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J Clin Oncol DOI:10.1200/JCO.2017.76.0033

Association of Cell-Free DNA Tumor Fraction and Somatic Copy Number Alterations With Survival in Metastatic Triple-Negative Breast Cancer.

Publication TypeJournal Article
Year of Publication2018
AuthorsStover, DG, Parsons, HA, Ha, G, Freeman, SS, Barry, WT, Guo, H, Choudhury, AD, Gydush, G, Reed, SC, Rhoades, J, Rotem, D, Hughes, ME, Dillon, DA, Partridge, AH, Wagle, N, Krop, IE, Getz, G, Golub, TR, J Love, C, Winer, EP, Tolaney, SM, Lin, NU, Adalsteinsson, VA
JournalJ Clin Oncol
PagesJCO2017760033
Date Published2018 Jan 03
ISSN1527-7755
Abstract

Purpose Cell-free DNA (cfDNA) offers the potential for minimally invasive genome-wide profiling of tumor alterations without tumor biopsy and may be associated with patient prognosis. Triple-negative breast cancer (TNBC) is characterized by few mutations but extensive somatic copy number alterations (SCNAs), yet little is known regarding SCNAs in metastatic TNBC. We sought to evaluate SCNAs in metastatic TNBC exclusively via cfDNA and determine if cfDNA tumor fraction is associated with overall survival in metastatic TNBC. Patients and Methods In this retrospective cohort study, we identified 164 patients with biopsy-proven metastatic TNBC at a single tertiary care institution who received prior chemotherapy in the (neo)adjuvant or metastatic setting. We performed low-coverage genome-wide sequencing of cfDNA from plasma. Results Without prior knowledge of tumor mutations, we determined tumor fraction of cfDNA for 96.3% of patients and SCNAs for 63.9% of patients. Copy number profiles and percent genome altered were remarkably similar between metastatic and primary TNBCs. Certain SCNAs were more frequent in metastatic TNBCs relative to paired primary tumors and primary TNBCs in publicly available data sets The Cancer Genome Atlas and METABRIC, including chromosomal gains in drivers NOTCH2, AKT2, and AKT3. Prespecified cfDNA tumor fraction threshold of ≥ 10% was associated with significantly worse metastatic survival (median, 6.4 v 15.9 months) and remained significant independent of clinicopathologic factors (hazard ratio, 2.14; 95% CI, 1.4 to 3.8; P < .001). Conclusion We present the largest genomic characterization of metastatic TNBC to our knowledge, exclusively from cfDNA. Evaluation of cfDNA tumor fraction was feasible for nearly all patients, and tumor fraction ≥ 10% is associated with significantly worse survival in this large metastatic TNBC cohort. Specific SCNAs are enriched and prognostic in metastatic TNBC, with implications for metastasis, resistance, and novel therapeutic approaches.

DOI10.1200/JCO.2017.76.0033
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/29298117?dopt=Abstract

Alternate JournalJ. Clin. Oncol.
PubMed ID29298117