Abstract A031: Association of tumor DNA in circulation with clinical characteristics and treatment response in HR+/HER2− advanced breast cancer

Abstract

Abstract Background: The sensitivity of plasma-based oncological assays is influenced by the amount of tumor DNA shed into the circulation (ctDNA fraction). Higher ctDNA fraction has been shown to correlate with later-stage cancers and poorer overall survival (Bettegowda C, et al. Sci Transl Med. 2014; Dawson SJ, et al. N Engl J Med. 2014). Other factors affecting ctDNA fraction are poorly understood. We present results from three large Phase III breast cancer studies (MONALEESA-2, -3, and -7) to evaluate correlations between ctDNA fraction and clinical characteristics and impact on progression-free survival (PFS) and best overall tumor response. Methods: Baseline plasma samples were collected from patients (pts) in the MONALEESA-2, -3, and -7 studies, which are Phase III registration trials testing ribociclib, a cyclin-dependent kinase 4/6 inhibitor, in hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer. For each trial, cell-free DNA was extracted from plasma and sequenced using a validated next-generation sequencing assay targeting approximately 550 genes. ctDNA fraction was estimated by analyzing short-read sequences using PureCN (Riester M, et al. Source Code Biol Med. 2016) and tested for correlations with various tumor characteristics (size at baseline, Ki67 expression, number and type of metastatic sites, hormone receptor status) and pt characteristics (type of prior therapy, line of therapy, ECOG performance status, age, body mass index, race, histological grade, menopausal status). We also evaluated the prognostic value of ctDNA fraction on PFS and best overall response. To evaluate the prognostic effect on PFS, ctDNA fraction was binned into 3 categories (not detectable; low, 0.5%-10%; high, > 10%). Results: Higher ctDNA fractions were observed in pts with more metastatic sites (P < 0.0001), larger tumor diameter (P < 0.0001), higher Ki67 expression (P = 0.0001), higher lactate dehydrogenase levels (P < 0.0001), higher-grade tumors (P = 0.0004), worse ECOG performance status (P < 0.0001), progesterone receptor–negative tumors (P = 0.01), presence of liver metastases (P < 0.0001), and shorter disease-free intervals (P < 0.0001). ctDNA fractions were also higher in younger pts (continuous variable; P < 0.0001) and pts with lower BMI (P = 0.0003), prior chemotherapy (P = 0.002), and prior endocrine therapy (P = 0.01). Lower ctDNA fractions were observed in pts with better overall response (P < 0.0001), with median ctDNA fractions lowest in pts with complete responses followed by partial response, stable disease, and progressive disease. Pts with low (0.5%-10%) ctDNA fractions had longer PFS than pts with high (> 10%) ctDNA fractions (HR [95% CI], 0.63 [0.48-0.82], 0.64 [0.51-0.80], and 0.67 [0.52-0.86] in the MONALEESA-2, -3, and -7 trials, respectively). A more pronounced effect on PFS was observed in pts with undetectable levels of ctDNA vs pts with higher ctDNA fractions (HR [95% CI], 0.35 [0.23-0.52], 0.34 [0.21-0.55], and 0.31 [0.21-0.47] in the MONALEESA-2, -3, and -7 trials, respectively). Conclusions: Generally, higher ctDNA fraction was associated with more aggressive tumor characteristics and prior exposure to therapy. Lower ctDNA fraction was associated with longer PFS and better overall response. Together these data suggest that ctDNA fraction is a robust prognostic factor. Citation Format: Nadia Solovieff, Faye Su, Rebecca Leary, Alejandro Balbin, Arunava Chakravartty, Karen Rodriguez Lorenc, Tetiana Taran, Naveen Babbar. Association of tumor DNA in circulation with clinical characteristics and treatment response in HR+/HER2− advanced breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A031. doi:10.1158/1535-7163.TARG-19-A031