According to results from a retrospective study published in the <em>Journal of Clinical Oncology, </em>low-coverage genome-wide sequencing of cell-free DNA from plasma is capable of profiling cancer genomes from blood and predicting survival outcomes for patients with metastatic triple-negative breast cancer.
Heather Parsons, MD
According to results from a retrospective study published in theJournal of Clinical Oncology,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).
Tumor fraction of cfDNA (DNA from both cancerous and normal cells shed into bloodstream) have proven to be an independent prognostic biomarker in mTNBC. Results of the study suggest 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). In patients with a tumor fraction ≥10%, survival was 6.4 months in comparison to the 15.9 months in patients with lower tumor fractions.
Genome-wide data was used to identify specific abnormal genes that are altered more frequently in mTNBC than with primary cases of the disease. Investigators discovered that abnormal genes were associated with survival outcomes in the patient population with mTNBC.
“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," Daniel Stover, MD, co-corresponding author of the study and a breast medical oncologist/researcher with The Ohio State University Comprehensive Cancer CenterArthur G. James Cancer Hospital and Richard J. Solove Research Institute, explained. "For metastatic breast cancer patients, however, tissue biopsy can be risky or painful. 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.”
506 plasma samples were identified between August 2010 and November 2016 from 164 patients with biopsy-proven mTNBC. Chemotherapy was given to all patients before blood collection, primarily neoadjuvant or adjuvant anthracycline and taxane-based chemotherapy. The median follow-up time from metastatic diagnosis was 17 months (range, 0-82 months).
The only predictive subset was patients with mTNBC-enriched loci, with the loci 18q11 and 19p13 becoming the strongest predictors for poor metastatic survival. This surprised investigators since these loci have never been associated with TNBC survival. Over half of mTNBC tumors harbored gain/amplification of 18q11, 19p13, or both, significantly more frequent than in primary TNBCs (χ2P<.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-rankP= .038).
The frequency of gain or loss was compared by investigators 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 (NOTCH2on 1p,AKT3on 1q,GATA3on 10p, and AKT2 on 19q; Fisher’s exactP<.05). Four other genesCDKN2Aon 9p,PTENon 10q,RB1on 13q, andNF1on 17qdemonstrated single copy loss more frequently in primary TNBC (Fisher’s exactP<.05).
“This is a very challenging disease," Heather Parsons, MD, co-first author of the study and breast medical oncologist/researcher at Dana-Farber Cancer Institute and Harvard Medical School shared in a statement. "Our team's findingsand others enabled by liquid biopsy—could improve how we track disease and treat our patients in the clinic."
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.