other than Hodgkin disease may also be at risk for secondary breast cancer (1, 13, 14). Practitioners caring for the growing population of young female survivors of childhood cancer are challenged with assessing breast cancer risk in order to recommend screening and preventive strategies. Although recent studies have shown that the risk for radiation-induced breast cancer is directly related to dose of chest radiation, specific details of previous treatment are not always available to clinicians and may not affect screening decisions (11, 12). In addition, whether primary cancer diagnosis, previous treatment other than chest radiation, or other well-established breast cancer risk factors contribute to a childhood cancer survivor's risk for breast cancer is unknown. Studies of Hodgkin disease survivors have shown that clinical examination and screening mammography can detect early-stage secondary breast cancer in young women (15-17), and although treatment options may be limited by previous therapy, early-stage secondary breast cancer is curable (16, 17). Thus, identifying specific groups of childhood cancer survivors who would benefit from early mammographic screening might reduce the morbidity and mortality of breast cancer in these young women. In this study, we analyzed a large series of women with secondary breast cancer from a cohort of childhood cancer survivors, the Childhood Cancer Survivor Study (CCSS), to describe clinical and pathologic features of breast cancer and to determine breast cancer risk relative to the general population. We hypothesized that breast cancer risk would be modified by previous treatment and factors unrelated to treatment. Thus, in this large cohort of women, we assessed the influence of primary cancer, previous treatment, family cancer history, and menstrual and reproductive history on breast cancer risk. Methods Study Sample: Childhood Cancer Survivors Study The CCSS is a follow-up study of childhood cancer survivors established in 1994. Eligibility criteria included diagnosis at an age younger than 21 years with leukemia, brain tumor, Hodgkin disease, non-Hodgkin lymphoma, renal tumor, neuroblastoma, or soft-tissue or bone sarcoma and survival of at least 5 years after diagnosis. The 20276 eligible participants received a diagnosis from 1 January 1970 to 31 December 1986 at 1 of 25 collaborating institutions (Appendix). Participants (n= 14054) completed a self-report questionnaire, providing information about their medical history, family medical history, reproductive history, and socioeconomic status. Follow-up questionnaires were sent to patients reporting second cancer diagnoses. Information on the cohort was updated in 2000. We used data available as of May 2002 for this analysis. No men in the CCSS reported breast cancer by that date; thus, this analysis was restricted to women. Detailed information on the study methods and cohort characteristics has been reported (18). The human subjects committee at each participating institution approved the CCSS protocol. Clinical Data We abstracted treatment data from medical records, including chemotherapeutic agents and dose, and radiation therapy dose, and site for primary cancer and relapses. We asked participants who self-reported breast cancer to sign a medical release to confirm the diagnosis. We confirmed all cases of breast cancer in this report and obtained the tumor size, histologic characteristics, hormone receptor status, involvement of axillary nodes, and metastatic sites from pathology records. Statistical Analysis We compared survivors who had breast cancer with those who did not have breast cancer with respect to primary cancer diagnosis, age at diagnosis, years of follow-up, and therapy for the primary cancer. We calculated standardized incidence ratios for breast cancer by using age-, sex-, and calendar-yearspecific incidence rates of the general population (Surveillance, Epidemiology, and End Results Program [SEER], National Cancer Institute, Bethesda, Maryland [19]). We considered survivors to be at risk for breast cancer from 5 years after the childhood cancer diagnosis until 1 of the following 3 events: death, breast cancer diagnosis, or completion of the CCSS questionnaire. To make the definition of incidence comparable in the calculation of the observed and expected numbers, we included only the first primary breast cancer diagnosis. We calculated cumulative incidences of breast cancer by attained age (20). We used Poisson multiple regression models for standardized incidence ratios to assess the modification of risk for developing breast cancer by several variables chosen a priori (21). We considered the following risk factors for breast cancer: age at and years since primary cancer diagnosis; age at menarche (<12 years or 12 years); age at first live birth (never, <20 years, 20 to 24 years, or 25 years), as queried in the CCSS questionnaire; history of breast cancer in first-degree female relatives (yes or no); exposure to chest radiation (yes or no); exposure to pelvic radiation (yes or no); family history of sarcoma (yes or no); history of thyroid disease (thyroid nodules, overactive or underactive thyroid, or enlarged thyroid); and exposure to an alkylating agent (alkylating agent score, measured as previously described, accounted for several drug exposures and dose) (22). The Poisson multiple regression incorporated all time-dependent factors by splitting each survivor's follow-up period into several time intervals, wherein each factor was assumed constant. We initially evaluated the relative rate of developing breast cancer for each risk factor, adjusting for the exposure to chest radiation (yes or no). We then stratified the analysis by the exposure to chest radiation and assessed the modification of risk with age at and years since primary cancer diagnosis, family history of breast cancer or sarcoma, history of thyroid disease, and exposure to pelvic radiation. The years since primary cancer diagnosis variable was the baseline time factor of the model for which we obtained fitted standardized incidence ratios relative to SEER data. For other variables, we calculated relative rates by comparing standardized incidence ratios across categories of each variable. All significance tests were 2-sided. We used SAS software, version 8 (SAS Institute Inc., Cary, North Carolina), and S-PLUS software, version 6 (Insightful Corp.), for this analysis. Role of the Funding Sources The funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Results Cohort Characteristics Of the 20276 survivors eligible for the CCSS cohort, 9062 were women. Of those, 6498 women participated, 6068 of whom had signed medical record release to be eligible for this analysis. Of the 6068 eligible women, 95 women had 111 confirmed cases of breast cancer. Primary cancer diagnosis and age at treatment were similar between participants and nonparticipants (Table 1). Survivors with breast cancer were older at diagnosis of primary cancer and at follow-up than those without breast cancer. As expected, a large proportion of the women with breast cancer (65 of 95 [68%] women) were Hodgkin disease survivors, and all but 2 of the 65 women were known to have received chest radiation therapy. However, 30 of 95 (32%) women with breast cancer were survivors of other childhood cancer, and 20 of 95 (21%) women did not receive chest radiation therapy. The proportion of patients exposed to alkylating agents was similar in both groups (49.5% vs. 49.2%) (Table 1). Table 1. Characteristics of Women Who Did and Did Not Develop Breast Cancer and of Eligible Nonparticipants Since the oldest survivors in this cohort were 51 years of age, all cases of breast cancer were diagnosed in relatively young women (median age at diagnosis, 35 years [range, 20 to 49 years]) (Table 2). However, 19% (18 of 95 women) of the breast cancer cases occurred in women 20 to 29 years of age and 64% (61 of 95 women) of cases occurred in women 30 to 39 years of age. Median time from childhood cancer diagnosis to breast cancer diagnosis was 19 years; however, the range extended from 6 years to 29 years after primary cancer diagnosis (Table 2). Table 2. Clinical and Pathologic Characteristics of Breast Cancer Cases Of the 111 cases of breast cancer, 21 cases were ductal carcinoma in situ (Table 2). Of those 21 cases, 19 were diagnosed in Hodgkin disease survivors and 2 in soft-tissue sarcoma survivors. Table 2 shows the distribution of histologic characteristics in the invasive cases. We determined the stage in 66 of 90 (73%) invasive cases from pathology reports (Table 2). Twenty-six (29%) cases involved axillary lymph nodes, and 5 (6%) cases involved distant metastatic disease. Estrogen receptor status was available in 37 cases, and 76% of those were positive. There was no predominant laterality. Sixteen cases (17%) were bilateral, 5 were syn