1109 - A Novel Comprehensive Multi-Omic Biosignature to Assess Recurrence Risk and Adjuvant Therapy Benefit in Early-Stage Hormone-Positive Invasive Breast Cancer Patients

N. K. Gerber¹, K. Mittal², C. S. Shah³, F. A. Vicini⁴, J. Mouabbi⁵, P. W. Whitworth⁶, S. Willey⁷, M. Krystel-Whittemore⁸, C. C. Yates⁹, B. Karanam¹⁰, G. Acs¹¹, E. Pernicone¹², M. Tempest¹³, C. E. Cox¹³, A. Beard¹³, B. Czerniecki¹⁴, D. Dabbs², J. Savala², C. Wadsten¹⁵, and T. Bremer²; ¹New York University Grossman School of Medicine, Department of Radiation Oncology, New York, NY, ²PreludeDx, Laguna Hills, CA, ³Department of Radiation Oncology, Cleveland Clinic Foundation, Cleveland, OH, ⁴MHP Radiation Oncology Institute/GenesisCare, Farmington Hills, MI, ⁵MD Anderson Cancer Center, Houston, TX, ⁶University of Tennessee, Knoxville, TN, ⁷Inova Schar Cancer Institute, Falls Church, VA, ⁸NYU Langone Health, New York, NY, ⁹Johns Hopkins School of Medicine, Baltimore, MD, ¹⁰Tuskegee University, Tuskegee, AL, ¹¹AdventHealth Tamp, Tampa, FL, ¹²Saint Francis Medical Center, Peoria, IL, ¹³University of South Florida Morsani College of Medicine, Tampa, FL, ¹⁴H. Lee Moffitt Cancer Center and Research Institute, Department of Breast Oncology, Tampa, FL, ¹⁵Umeå University, Umeå, Sweden

Purpose/Objective(s): The landscape of breast cancer management is evolving with emphasis on the need for personalized treatment regimens to tailor treatment in early-stage, hormone receptor-positive (HR+) invasive breast cancer (BC) patients. Given that locoregional recurrence (LRR) rates are lower in HR+ BC patients, multiple studies have evaluated the role of adjuvant radiation therapy (RT) and/or endocrine therapy (ET) in these patients. Ongoing studies are exploring the integration of clinical and biological factors to better assess patient-specific recurrence risk profiles to individualize treatment in the adjuvant setting. The present study hypothesizes that the interaction of cellular pathways influencing tumor biology can be used as part of a biosignature to predict recurrence risk and the RT and ET benefit for early-stage HR+ HER2-negative BC. Materials/

Methods: A subset of 704 HR+ T1/T2N0M0 patients with BC who underwent BCS with or without RT between 1987-2002 were identified from a multi-institutional cohort of women. A biosignature that calculates an individualized risk profile was developed and cross-validated. The association between the biosignature and the 10-year LRR rate was assessed. RT and ET benefit were assessed as a function of the biosignature score, using survival analyses and multivariable Cox proportional hazards adjusted for treatment and clinicopathologic (CP) risk factors age, grade, and tumor size.
Results: Median follow-up was 126 months and the median age was 63 years old for the cohort with 93% (n=661) having T1 disease. 36% of patients (n=253) received ET, 82% (n=584) received RT, with 29% (n=205) receiving both. On multivariable analysis, higher grade (p=.04), younger age (p=.05), and receipt of RT (p=.007) were associated with LRR. However, in a multivariable analysis that incorporated treatment and CP factors, the biosignature was prognostic (p <.001), while the CP factors were not associated with the LRR rate. The biosignature also predicted the benefit from RT (interaction with RT, p<.001) and incremental ET benefit after RT (interaction with ET, p=.0018) over 10 years. Collectively, the biosignature identified a) a Low-Risk Group with a 1% 10-year LRR rate +/- RT (HR~1, p=0.99, n=146), b) an Elevated-Risk Group with a 17% LRR rate without RT and 10% with RT (HR=0.45, p=.018, n=462) and c) a Residual-Risk Group with a 31% LRR rate without RT and 23% with RT (HR=0.62, p=.4, n=96).
Conclusion: The novel biosignature was prognostic for LRR after BCS and identified clinically meaningful risk groups, predicting differential RT and incremental ET benefit associated with 10-year LRR. This initial validation indicates that the biosignature may be a useful tool to aid in the assessment of the benefit of adjuvant therapy in early-stage HR+ HER2-negative invasive BC.