353 - Validation of a Multi-Omic Biosignature in a Multi-Institutional Cohort to Predict Locoregional Recurrence Risk and Differential RT Effect In Early-Stage Invasive Breast Cancer
Presenter(s)
A. J. Khan1, G. B. Mann2, G. J. Liefers3, L. Bouwman3, V. Rebattu3, W. Li4, S. Niu5, H. S. Lu5, F. A. Vicini6, C. S. Shah7, N. K. Gerber8, M. Kruse9, Z. Al-Hilli10, C. MacCallum11, P. Whitworth12, S. Shivers13, D. Dabbs13, K. Mittal13, and T. Bremer13; 1Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, 2The University of Melbourne, Melbourne, Australia, 3Leiden University Medical Center, Leiden, Netherlands, 4Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, 5Wake Forest School of Medicine, Winston Salem, NC, 6Michigan Health Professionals, Farmington Hills, MI, 7Allegheny Health Network Cancer Institute, Department of Radiation Oncology, Pittsburgh, PA, 8New York University Grossman School of Medicine, Department of Radiation Oncology, New York, NY, 9Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland, OH, 10Breast Center, Integrated Surgical Institute, Cleveland Clinic Foundation, Cleveland, OH, 11Peter MacCallum Cancer Centre, Melbourne, Australia, 12PreludeDx, Laguna Hills, CA, United States, 13PreludeDx, Laguna Hills, CA
Purpose/Objective(s): Ongoing trials evaluating omission of adjuvant radiotherapy (RT) and endocrine therapy (ET) in older women with low-risk early-stage invasive breast cancer (IBC) rely on clinicopathological criteria or expression assays not specifically developed to assess locoregional recurrence (LRR) and RT benefit. We developed and previously validated a multi-omic biosignature that predicts 10-year LRR and the differential RT effect. Here, we perform independent validation in a multi-institutional cohort.
Materials/Methods: The biosignature was independently validated in a prospective-retrospective cohort of HR+HER2- T1T2N0M0 IBC women treated with breast conserving surgery (BCS) ± RT ± endocrine therapy (ET) at (39 hospitals for LUMC cohort (n=836) 2003-2009; WF (n=244) 2008-2017; RMH (n=526) 2006-2017). Central pathology review was performed at the study institutions and long-term outcomes were collected. Specimens were submitted to PreludeDX for blinded biomarker testing in a CLIA lab (Laguna Hills, CA). The test combines multi-omic data (RNA seq and proteomics by multiplex immunofluorescence) to calculate 2 biosignatures: 1) the Decision Score (DS) to determine LRR prognosis and 2) the Radio Resistance Index (RRI) to determine differential RT effect. Independent third-party statistical analysis was performed following a pre-specified analysis plan (retrospective case–cohort propensity score (PS)-matched validation study 20:1). Hazard ratios (HR) for LRR risk were estimated using Cox models, evaluating the prognostic term DS and the interaction of the RRI and RT effect.
Results: Complete biomarker and clinical data were available for 1005 women from the case-cohort analysis, with 62 LRRs within 10-years of diagnosis. Multivariable analysis (MVA) of CP and RT demonstrated that RT was associated with decreased LRR risk (HR=.2, p<.001) and younger age was associated with increased LRR risk (HR=5.6, p<.001). In the MVA with biosignatures, increasing DS (0-10 scale) was associated with increasing LRR risk (HR=2.4; p=.006), and there was a statistically significant interaction between RRI and RT. Despite RT treatment, patients with increasing RRI had increasing LRR risk (HR=2.9, p=.002). The DS identified 60% patients as elevated risk (DS>5), in whom RT was associated with decreased LRR risk (HR=0.3, p<.001). In the Low Risk group (DS=5, 40%), RT did not significantly reduce LRR risk (HR=0.4; p=.13). Nested Cox regression ANOVA confirmed the biosignatures provided more information than CP and RT alone.
Conclusion: This validation in an independent multi-institutional cohort demonstrates the prognostic utility of the DS for LRR and the predictive utility of the RRI for differential RT effect beyond CP alone. Biosignature stratified HR+ HER2- IBC patients into DS Low (=5, no significant LRR reduction with RT) and DS Elevated (DS>5, significant LRR reduction by RT). These data suggest that the DS biosignature can aid clinicians and patients in choosing the optimal RT strategy.