Association of Breast Cancer Risk After Childhood Cancer With Radiation Dose to the Breast and Anthracycline Use

Abstract

IMPORTANCE Chest irradiation for childhood cancer is associated with increases in breast cancer risk. Growing evidence suggests that anthracyclines increase this risk, but the outcome of combined anthracycline use and radiotherapy has not been studied.OBJECTIVES To evaluate breast cancer risk in childhood cancer survivors following radiotherapy and chemotherapy and assess whether risks varied by estrogen receptor (ER) status. DESIGN, SETTING, AND PARTICIPANTSIn a North American hospital-based nested case-control study, a retrospective cohort of 14 358 five-year survivors of childhood cancer, diagnosed from 1970 to 1986 and followed up through December 31, 2016, was analyzed. Cases (n = 271) were defined as women with subsequent breast cancer. Controls (n = 1044) were matched 4:1 to cases by age at first cancer and duration of follow-up (± 2 years). Data analysis was conducted from September 2017 to July 2018.EXPOSURES Radiation dose to breast tumor site and ovaries and cumulative chemotherapy doses, including anthracyclines and alkylating agents. MAIN OUTCOMES AND MEASURES Odds ratios (ORs) for subsequent breast cancer by ER status. RESULTS A total of 271 women served as breast cancer cases (median age at first cancer diagnosis, 15 years [range, 3-20]; median age at breast cancer diagnosis, 39 years [range, 20-57]): 201 invasive (113 ER positive [ER+], 41 ER negative [ER-], and 47 unknown) and 70 in situ breast cancers.The OR for breast cancer increased with increasing radiation dose to the breast (OR per 10 Gy, 3.9; 95% CI, 2.5-6.5) and was similar for ER+ (OR per 10 Gy, 5.5; 95% CI, 2.8-12.6) and ER-(OR per 10 Gy, 4.8; 95% CI, 1.7-22.3) cancers. For women who received ovarian doses less than 1 Gy, the OR per 10 Gy to the breast was higher (OR, 6.8; 95% CI, 3.9-12.5) than for women who received ovarian doses greater than or equal to 15 Gy (OR, 1.4; 95% CI, 1.0-6.4). The OR for breast cancer increased with cumulative anthracycline dose (OR per 100 mg/m 2 , 1.23; 95% CI, 1.09-1.39; P < .01 for trend), and was 1.49 (95% CI, 1.21-1.83) for ER+ cancer vs 1.10 (95% CI, 0.84-1.45) for ER-cancers (P value for heterogeneity = .47). There was an additive interaction between radiotherapy and anthracycline treatment (P = .04) with the OR for the combined association between anthracycline therapy and breast radiation dose of 10 Gy or more (compared with 0 to less than 1 Gy) of 19.1 (95% CI, 7.6-48.0) vs 9.6 (95% CI, 4.4-20.7) without anthracycline use. CONCLUSIONS AND RELEVANCEThis study provides the first evidence to date that the combination of anthracyclines and radiotherapy may increase breast cancer risks compared with use of neither treatment with a similar radiation dose response for ER+ and ER-cancers and possibly higher anthracycline risks for ER+ cancers. These results might help inform surveillance guidelines for childhood cancer survivors.

The Burden of Late Effects and Related Risk Factors in Adolescent and Young Adult Cancer Survivors: A Scoping Review

“…Studies included in this review reported that AYAs in mixed-cancer cohorts experience an estimated 2.6-, 1.9-, and 10.4-fold increase in the risk for SMNs, hospitalization from any health condition, and 25-year all-cause mortality, respectively, compared to control groups [ 25 , 81 , 120 ]. Studies of childhood cancer survivors have shown a dose-response relationship between radiotherapy and the development of secondary sarcomas and breast, thyroid, CNS, and gastrointestinal cancers [ 22 , 121 , 122 , 123 ]. Similarly, specific chemotherapeutic drugs have been identified as risk factors for the late effects investigated in this review, with specific thresholds (e.g., high-dose intravenous methotrexate defined as any single dose ≥1000 mg/m 2 ) noted by the Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent and Young Adult Cancers [ 124 ].…”

Cisplatin Reduces the Frequencies of Radiotherapy-Induced Micronuclei in Peripheral Blood Lymphocytes of Patients with Gynaecological Cancer: Possible Implications for the Risk of Second Malignant Neoplasms

“…However, several studies reported the reverse effect. A nested study on the (CCSS) cohort with focus on therapy-induced breast cancer showed that the combination of anthracyclines and radiation potentiates the risk of SMN as compared to radiotherapy alone [16]. A potentiating effect of doxorubicin was observed for radiotherapy-induced SMN among Wilms' tumour patients [49].…”

“…A recent metanalysis revealed that treatment with cisplatin is not associated with a significantly increased risk of SMN [13]. More recent studies on the CCSS cohort revealed that high doses of cisplatin, alkylating agents and anthracyclines can lead to SMN [16,17]. In addition, results from the Dutch Childhood Cancer Oncology Group show that doxorubicin increases the risk of subsequent solid cancers and cyclophosphamide increases the risk of subsequent sarcomas [14].…”

“…The drugs differ in their modes of action and specificity to induce various SMN types [14]. Among the various types of chemotherapies, some studies suggest that anthracyclines have a particularly high carcinogenic potential [14][15][16], while others suggest the opposite [12,17]. A recent systematic review revealed that the carcinogenic potential of cisplatin is, contrary to common belief, not higher than that of other chemotherapy drugs [13].…”

Reflecting on 20 years of breast cancer modeling in CISNET: Recommendations for future cancer systems modeling efforts

“…As noted earlier, the CISNET models can also be useful to assess the potential impact of hormonal therapy for primary prevention in women who have survived childhood cancer and are at high risk for developing a subsequent breast cancer. This includes female survivors who received chest radiation [52] and potentially those who were exposed to high doses of anthracycline chemotherapy [73][74][75][76][77]. Risk-reducing medications could allow some survivors to avoid breast cancer entirely (versus avoiding breast cancer death via early detection with screening and treatment), but are not currently standard of care.…”