Anthracycline, Radiation Treatment for Childhood Cancer Shown to Increase Risk of Adult Breast Cancer

With more children receiving chemotherapy and radiation to treat their diseases, leading to more survivors, awareness has grown of the belated effects of those treatments once patients reach adulthood. According to recent research in JAMA Pediatrics, there may be a connection between female childhood cancer survival and adult-onset breast cancer, and it may be related to combination treatment of the anthracyclines used for chemotherapy and, possibly, to radiation.

Anthracyclines are a class of highly toxic, yet highly effective, chemotherapy drugs derived from Streptomyces bacterium that spur cancer cell lysis by damaging the cells’ DNA, and radiation has been linked to a greater risk of estrogen-receptor positive (ER+) breast cancers. Owing to a lack of extensive knowledge of these effects of this combination treatment, the JAMA Pediatrics study authors investigated this treatment combination in female patients with breast cancer who also had childhood cancer.

They conducted a nested case-control study using data on 271 childhood cancer survivors from the ongoing Childhood Cancer Survivor Study at St. Jude Children’s Research Hospital who now have invasive or in situ breast cancer diagnosed at least 5 years after their first cancer diagnosis; a previous nested case-control study from 2009 had 109 such cases. That is a 148% increase in adult-onset breast cancer among childhood cancer survivors in just 10 years. Their median age of childhood cancer diagnosis was 15 years (range, 3-20), and breast cancer, 39 years (range, 20-57).

Overall, compared with the control group (n = 1044), Hodgkin lymphoma was the most common childhood cancer diagnosis in the patient group, and for the patients with breast cancer, there was a greater likelihood of leukemia or soft-tissue sarcoma among those with estrogen-receptor negative (ER-) disease compared with ER+ disease.

Not surprisingly, the overall odds ratio (OR) for breast cancer rose as the amount of radiation absorption rose. Per 10 Gy, the OR was 3.9 (95% CI, 2.7-7.3) compared with 5 Gy and lower, 1.77 (95% CI, 1.0-3.0), itself a still significant increased risk compared with a 0-Gy dose. And between in situ and invasive cases of breast cancer, the ORs per 10 Gy were 2.2 (95% CI, 1.2-6.9) versus 4.5 (95% CI, 2.7-7.3), respectively; however, between ER+ and ER- cases of invasive breast cancer, the response was similar (P = .94).

Interestingly, when considering radiation exposure to the ovaries during childhood cancer treatment, the higher the dose, the lower the odds of subsequent breast cancer: The OR per 10 Gy for those who actually received <1 Gy was 6.8 (95% CI, 3.9-12.5) versus 1.4 (95% CI, 1.0-6.4) for those who received at least 15 Gy, most of whom reported acute ovarian failure. This effect was also evident among those who received between 5 and 15 Gy.

According to the authors, “This protective effect of ovarian radiation was evident for ER+ and ER- breast cancers.”

Anthracycline use was also associated with a greater risk of breast cancer. At a cumulative dose of 100 mg/m², the overall OR was 1.23 (95% CI, 1.09-1.39). Patients with ER+ breast cancer responded more than those with ER- cancer: 1.49 (95% CI, 1.21-1.83) versus 1.10 (95% CI, 0.84-1.45).

Taken together, however, the risk for breast cancer following the combination of radiation and anthracycline use jumped. What the authors called an additive effect can be seen in the ORs of 19.1 (95% CI, 7.6-48.0) and 9.6 (95% CI, 4.4-20.7) at radiation doses of 10 Gy or more and 0 to <1 Gy, respectively, plus anthracycline treatment.

The authors believe further investigation is needed, especially for the different responses between patients with ER+ and ER- breast cancer, and think their findings can add to the current surveillance guidelines for childhood cancer survivors.

“Anthracyclines can cause radiation recall, which is an inflammatory skin reaction confined to previously irradiated areas trigged when chemotherapy agents are administered. This phenomenon suggests a biological interaction between radiation and anthracyclines and highlights the need for further research into their combined effect,” they conclude.

Reference

Veiga LH, Curtis RE, Morton LM, et al. Association of breast cancer risk after childhood cancer with radiation dose to the breast and anthracycline use: a report from the childhood cancer survivor study. JAMA Pediatr. 2019;173(12):1171-1179. doi: 10.1001/jama.2019.16658.