Anthracycline exposure and breast cancer risk in female Hodgkin lymphoma survivors.

Abstract

12074 Background: Female Hodgkin lymphoma (HL) survivors treated with chest radiotherapy (RT) at a young age have a strongly increased risk of breast cancer (BC). Recently concern has been raised that anthracyclines may also increase BC risk, based on studies in childhood cancer survivors with/without a history of chest RT. So far, the association between anthracyclines and BC risk has not been examined in cancer survivors treated at adolescent/adult ages. Now that RT dose and volumes are decreasing, the potential contribution of anthracyclines to BC risk is an important issue. Methods: We assessed BC risk in a cohort of 2314 female 5-year HL survivors, treated at ages 15-50 years and diagnosed between 1965 and 2008 in 20 Dutch hospitals. Treatment factors were time-dependently included in the analysis, focusing on the effect of anthracycline exposure on BC risk. Results: After a median follow-up of 18.8 years, 258 women developed invasive BC or ductal carcinoma in situ as a subsequent malignancy. The 30-year cumulative incidence was 15.0% (95% Confidence Interval (CI) 12.8-17.4%). Mantle field RT (or other RT involving both axillae) was associated with increased risk of BC (Hazard ratio (HR) 1.9; 95% CI 1.2-2.8) compared to no supradiaphragmatic RT or RT to the neck only (Table 1). Gonadotoxic treatment (>4.2 g/m2 procarbazine or pelvic RT) significantly decreased this risk. In a multivariable analysis, anthracycline exposure was associated with increased BC risk (HR 1.8; 95% CI 1.3-2.5) in patients who received a cumulative dose of >200 mg/m2. Among patients exposed to gonadotoxic treatment, the HR of BC associated with >200mg/m2 anthracyclines was 3.8 (95% CI 2.0-7.2), with a trend for higher risk with higher anthracycline dose (HR 1.58 per 100mg/m2 anthracycline, p<0.001). Conclusions: Our results suggest an association of anthracyclines with BC risk in HL survivors. Also when accounting for the protective effect of gonadotoxic treatment on RT-associated BC risk, anthracyclines significantly contributed to a higher BC risk.[Table: see text]

Doxorubicin and Breast Cancer Risk: The Importance of Long-Term Follow-Up in Curable Cancers

“…In conclusion, the study by Neppelenbroek et al 12 highlights the important issue of second cancers and particularly the increased risk of breast cancer, after cure of Hodgkin lymphoma. Their work shows that although the effects of radiotherapy have been known for many years, chemotherapy and specifically doxorubicin, is also a factor in generating increased risk meaning that the consequences of all treatment being considered for the newly diagnosed patient have to be carefully weighed in the decision-making process.…”

“…Paradoxically, when considering breast cancer risk due to radiotherapy, these older regimens had a protective effect because of the high incidence of premature menopause they induced. ABVD is far less damaging in terms of gonadal toxicity 16 but contains doxorubicin, which we now know from the work by Neppelenbroek et al, 12 has an independent effect on breast cancer risk. Confirmatory studies using independent data sets will of course be crucial, and we look forward to seeing the results of these.…”

“…However, extreme caution is required because 10 years is still early for evaluating a second cancer end point when these events typically emerge beyond this time and persist for 30 years. 1,11 With a focus over many years on the breast cancer risk posed by radiotherapy in women treated for Hodgkin lymphoma, the article accompanying this editorial by Neppelenbroek et al 12 describing the breast cancer risk associated with exposure to doxorubicin is intriguing and thought provoking. This study from the Netherlands involved a cohort of 1,964 females age 15-50 years when treated for Hodgkin lymphoma between 1975 and 2008 and who subsequently survived at least 5 years.…”

Comparison of outcomes between Hodgkin's lymphoma patients treated in and outside clinical trials: A study based on the EORTC‐Dutch late effects cohort‐linked data

“…Maybe the results were biased by an increase in smoking rates among women during the same period, leading to an increased incidence of lung cancers among female survivors 32 , 37 or maybe the advantage of using smaller radiotherapy volumes disappeared, as a result of the increased usage of anthracyclines. 38 , 39 Also, because of the long latency to second cancers, the lack of trial effect could simply be due to a shorter observation time. 20 According to Schaapveld et al, the risk of second cancer is still elevated 35 years or more after treatment.…”

Proton Therapy in Supradiaphragmatic Lymphoma: Predicting Treatment-Related Mortality to Help Optimize Patient Selection

“…Second, despite recent evidence for chemotherapy-related mortality risk of second breast cancer in Hodgkin lymphoma patients 34,35 , there is no published dose-response relationship and so we could not take account of this additional risk in our model. Third, the late-effects from HL treatments typically do not manifest for at least a decade after completion of therapy, and continue to develop beyond 30 years from treatment.…”