Sander Roberti

We built models to predict absolute breast cancer (BC) risk in women treated with radiotherapy for Hodgkin lymphoma (HL). We first estimated relative risks (RRs) for risk factors, including radiation dose to 10 breast segments to accommodate heterogeneity of treatment effects, using a case-control sample nested in an HL survivor cohort. To estimate RRs of case-control matching factors we developed novel weighting approaches. We then combined RRs with age-specific BC incidence and competing mortality rates from the HL survivor cohort and a population-based registry, accommodating differences between them. We compared the performance of models using segment-specific doses with using mean dose only.

Although female survivors of Hodgkin lymphoma (HL) have an increased risk of breast cancer (BC), no BC risk prediction model is available. We developed such models incorporating mean radiation dose to the breast or breast quadrant-specific radiation doses.Relative risks and age-specific incidence for BC and competing events (mortality or other subsequent cancer) were estimated from 1194 Dutch 5-year HL survivors, treated at ages 11-40 during 1965-2000. Predictors were doses to 10 breast segments or mean breast radiation dose, BC family history, year of and age at HL diagnosis, and ages at menopause and first live birth. Models were independently validated using US Childhood Cancer Survivor Study cohort participants.Predicted absolute BC risks 25 years after HL diagnosis ranged from 1.0% for survivors diagnosed at ages 20-24 with less than 10 Gy mean breast radiation dose and who were menopausal 5 years after HL diagnosis, to 22.0% for survivors 25-29 years at diagnosis, with at least 25 Gy mean breast dose and no menopause within 5 years. In external validation, the observed/expected BC case ratio was 1.19 (95% confidence interval 0.97 to 1.47) for the breast segment-specific dose model, and 1.29 (1.05 to 1.60) for the mean breast dose model. The areas under the receiver operating characteristic curve were 0.68 (0.63 to 0.74) and 0.68 (0.62 to 0.73), respectively.Breast segment-specific or mean breast radiation dose with personal and clinical characteristics predicted absolute BC risk in HL survivors with moderate discrimination but good calibration, rendering the models useful for clinical decision-making.

Background: Breast cancer (BC) risk is increased among Hodgkin lymphoma (HL) survivors treated with chest radiotherapy. Case-control studies showed a linear radiation dose-response relationship for estimated dose to the breast tumor location. However, these relative risks cannot be used for absolute risk prediction of BC anywhere in the breasts. Furthermore, the independent and joint effects of radiation dose and irradiated volumes are unclear. Therefore, we examined the effects of mean breast dose and various dose-volume parameters on BC risk in HL patients. Methods: We conducted a nested casecontrol study of BC among 5-year HL survivors (173 case patients, 464 matched control patients). Dose-volume histograms were obtained from reconstructed voxel-based 3-dimensional dose distributions. Summary parameters of dose-volume histograms were studied next to mean and median breast dose, Gini index, and the new dose metric mean absolute difference of dose, using categorical and linear excess odds ratio (EOR) models. Interactions between dose-volume parameters and mean dose were also examined. Results: Statistically significant linear dose-response relationships were observed for mean breast dose (EOR per Gy \frac14 0.19, 95% confidence interval [CI] \frac14 0.05 to 1.06) and median dose (EOR/Gy \frac14 0.06, 95% CI \frac14 0.02 to 0.19), with no statistically significant curvature. All metrics except Gini and mean absolute difference were positively correlated with each other. These metrics all showed similar patterns of dose-response that were no longer statistically significant when adjusting for mean dose. No statistically significant modification of the effect of mean dose was observed. Conclusion: Mean breast dose predicts subsequent BC risk in long-term HL survivors.