Cell-Free DNA Tumor Fraction and Somatic Copy Number Alterations May Affect Survival in Metastatic Triple-Negative Breast Cancer

Key Points

  • cf-DNA tumor fraction ≥ 10% was associated with significantly worse survival.
  • Several somatic copy number alterations were more common in metastatic triple-negative breast cancers, with chromosomal gain/amplification associated with poorer survival.

In a study reported in the Journal of Clinical Oncology, Stover et al found that cell-free (cf) DNA tumor fraction ≥ 10% was associated with worse survival in metastatic triple-negative breast cancer, and that several somatic copy number alterations are enriched and prognostic in metastatic disease.

Study Details

The retrospective cohort study involved 506 plasma samples from 164 patients with biopsy-proven metastatic triple-negative breast cancer at a single tertiary care institution who had received chemotherapy in the neoadjuvant/adjuvant or metastatic setting between August 2010 and November 2016. Low-coverage genome-wide sequencing of cfDNA from plasma was performed.

cfDNA and Somatic Copy Number Alterations

Without prior knowledge of extant tumor mutations, cfDNA tumor fraction was determined for 96.3% of patients and somatic copy number alterations for 63.9%.

Copy number profiles and percent genome altered were highly similar between metastatic and primary triple-negative breast cancers. Several somatic copy number alterations were more frequent in metastatic triple-negative breast cancers vs paired primary tumors and primary triple-negative breast cancers in publicly available data sets, including chromosomal gains in the drivers NOTCH2, AKT2, and AKT3. Gain/amplification of both 18q11 and 19p13 was associated with poorer survival in metastatic disease in multivariate analysis (hazard ratio [HR] = 3.30, P = .012), as well as in primary triple-negative breast cancers.

The prespecified cfDNA tumor fraction threshold of ≥ 10% was associated with significantly poorer overall survival in metastatic disease (median = 6.4 vs 15.9 months for < 10%), with the association remaining significant on multivariate analysis including clinicopathologic factors (HR = 2.14, P < .001).

The investigators concluded, “We present the largest genomic characterization of metastatic [triple-negative breast cancer] 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 [triple-negative breast cancer] cohort. Specific [somatic copy number alterations] are enriched and prognostic in metastatic [triple-negative breast cancer], with implications for metastasis, resistance, and novel therapeutic approaches.”

The study was supported by the Gerstner Family Foundation, Susan G. Komen for the Cure, The Pink Agenda, Breast Cancer Research Foundation, V Foundation for Cancer Research, and National Cancer Institute grants.

Viktor A. Adalsteinsson, PhD, of the Broad Institute of Harvard and Massachusetts Institute of Technology, is the corresponding author for the Journal of Clinical Oncology article. 

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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