Anthracyclines and Alkylating Agents: New Risk Factors for Breast Cancer in Childhood Cancer Survivors?
Authors: Flora E. van Leeuwen, Cécile M. Ronckers
Journal: Journal of Clinical Oncology (2016)

For at least two decades, we have known that chest radiotherapy increases breast cancer risk in survivors of childhood cancer, as well as in adolescents and adults with Hodgkin lymphoma (HL). In the article accompanying this editorial, Henderson et al used the unique resource of the Childhood Cancer Survivor Study (CCSS) to investigate breast cancer risk in childhood cancer survivors without a history of chest radiotherapy. They report an overall four-fold elevated risk compared with the general population; risks were especially increased after treatment of sarcoma and leukemia. A novel finding is that alkylating agents and anthracyclinecontaining chemotherapy were associated with increased breast cancer risk in a dose-dependent manner. An earlier study from the CCSS investigators and a SEER-based report had already observed increased breast cancer risk in survivors of bone and soft tissue sarcoma unexposed to chest radiotherapy. The earlier CCSS report included all female childhood cancer survivors, irrespective of chest radiotherapy status. In 1,064 5-year survivors of sarcoma, 18 breast cancers were observed, 13 of which (72%) developed in women not treated with chest radiotherapy. Although significantly increased risks of breast cancer were reported for sarcoma survivors without a history of chest radiation (standardized incidence ratios of 6.7 and 7.6 for bone and soft tissue sarcoma survivors, respectively), much higher standardized incidence ratios (approximately 20-fold) were found for sarcoma survivors treated with chest radiation therapy. In contrast, in the British CCSS, with 17 breast cancers observed among 821 5-year sarcoma survivors, risk was elevated only after radiotherapy. Survivors of hereditary retinoblastoma also experienced elevated breast cancer risk in the absence of radiotherapy, likely attributable to genetic predisposition. None of the above studies reported increased risk of breast cancer after leukemia, or evaluated the influence of chemotherapy on breast cancer risk in survivors unexposed to chest radiotherapy. In the current study, breast cancer risk was evaluated in 3,768 female 5-year childhood cancer survivors treated without chest radiotherapy between 1970 and 1986. During a median follow-up time of 25.5 years 47 breast cancers were diagnosed, including 13 reported previously. Forty breast cancers (85%) occurred in sarcoma (55%) or leukemia (30%) survivors, representing 21% and 41% of the cohort, respectively. The cumulative incidence of breast cancer by the age of 45 years was 4.5% (95% CI, 3.2% to 6.2%) overall, and amounted to 5.8% and 6.3% in survivors of sarcoma and leukemia, respectively, corresponding to a fourto five-fold increased risk compared with the general population. Much higher risks of breast cancer, comparable to those observed in carriers of BRCA1/2 mutations, have been observed after chest radiotherapy before the age of 21 years, with cumulative incidence estimates by the age of 45 years varying between 12% and 22%. Henderson et al are the first to show increased risk of breast cancer after exposure to anthracyclines and alkylating agents, in the absence of chest radiotherapy. This is an important finding that could have clinical implications extending beyond the population of childhood cancer survivors treated without chest radiotherapy. The dose-response relationships observed for anthracyclines as well as alkylating agents suggest potential causal associations. Unfortunately, however, because most survivors received chemotherapeutic agents from both classes, and numbers were rather small, the agent-specific contributions could not be distinguished, nor could potential interactions be assessed. Alkylating agents are established human carcinogens and have been associated with increased risks of acute myeloid leukemia (AML), sarcoma, lung cancer, stomach cancer, pancreatic cancer, colorectal cancer, and thyroid cancer. For gastrointestinal tract cancers, increased risks after alkylating chemotherapy were observed only in patients who also received radiotherapy, whereas associations of alkylating chemotherapy with AML, sarcoma, thyroid cancer, and lung cancer were also observed in patients treated with chemotherapy alone. Anthracyclines are known carcinogens in animals and highly potent in producing malignant transformation and mutation in mammalian cell systems in vitro. In humans, they have been associated with increased risks of AML (especially in combination with alkylators), sarcoma (among patients who also had radiotherapy), and thyroid cancer. Animal studies support an anthracycline–breast cancer association, with positive findings in rats of both sexes.