Liquid Biopsy Demonstrates Prognostic Potential in Metastatic TNBC

Heather Parsons, MD

Low-coverage genome-wide sequencing of cell-free DNA (cfDNA) from plasma is capable of profiling cancer genomes from blood and predicting survival outcomes for patients with metastatic triple-negative breast cancer (mTNBC), according to results from a retrospective study published in the Journal of Clinical Oncology.

Tumor fraction of cfDNA (DNA from both cancerous and normal cells shed into bloodstream) proved to be an independent prognostic biomarker in mTNBC. Investigators determined that a tumor fraction of ≥10%, identified in 64% of the cohort, correlated with poor survival outcomes in patients with metastatic TNBC (HR, 2.14; 95% CI, 1.4-3.8; P <.001). Survival was 6.4 months for patients with a tumor fraction ≥10% compared with 15.9 months for those with a lower tumor fraction.

Investigators also used genome-wide data to identify specific abnormal genes that are more frequently altered in mTNBC compared with primary cases of the disease. They found that those abnormal genes were associated with survival outcomes in the mTNBC patient population.

“Traditionally, we would need to obtain a tissue biopsy to perform the whole genome sequencing tests that could reveal potential DNA-level mutations driving a patient's specific cancer. For metastatic breast cancer patients, however, tissue biopsy can be risky or painful,” Daniel Stover, MD, co-corresponding author of the study and a breast medical oncologist/researcher with The Ohio State University Comprehensive Cancer Center—Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, said in a statement.

“Being able to do this type of genomic analysis from a simple blood draw allows us to get a picture of a patient’s specific cancer genomic characteristics in a less invasive way,” added Stover.

Investigators identified 506 plasma samples between August 2010 and November 2016 from 164 patients with biopsy-proven mTNBC. All patients received chemotherapy before blood collection, primarily neoadjuvant or adjuvant anthracycline and taxane-based chemotherapy. The median time to follow-up from metastatic diagnosis was 17 months (range, 0-82 months).

Only a subset of mTNBC-enriched loci were predictive. The loci 18q11 and 19p13 were the strongest predictors for poor metastatic survival, which surprised investigators because those loci have never been associated with TNBC survival. More than half of mTNBC tumors harbored gain/amplification of 18q11, 19p13, or both, significantly more frequent than in primary TNBCs (χ² P <.001).

Gain/amplification of both 18q11 and 19p13 was strongly associated with poorer survival in both univariate analyses and multivariable Cox proportional hazard models that included clinicopathologic factors and tumor fraction (HR, 3.30; 95% CI, 1.30-8.38; P =.012). Gain/amplification of those loci was also associated with poor prognosis in primary TNBC (log-rank P = .038).

Investigators compared frequency of gain or loss for 25 cancer-related genes commonly altered in breast cancer between primary tumor panel sequencing and metastatic low-coverage cfDNA sequencing. Four genes demonstrated greater frequency of gain in mTNBC versus primary TNBC samples (NOTCH2 on 1p, AKT3 on 1q, GATA3 on 10p, and AKT2 on 19q; Fisher’s exact P <.05). Four other genes—CDKN2A on 9p, PTEN on 10q, RB1 on 13q, and NF1 on 17q—demonstrated single copy loss more frequently in primary TNBC (Fisher’s exact P <.05).

“This is a very challenging disease. Our team's findings—and others enabled by liquid biopsy—could improve how we track disease and treat our patients in the clinic," says Heather Parsons, MD, co-first author of the study and breast medical oncologist/researcher at Dana-Farber Cancer Institute and Harvard Medical School, said in a statement.

Stover DG, Parsons HA, Ha G, et al. Association of cell-free DNA tumor fraction and somatic copy number alterations with survival in metastatic triple-negative breast cancer. J Clin Oncol. 2018; 36:543-553. doi: 10.1200/JCO.2017.76.0033.