Subsequent female breast cancer risk associated with anthracycline chemotherapy for childhood cancer

Abstract

Anthracycline-based chemotherapy is associated with increased subsequent breast cancer (SBC) risk in female childhood cancer survivors, but the current evidence is insufficient to support early breast cancer screening recommendations for survivors treated with anthracyclines. In this study, we pooled individual patient data of 17,903 survivors from six well-established studies, of whom 782 (4.4%) developed a SBC, and analyzed dose-dependent effects of individual anthracycline agents on developing SBC and interactions with chest radiotherapy. A dose-dependent increased SBC risk was seen for doxorubicin (hazard ratio (HR) per 100 mg m^-2: 1.24, 95% confidence interval (CI): 1.18-1.31), with more than twofold increased risk for survivors treated with ≥200 mg m^-2 cumulative doxorubicin dose versus no doxorubicin (HR: 2.50 for 200-299 mg m^-2, HR: 2.33 for 300-399 mg m^-2 and HR: 2.78 for ≥400 mg m^-2). For daunorubicin, the associations were not statistically significant. Epirubicin was associated with increased SBC risk (yes/no, HR: 3.25, 95% CI: 1.59-6.63). For patients treated with or without chest irradiation, HRs per 100 mg m^-2 of doxorubicin were 1.11 (95% CI: 1.02-1.21) and 1.26 (95% CI: 1.17-1.36), respectively. Our findings support that early initiation of SBC surveillance may be reasonable for survivors who received ≥200 mg m^-2 cumulative doxorubicin dose and should be considered in SBC surveillance guidelines for survivors and future treatment protocols.

Fig. 1. Cohort composition diagram of eligible female 5-year childhood cancer survivors in each analysis.

*The number of included survivors in each analysis may vary due to missing values of analysis variables.

Fig. 2. Cumulative incidence of subsequent breast cancer in female 5-year childhood cancer survivors by cumulative doxorubicin dose, stratified by chest radiotherapy status (primary cancer diagnosis year 1946–2012).

Stratification by a, chest radiotherapy status; b, Mantle field; c, Mediastinal field; d, TBI/whole lung field; e, Other chest field. The SCCSS was excluded from cumulative incidence analyses due to the case–cohort design. The cumulative incidence figures represent univariable comparisons. Multivariable Cox regression results for the cumulative doxorubicin dose categories presented in this figure are shown in Extended Data Table 4. No., number; RT, radiotherapy.