Breast Cancer Risk in Childhood Cancer Survivors Without a History of Chest Radiotherapy: A Report From the Childhood Cancer Survivor Study

Abstract

Purpose Little is known about the breast cancer risk among childhood cancer survivors who did not receive chest radiotherapy. We sought to determine the magnitude of risk and associated risk factors for breast cancer among these women. Patients and Methods We evaluated cumulative breast cancer risk in 3,768 female childhood cancer survivors without a history of chest radiotherapy who were participants in the Childhood Cancer Survivor Study. Results With median follow up of 25.5 years (range, 8 to 39 years), 47 women developed breast cancer at a median age of 38.0 years (range, 22 to 47 years) and median of 24.0 years (range, 10 to 34 years) from primary cancer to breast cancer. A four-fold increased breast cancer risk (standardized incidence ratio [SIR] = 4.0; 95% CI, 3.0 to 5.3) was observed when compared with the general population. Risk was highest among sarcoma and leukemia survivors (SIR = 5.3; 95% CI, 3.6 to 7.8 and SIR = 4.1; 95% CI, 2.4 to 6.9, respectively). By the age of 45 years, the cumulative incidence of breast cancer in sarcoma and leukemia survivors was 5.8% (95% CI, 3.7 to 8.4) and 6.3% (95% CI, 3.0 to 11.3), respectively. No other primary cancer diagnosis was associated with an elevated risk. Alkylators and anthracyclines were associated with an increased breast cancer risk in a dose-dependent manner (P values from test for trend were both < .01). Conclusions Women not exposed to chest radiotherapy who survive childhood sarcoma or leukemia have an increased risk of breast cancer at a young age. The data suggest high-dose alkylator and anthracycline chemotherapy increase the risk of breast cancer. This may suggest a possible underlying gene-environment interaction that warrants further study.

Risk factors for subsequent endocrine-related cancer in childhood cancer survivors

“…Note that in a recent study in childhood cancer survivors not treated with chest irradiation, Henderson and coworkers could not demonstrate a protective effect of ovarian irradiation or alkylating agent chemotherapy on secondary breast cancer risk (Henderson et al 2015). This indicates that gonadotoxic treatment only protects for radiationinduced breast cancer development.…”

“…The increased risk for secondary breast cancer in survivors of sarcoma might also be partly related to genetic factors. Data from the Childhood Cancer Survivor Study demonstrated an increased standardized incidence ratio for secondary breast cancer in sarcoma survivors not treated with chest irradiation (5.3 (95% CI: 3.6-7.8)) (Henderson et al 2015). In addition, a positive family history for sarcoma was associated with an increased secondary breast cancer risk (RR 5.3 (95% CI: 1.3-21.5)) (Kenney et al 2004).…”

“…After 15 years of follow-up since Hodgkin lymphoma, secondary breast cancer risk became equivalently increased in both treatment groups (SIR 14.8 (95% CI: 3.7-40.4) for combination chemoradiation therapy vs SIR 13.0 (95% CI: 6.6-23.1) for radiotherapy alone) (Hancock et al 1993). In addition, in a recent Childhood Cancer Survivor Study report by Henderson and coworkers on the risk for secondary breast cancer in childhood cancer survivors not treated with chest irradiation, exposure to anthracyclines and alkylating agents was associated with an increased secondary breast cancer risk (relative SIR 3.8 (95% CI: 1.7-8.3) for anthracyclines dosed ≥250 mg/m 2 , and relative SIR 3.0 (95% CI: 1.2-7.7) for alkylating agents dosed ≥18,000 mg/m 2 compared with no treatment with anthracyclines or alkylating agents) (Henderson et al 2015). As suggested by Van Leeuwen and coworkers, the observed increased risk for secondary breast cancer attributable to anthracyclines and alkylating agents in childhood cancer survivors not treated with chest irradiation might be partly related to genetic susceptibility (van Leeuwen & Ronckers 2016).…”

“…This represents a standardized incidence ratio of 2.2-9.8 in comparison with the general population (Inskip & Curtis 2007, Olsen et al 2009, Friedman et al 2010, Reulen et al 2011. Latency periods for the development of secondary breast cancer following childhood cancer vary between 6.7 and 39 years (average 21.8 years) (Table 3) (Gold et al 2003, Taylor et al 2007, Constine et al 2008, Diallo et al 2009, Friedman et al 2010, O'Brien et al 2010, Lange et al 2014, Dorffel et al 2015, Henderson et al 2015. This is illustrated by Reulen and coworkers, who observed an increased risk for secondary breast cancer in female childhood cancer survivors during the first three decades following primary cancer diagnosis, which gradually declined to general population norms at an attained survivor's age of 50 years (Reulen et al 2008).…”

“…However, two studies reported an increased risk for secondary breast cancer attributable to chemotherapy (Hancock et al 1993, Henderson et al 2015. In a combined cohort of childhood-and adult-onset Hodgkin lymphoma survivors, Hancock and coworkers observed a higher risk for secondary breast cancer following treatment with mechlorethamine, vincristine, procarbazine and prednisone in combination with radiotherapy compared with treatment with radiotherapy alone during the first 15 years following Hodgkin lymphoma (SIR 6.3 (95% CI: 3.1-11.6) for combination chemoradiation therapy vs SIR 0.8 (95% CI: 0.1-2.5) for radiotherapy alone).…”