Abstract GS5-02: Detection of circulating tumor DNA (ctDNA) after neoadjuvant chemotherapy is significantly associated with disease recurrence in early-stage triple-negative breast cancer (TNBC): Preplanned correlative results from clinical trial BRE12-158

Abstract

Background: A significant proportion of patients with early-stage TNBC are treated with neoadjuvant chemotherapy (NAC). Sequencing of ctDNA after surgery can be used to detect minimal residual disease and predict which patients may experience clinical recurrence. Methods: BRE12-158 is a recently completed Phase II clinical trial which randomized early-stage TNBC patients with residual disease after NAC to post-neoadjuvant genomically-directed therapy vs treatment of physician choice. 151 patients had a plasma sample collected at the time of treatment assignment (after surgery and radiation). ctDNA was successfully sequenced in 150 patients. 148 of the 150 sequenced patients had clinical follow-up. Sequencing was performed by Foundation Medicine using the FoundationOne Liquid assay which profiles for 70 commonly mutated oncogenes. Presence of mutated ctDNA was associated with distant disease free survival (DDFS) and overall survival (OS) in univariate analysis using the Log-Rank test, and in multi-variate analysis using Cox proportional hazards model. Results: Mutated ctDNA was detected in 94 of 148 sequenced patients (64%). TP53 was the most commonly mutated gene consistent with prior genomic studies of TNBC. At 16.7 months of median follow-up, detection of ctDNA was significantly associated with an inferior DDFS (median DDFS 32.5 months vs. Not Reached, p=0.0030). At 24 months, the DDFS probability was 53% in ctDNA-positive patients as compared to 81% in ctDNA-negative patients. In multi-variate analysis, when considering significant covariates, including: residual cancer burden (RCB); number of positive lymph nodes; tumor size; stage; grade; age; and race; detection of ctDNA remained independently associated with inferior DDFS (HR=3.1, CI: 1.4-6.8, p=0.0048). Similarly, detection of ctDNA was associated with inferior OS in univariate (p=0.021) and multi-variate analysis (HR=2.7, CI:1.1-6.2, p=0.022). Lastly, we observed a correlation between higher maximum somatic allele frequency and a shorter DDFS interval in multivariate analysis (HR=4.7, CI: 1.04-21.1, p=0.044) and shorter OS (HR=4.9, CI:1.06-22.4, p=0.041), suggesting that the quantitative degree of ctDNA burden is associated with clinical outcome. Conclusions: Detection of ctDNA in early-stage TNBC after neoadjuvant chemotherapy is an independent predictor of disease recurrence, and represents an important novel stratification factor for future post-neoadjuvant trials. Citation Format: Milan Radovich, Guanglong Jiang, Christopher Chitambar, Rita Nanda, Carla Falkson, Filipa C. Lynce, Christopher Gallagher, Claudine Isaacs, Marcelo Blaya, Elisavet Paplomata, Radhika Walling, Karen Daily, Reshma Mahtani, Michael A. Thompson, Robert Graham, Maureen E. Cooper, Dean C. Pavlick, Lee Albacker, Jeff Gregg, Casey L. Bales, Bradley A. Hancock, Erica Cantor, Fei Shen, Anna Maria V. Storniolo, Sunil Badve, Tarah Ballinger, Kathy D. Miller, Bryan P. Schneider. Detection of circulating tumor DNA (ctDNA) after neoadjuvant chemotherapy is significantly associated with disease recurrence in early-stage triple-negative breast cancer (TNBC): Preplanned correlative results from clinical trial BRE12-158 [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS5-02.

Triple‑negative breast cancer: A run‑through of features, classification and current therapies (Review)

“…ctDNA has been associated with chemotherapy in studies by Riva et al ( 65 ), in which ctDNA-positive patients before and after chemotherapy experienced poor OS and disease-free survival (DFS). Additionally, Radovich et al ( 66 ) reported that patients with early-stage TNBC and positive ctDNA after chemotherapy had a higher risk of disease relapse. Therefore, liquid biopsies are being developed as a non-invasive method to study recurrence, treatment response, and survival in the clinical setting.…”

Triple-negative breast cancer: promising prognostic biomarkers currently in development

“…The prognostic significance of ctDNA has also been evaluated during and after NACT for TNBC [ 113 , 114 ]. Riva et al found that ctDNA was positive in 75% of the patients prior to NACT and continued positivity after one cycle of chemotherapy was associated with shorter DFS (p < 0.001) and OS (p = 0.006) [ 113 ].…”

“…Riva et al found that ctDNA was positive in 75% of the patients prior to NACT and continued positivity after one cycle of chemotherapy was associated with shorter DFS (p < 0.001) and OS (p = 0.006) [ 113 ]. Radovich et al found that detection of ctDNA in patients with early-stage TNBC with residual disease after NACT was an independent prognostic risk factor for disease recurrence [ 114 ]. Out of 148 patients, ctDNA was detected in 64% and at a median follow-up of 16.7 months, detection was associated with inferior distant DFS (32.5 mos.…”

Update Breast Cancer 2020 Part 2 – Advanced Breast Cancer: New Treatments and Implementation of Therapies with Companion Diagnostics

“…In a neoadjuvant study, Radovich et al investigated the prognostic significance of CTCs and ctDNA in 196 patients with TNBC and no pathological complete remission (pCR) following the neoadjuvant situation [27]. The clinical follow-up was 17.2 months.…”