Radiation + anthracyclines in childhood cancer may increase breast cancer risk

Childhood cancer survivors who were treated with radiotherapy and anthracyclines may have an elevated risk of developing subsequent breast cancer, according to an analysis of patients in the North American Childhood Cancer Survivor Study.

“[T]he combination of anthracyclines and radiotherapy may markedly increase breast cancer risks and is greater than the sum of their individual effects, consistent with an additive interaction,” said the researchers.

From data of 14,358 childhood cancer survivors (≥5-year survivors), the researchers identified 271 women who subsequently developed breast cancer (median age at initial cancer diagnosis 15 years, median age at breast cancer diagnosis 39 years). Of these, 201 and 70 were invasive and in situ breast cancers, respectively. Of the invasive breast cancer cases, 113 and 41 were oestrogen receptor-positive (ER+) and -negative (ER-), respectively. They were matched by age at first cancer and duration of follow-up with 1,044 individuals (control group).

Higher radiation dose to the breast for childhood cancer was associated with an elevated risk of subsequent breast cancer (odds ratio [OR] per 10 Gy, 3.9, 95 percent confidence interval [CI], 2.5–6.5). This risk was comparable between patients who had ER+ (OR per 10 Gy, 5.5, 95 percent CI, 2.8–12.6) and ER- (OR per 10 Gy, 4.8, 95 percent CI, 1.7–22.3; p_{heterogeneity}=0.94) cancers. [JAMA Pediatr 2019;doi:10.1001/jamapediatrics.2019.3807]

The risk of breast cancer was increased in women who received low or no radiation to the ovaries (<1 Gy) compared with those who received high radiation dose to the ovaries (≥15 Gy; OR per 10 Gy to the breast, 6.8, 95 percent CI, 3.9–12.5 vs 1.4, 95 percent CI, 1.0–6.4).

The risk of subsequent breast cancer was also elevated with increasing cumulative doses of anthracyclines for the initial cancer (OR per 100 mg/m², 1.23, 95 percent CI, 1.09–1.39; p_trend<0.01), with a trend toward a higher risk among patients with ER+ (OR per 100 mg/m², 1.49, 95 percent CI, 1.21–1.83) than ER- (OR per 100 mg/m², 1.10, 95 percent CI, 0.84–1.45; p_{heterogeneity}=0.47) cancers.

Patients who received anthracyclines in addition to breast radiation of ≥10 Gy (vs 0 to <1 Gy) had a greater risk of subsequent breast cancer than those who did not receive anthracyclines (OR, 19.1, 95 percent CI, 7.6–48.0 vs OR, 9.6, 95 percent CI, 4.4–20.7). 

“Ovarian radiation dose was a strong modifier of the risk associated with breast dose (p<0.01) … [and] there was an additive interaction between radiotherapy and anthracycline treatment (p=0.04),” said the researchers.

Use of alkylating agents was not associated with breast cancer risk, although there was a potentially increased risk of ER- invasive cancers (OR, 2.1) and for the highest quartile of cyclophosphamide-equivalent dose (>13,955 mg/m²; OR, 3.1) compared with non-use, though this only significantly pertained to the use of procarbazine (OR, 5.2) and not cyclophosphamide or mechlorethamine.

Type of first cancer, age at radiation exposure, age at menarche, or menopausal status did not appear to modify the radiation dose-response relationship for breast cancer, said the researchers.

The increased breast cancer risk associated with radiation is surprising, noted the researchers, given the reduction in radiotherapy doses and volume of irradiated tissue for childhood cancers in recent years. However, the increase in anthracycline use may have a role to play, they suggested.

While further research into the effect of the radiotherapy-anthracycline combination on breast cancer risk is warranted, the current findings may be useful in managing breast cancer risk in childhood cancer survivors with a history of chest irradiation and anthracycline use, they said.