The tumor fraction of cell-free DNA (cfDNA) sample can be used to predict survival in patients with metastatic triple-negative breast cancer (TNBC), investigators reported.
This suggests that determining cfDNA tumor fraction via a minimally invasive blood test can provide “important prognostic information beyond standard clinicopathologic factors,” according to Daniel G. Stover, MD, of the Ohio State University Comprehensive Cancer Center in Columbus, and colleagues.
A diagnosis of TNBC means that the breast cancer cells have tested negative for hormone epidermal growth factor receptor 2 (HER-2), and estrogen and progesterone receptors. TNBC accounts for 10% to 15% of breast cancers, yet is responsible for more than one-third of breast cancer deaths, the authors wrote in the Journal of Clinical Oncology.
They also noted that TNBC is characterized by relatively few mutations, but widespread somatic copy number alterations (SCNAs), suggesting SCNAs play a critical from in the formation of TNBC tumors. Stover’s group evaluated SCNAs in metastatic TNBC via cfDNA to determine whether cfDNA tumor fraction was associated with overall metastatic TNBC survival.
For this retrospective cohort study, they identified 506 plasma samples from 164 patients with biopsy-proven metastatic TNBC. All patients received chemotherapy before blood collection, with most patients receiving neoadjuvant or adjuvant anthracycline and taxane-based chemotherapy.
The researchers used an algorithm, ichorCNA, to profile SCNAs and quantify tumor fraction (TFx) in cfDNA from low-coverage whole-genome sequencing without prior knowledge of the genomic changes in the patient’s tumor.
Stover’s group was able to determine tumor fraction of cfDNA for 158 patients (96.3%). Also, 101 of those 158 patients (63.9%) had at least one sample with TFx equal to or greater than the prespecified cfDNA tumor fraction threshold of 10%.
Crucially, they found that patients with the higher tumor fraction of ≥10% was associated with a “significantly shorter survival” — median 6.4 months versus 15.9 months — and that this association remained significant independent of clinicopathologic factors (hazard ratio 2.14, 95% CI 1.4-3.8).
The analysis also identified several genes — NOTCH2, AKT2, and AKT3 — that had copy number gains enriched in metastatic TNBCs relative to primary TNBCs. In an accompanying commentary, Sarah-Jane Dawson, MD, PhD, of the Peter MacCallum Cancer Center in Melbourne, Australia, and colleague observed that this “sheds light on important genes and signaling pathways that may be perturbed in metastatic disease.”
Stover’s group also found that more than half of metastatic TNBCs harbored gains or amplification of 18q11, 19p13, or both, which was significantly more frequent than in primary TNBCs. “Gain or amplification of both regions identifies a subset of TNBC rapid progressors with remarkably poor survival in the metastatic, and also the primary setting,” they wrote.
The study illustrates a “framework for minimally invasive genomic characterization of metastatic cancer and subsequent integration with clinicopathologic data and patient outcomes,” the authors noted. “This approach has the potential to reveal clinically useful biomarkers while identifying unique genomic features of metastatic cancer and may advance our understanding of metastasis, drug resistance, and novel therapeutic targets.”
Dawson’s group wrote that with “the current lack of prognostic markers in metastatic TNBC, a reliable marker that can be obtained using a minimally invasive blood draw could have important implications.”
They also pointed out that it was important to note that the SCNA analysis was only performed on those patients (63.9% of the cohort) whose TFx was ≥10%. “High-confidence copy number calls could not be achieved for samples with a TFx < 10%, " they wrote, adding this would "limit the applicability of this approach in patients with early-stage disease."
But considering the challenges posed by the heterogeneity of TNBC, and the lack of targeted therapeutic options in treating the disease, the “era of comprehensive molecular characterization promises to pave the way forward,” Dawson’s group wrote.
The study was supported by the Gerstner Family Foundation, Susan G. Komen for the Cure, The Pink Agenda, Breast Cancer Research Foundation, the V Foundation for Cancer Research, and Dana-Farber/Harvard Cancer Center National Cancer Institute Specialized Programs of Research Excellence in Breast Cancer.
Stover disclosed no relevant relationships with industry. Co-authors disclosed multiple relevant relationships with industry.
Dawson and co-author disclosed support from Cancer Therapeutics CRC, the National Breast Cancer Foundation, the Victorian Cancer Agency, and the National Health and Medical Research Council of Australia.
F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner