Abstract P4-05-10: Composite score combining multi-gene testing with liquid biopsy may have stronger prognostic value in HR+/HER2- breast cancer
Authors: Bilani Nadeem , Yaghi Marita , Saravia Diana , Jabbal Iktej , Zerdan Maroun Bou , Elson Leah , Liang Hong , Nahleh Zeina 
Published: March 2022

Background: For patients with early-stage, hormone receptor-positive (HR+) and HER2-negative breast cancer, multigene testing (MGT) is commonly used to personalize treatment. Published data suggests that the 70-gene MammaPrint (MP) assay, while used less commonly, may be superior to the 21-gene OncotypeDX panel at identifying high-risk patients requiring chemotherapy adjunct to endocrine therapy, versus endocrine therapy alone. We previously showed that the presence of circulating tumor cells (CTCs) has prognostic and predictive value in breast cancer. We assess the prognostic value of composite scoring combining liquid biopsy data with MGT. Methods: This retrospective analysis of the National Cancer Database explores the prognostic value of ODX, MP and liquid biopsy identifying CTCs in patients diagnosed between 2004-2017 with early-stage (AJCC clinical stage I-II), HR+/HER- breast cancer. We examined the prognostic value of the following models: 1) ODX alone, 2) MP alone, and 3) ODX-liquid biopsy composite score. The ODX-liquid biopsy composite score was created to be a binary risk stratification as follows: when circulating tumor cells were present, intermediate-risk as per ODX was upstaged to high-risk, but when absent, intermediate-risk was down-staged to low-risk. We compared the effect size of hazard ratios generated by each model’s inclusion in Cox regressions for overall survival that controlled for age and race. We also evaluated the prognostic value of each model through generated Harrell’s C-indices (i.e. area under ROC curve), with a C-index closer to 1 indicating superiority of a model in differentiating high- from low-risk groups. Results: Among early-stage, HR+/HER2- patients (n=841,716), n=271,416 (32.2%) had documented ODX data, n=12,417 (1.5%) had MP data, and n=1,141 (0.14%) had both ODX and CTC data. Based on liquid biopsy results, n=63 patients were upstaged from intermediate- to high-risk in the partial composite ODX-CTC model (20.5% of all intermediate-risk), while the rest (79.5%) were down-staged. A comparison of effect sizes for HRs corroborates preliminary data in the literature that MP alone (HR 2.49, 95% CI 1.94-3.19) may be superior to ODX alone (HR 2.23, 95% CI 2.07-2.39) at prognosticating overall survival. Additionally, we show that a binary composite score of ODX with liquid biopsy may better identify patients with a higher risk of mortality (HR 3.46, 95% CI 1.63-7.31). Comparison of C-indices was not possible for MP scoring or ODX-liquid biopsy scoring, likely due to an inadequate sample size leading to non-significance. Conclusion: Composite scoring based on ODX and liquid biopsy using CTCs may be superior to ODX/MP alone to differentiate high-risk from low-risk prognosis in patients with early-stage, HR+/HER2- BC. If confirmed in larger studies, this composite scoring would be useful in practice to more accurately identify a higher risk patient population to target for additional treatment and close monitoring.

Table 1. Summary of prognostic parameters (HR and C-index) of 3 scoring systems.Prognostic ModelCOX RegressionROC AnalysisHR* (95% CI)C-index (95% CI)p-value1. ODX scoring alone (n=182,861)2.23 (2.07-2.39)0.566 (0.558-0.573)&lt;0.0012. MP scoring alone (n=8,643)2.49 (1.94-3.19)0.527 (0.492-0.562)0.1213. ODX-liquid biopsy composite scoring (n=685) 3.46 (1.63-7.31)0.497 (0.391-0.602)0.952*HRs comparing high-risk to low-risk stratifications, calculated from COX regression for overall survival after controlling for age (5-70) and race (White).

Citation Format: Nadeem Bilani, Marita Yaghi, Diana Saravia, Iktej Jabbal, Maroun Bou Zerdan, Leah Elson, Hong Liang, Zeina Nahleh. Composite score combining multi-gene testing with liquid biopsy may have stronger prognostic value in HR+/HER2- breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-05-10.