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A common chemotherapy drug used to treat Hodgkin lymphoma conferred a significantly increased risk of breast cancer among women treated during adolescence and adulthood, a large retrospective study showed.

Women who received a cumulative doxorubicin dose >200 mg/m² had a 50% greater risk of breast cancer as compared with women who did not receive doxorubicin. The risk of breast cancer increased by 18% for every additional 100 mg/m² cumulative doxorubicin dose.

The breast cancer risk associated with doxorubicin was not affected by age at first treatment or receipt of radiation therapy (RT) to the chest, according to Michael Schaapveld, PhD, of the Netherlands Cancer Institute in Amsterdam, and co-authors in .

"Female patients with HL [Hodgkin lymphoma] receiving more contemporary treatments continue to have an increased BC [breast cancer] risk compared with the general population, despite efforts to limit radiation-associated subsequent cancers," the authors stated. "Our study shows that it remains of great importance to follow patients for more than 20 years after their treatment has been completed. Our findings confirm the importance of risk-based long-term follow-up care for lymphoma survivors and possibly survivors of other cancers treated with doxorubicin."

"Our results are also relevant for treatment strategies for patients with newly diagnosed HL, when balancing the risks and benefits of systemic therapy and RT," they added. "Since effective novel agents ... have been introduced in the treatment for patients with HL, future clinical trials should also aim at reducing the dose of doxorubicin."

The fact that chest RT did not modify the risk of breast cancer shows "this observation appears to be a standalone doxorubicin effect," wrote John Radford, MD, of the University of Manchester in England, .

"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," Radford continued.

"It also emphasizes the point that late consequences of treatment should be a key topic of discussion with our patients, appropriate information provided, and relevant interventions put in place so their impact can be minimized and the duration and quality of survival optimized," he added. "Finally, the critical importance of long-term follow-up in curable cancers, without which the impact of treatment on risk of second malignancy and other late consequences of treatment remain undiscovered, is brought into sharp focus."

Studies have shown that female Hodgkin lymphoma survivors who received chest radiotherapy at a young age have an increased risk of subsequent breast cancer. Treatment at a younger age with higher radiation doses or treatment volumes further increase the risk, Schaapveld and co-authors noted in their introduction. Other studies of Hodgkin lymphoma survivors or childhood cancer survivors showed a reduced risk of radiation-associated breast cancer in women who also received gonadotoxic treatments with high doses of alkylating agents or pelvic RT as compared with patients who did not receive such treatment.

To reduce treatment-related gonadotoxicity, doses of alkylating agents and use of pelvic RT have been reduced since the 1980s, and anthracyclines, such as doxorubicin, have become standard chemotherapy for Hodgkin lymphoma, the authors continued. At the same time, chest RT doses and volumes have decreased.

As the authors , an analysis of Hodgkin lymphoma survivors treated from 1965 to 2000 showed no decrease in breast cancer risk among patients treated more recently. Several studies of childhood cancer survivors have shown an increased risk of breast cancer after exposure to doxorubicin, irrespective of chest RT, and the data suggested a dose-dependent increase in breast cancer risk.

"To the best of our knowledge, the association between doxorubicin exposure and BC risk has not yet been examined in HL survivors treated at adult ages," the authors stated. "If doxorubicin exposure at adult ages were associated with BC risk, this could have implications for follow-up care of HL survivors, as well as for treatment strategies for newly diagnosed patients."

To address the missing data, the investigators retrospectively reviewed records of 1,964 female 5-year survivors of Hodgkin lymphoma, treated from 1975 to 2008 at 20 Dutch facilities. During a median follow-up of 21.6 years, 252 women developed invasive breast cancer or ductal carcinoma in situ, translating into a 30-year cumulative incidence of 20.8%

The data showed a 1.5-fold increased risk of breast cancer among women who received a cumulative doxorubicin dose >200 mg/m² as compared with patients who were not treated with doxorubicin (95% CI 1.08-2.1). Breast cancer risk increased by 1.18-fold per additional 100 mg/m² dose of doxorubicin (95% CI 1.05-1.32, P_trend=0.004). The hazard ratio remained elevated whether patients' doxorubicin occurred before age 21 (HR 1.5) or afterward (HR 1.3) and whether patients received chest RT (no, HR 1.9; yes, HR 1.2).

Addressing the relevance of the study, JCO editor in chief Jonathan W. Friedberg, MD, of the University of Rochester in New York, wrote, "These results emphasize the importance of very long follow-up for survivors of HL, and, if validated in other datasets, provide another factor to consider when evaluating risks of therapy. Ongoing trials incorporating checkpoint blockade and decreasing chemotherapy exposure have particular relevance given these findings."

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