Abstract P3-12-03: Utilizing the genomically adjusted dose (GAD) to personalize radiotherapy in adjuvant breast cancer management

Abstract

Abstract Background: We have previously validated a multi-gene model of tumor radiosensitivity (RSI) with validation in multiple independent cohorts including breast, rectal, esophageal, head and neck, glioblastoma, and prostate malignancies. Utilizing the linear quadratic model and RSI, we derived an expression for the genomically adjusted dose (GAD) to model radiation dose effect for individual patients. Methods: As RSI models the surviving fraction of cells at 2 Gy (SF2), we are able to derive a patient specific alpha. These terms were used in the linear quadratic model to calculate a GAD to model radiation effect and its association with local control. A higher GAD implies a higher predicted radiation therapy effect. Clinical and array-based gene expression were obtained from 75 ER negative patients from the Netherlands Cancer Institute (NKI) and the Institut Curie treated with breast conservation therapy. Results: Median follow-up for all patients was 10 years with a median age of 42 years (range: 23-50 years). Adjuvant radiation dose to the whole breast was 50 Gy (range: 45-55 Gy). When assessing local recurrence on multivariate analysis, we found GAD to be a significant predictor of local recurrence when dichotomized at the median (GAD-low vs GAD-high Hazard Ratio (HR) 4.5; 95% CI 1.7-13.5; p=0.0031). GAD was also significant per unit change (HR 0.91; 95% CI 0.83-0.99; p=0.021). We then modeled GAD for an escalated dose up to 60 Gy and found an additional 48% of GAD-low patients could achieve a GAD-high with dose escalation. Conclusions: We found GAD to be significantly correlated with local control following breast conservation therapy. Modeling dose escalation with GAD, we identified a select population of patients whom we hypothesize may benefit from genomically guided increased dose in the adjuvant setting. This population may represent a cohort for future clinical trial enrollment. Citation Format: Ahmed KA, Venkat PS, Scott JG, Diaz RJ, Fulp WJ, Torres-Roca JF. Utilizing the genomically adjusted dose (GAD) to personalize radiotherapy in adjuvant breast cancer management. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-12-03.