Background: Female Hodgkin lymphoma (HL) survivors treated with chest radiotherapy at a young age have a strongly increased risk of breast cancer (BC). Recent studies in childhood cancer survivors have shown that doxorubicin may also increase BC risk. So far, the association between doxorubicin and BC risk has not been examined in cancer survivors treated at adolescent/adult ages.
Methods: We assessed BC risk in a cohort of 1964 female five year HL survivors, treated at ages 15-50 years in 20 Dutch hospitals between 1975 and 2008. Cumulative BC incidence was estimated in the presence of death as a competing risk. Treatment factors were time-dependently included in the multivariable Cox regression analysis, focusing on the effect of doxorubicin exposure on BC risk.
Results: HL survivors were treated at a median age of 27.8 years (interquartile range (IQR) 21.9-35.2 years). After a median follow-up of 18.3 years (IQR 12.9-24.7) years, 200 women had developed invasive BC (n=190) and/or ductal carcinoma in situ (n=49). The 30-year cumulative incidence was 19.4% (95% confidence Interval (CI) 16.6-22.3%). Among patients treated with chemotherapy (n=1113), receipt of doxorubicin-containing chemotherapy increased from 32.6% in 1975-1986 to 84.5% in 1998-2008. In multivariable analysis a cumulative dose of >200 mg/m2 was associated with increased BC risk (HR 1.7; 95% CI 1.1-2.4), compared to patients not treated with doxorubicin. BC risk increased 19% (HR 1.19; 95% CI 1.1-1.3) per additional 100 mg/m2 doxorubicine (ptrend=0.003). Receipt of mantle or axillary field irradiation or gonadotoxic therapy did not modify the association between doxorubicin and BC risk. Among patients who received >200 mg/m2 doxorubicin, the HR was 1.6 (95% CI 1.1-2.5) for patients treated with and 2.0 (95% CI 0.9-4.2) for patients treated without mantle or axillary field irradiation (Pinteraction=0.35). Gonadotoxic treatment (>8.4 g/m2 procarbazine or pelvic irradiation) significantly decreased the risk of BC.
Conclusion: This study shows that doxorubicin is associated with an increased BC risk among adolescent and adult HL survivors. Now that radiotherapy doses and volumes have decreased and doxorubicin increasingly forms the backbone of HL treatment, the potential association of doxorubicin with increased BC risk is an important issue.
Suzanne I.M. Neppelenbroek, Yvonne M.G. Geurts, Berthe M. P. Aleman, Cécile P.M. Janus, Pieternella J. Lugtenburg, Saskia E. Rademaker, Roel J. de Weijer, Maaike G.A. Schippers, Bastiaan D.P. Ta, Wouter J. Plattel, Josée M. Zijlstra, Richard W.M. van der Maazen, Marten R. Nijziel, Francisca Ong, Erik C. Schimmel, Eduardus F.M. Posthuma, Marie José Kersten, Lara H. Böhmer, Karin Muller, Harry R. Koene, Liane C.J. te Boome, Yavuz M. Bilgin, Eva de Jongh, Flora E. van Leeuwen, Michael Schaapveld