Association of Circulating Tumor DNA and Circulating Tumor Cells After Neoadjuvant Chemotherapy With Disease Recurrence in Patients With Triple-Negative Breast Cancer

Abstract

IMPORTANCE A significant proportion of patients with early-stage triple-negative breast cancer (TNBC) are treated with neoadjuvant chemotherapy. Sequencing of circulating tumor DNA (ctDNA) after surgery, along with enumeration of circulating tumor cells (CTCs), may be used to detect minimal residual disease and assess which patients may experience disease recurrence. OBJECTIVE To determine whether the presence of ctDNA and CTCs after neoadjuvant chemotherapy in patients with early-stage TNBC is independently associated with recurrence and clinical outcomes. DESIGN, SETTING, AND PARTICIPANTSA preplanned secondary analysis was conducted from March 26, 2014, to December 18, 2018, using data from 196 female patients in BRE12-158, a phase 2 multicenter randomized clinical trial that randomized patients with early-stage TNBC who had residual disease after neoadjuvant chemotherapy to receive postneoadjuvant genomically directed therapy vs treatment of physician choice. Patients had blood samples collected for ctDNA and CTCs at time of treatment assignment; ctDNA analysis with survival was performed for 142 patients, and CTC analysis with survival was performed for 123 patients. Median clinical follow-up was 17.2 months (range, 0.3-58.3 months).INTERVENTIONS Circulating tumor DNA was sequenced using the FoundationACT or FoundationOneLiquid Assay, and CTCs were enumerated using an epithelial cell adhesion molecule-based, positive-selection microfluidic device.MAIN OUTCOMES AND MEASURES Primary outcomes were distant disease-free survival (DDFS), disease-free survival (DFS), and overall survival (OS). RESULTS Among 196 female patients (mean [SD] age, 49.6 [11.1] years), detection of ctDNA was significantly associated with inferior DDFS (median DDFS, 32.5 months vs not reached; hazard ratio [HR], 2.99; 95% CI, 1.38-6.48; P = .006). At 24 months, DDFS probability was 56% for ctDNA-positive patients compared with 81% for ctDNA-negative patients. Detection of ctDNA was similarly associated with inferior DFS (HR, 2.67; 95% CI, 1.28-5.57; P = .009) and inferior OS (HR, 4.16; 95% CI,1.66-10.42; P = .002). The combination of ctDNA and CTCs provided additional information for increased sensitivity and discriminatory capacity. Patients who were ctDNA positive and CTC positive had significantly inferior DDFS compared with those who were ctDNA negative and CTC negative (median DDFS, 32.5 months vs not reached; HR, 5.29; 95% CI, 1.50-18.62; P = .009). At 24 months, DDFS probability was 52% for patients who were ctDNA positive and CTC positive compared with 89% for those who were ctDNA negative and CTC negative. Similar trends were observed for DFS (HR, 3.15; 95% CI, 1.07-9.27; P = .04) and OS (HR, 8.60; 95% CI, 1.78-41.47; P = .007). CONCLUSIONS AND RELEVANCEIn this preplanned secondary analysis of a randomized clinical trial, detection of ctDNA and CTCs in patients with early-stage TNBC after neoadjuvant chemotherapy was independently associated with disease recurrence, which represents an important stratification factor for future pos...

Practical classification of triple-negative breast cancer: intratumoral heterogeneity, mechanisms of drug resistance, and novel therapies

“…Accordingly, some tools, referred to as “liquid biopsies”, have been implemented to identify and quantify tumor fractions released into the peripheral blood, including circulating tumor cells (CTCs), exosomes, and circulating tumor DNA (ctDNA) 42 . Different studies highlighted that CTCs-based and ctDNA-based liquid biopsies are able to real-time monitor disease evolution and identify patient with high-risk of disease recurrence and poor prognosis 43 – 45 . In TNBC, ctDNA-based genome-wide profiling demonstrated to be useful in characterizing tumor-specific alterations, as well as in predicting patient prognosis 46 – 48 .…”

Challenges and achievements of liquid biopsy technologies employed in early breast cancer

“…The results showed that the detection of either ctDNA or CTCs is independently associated with recurrence. Both DFS and distant disease-free survival (DDFS) were inferior for patients with detectable ctDNA and CTCs in contrast to those with undetectable circulating analytes [65].…”

“… DFS was associated with ctDNA and CTCs detection. [65] Roth et al., 2010 cfmiRNAs RT-qPCR Total circulating RNA and serum miR155 concentration can differentiate patients with localized tumours from healthy individuals. miR-10b and miR-34a differentiates metastatic patients from healthy individuals.…”

“…Liquid biopsy is a non-invasive methodology which serves to obtain key tumour information and it is rapidly transforming the cancer patient's clinical management. The assessment of the tumour circulating components in the early and advanced setting is very well documented and it is also reflected in the multitude of commercial assays that use ctDNA to determine the tumour genetic profiles, the treatment response including resistance as well as a biomarker for disease monitoring [ 65 , 85 ]. Indeed, the clinical validity of liquid biopsy in the early breast cancer setting is more than evident; multitude of clinical trials, aiming to demonstrate that the clinical decision-making based on these circulating components could serve to increase patient´s survival, are on-going or already finished.…”

Circulating Tumor Cells and Bevacizumab Pharmacokinetics during Neoadjuvant Treatment Combining Chemotherapy and Bevacizumab for Early Breast Cancer: Ancillary Analysis of the AVASTEM Trial

“…CTC detection at diagnosis is also correlated to a poorer outcome with decreased disease-free survival and overall survival in chemonaive patients diagnosed with early breast cancer [ 10 , 11 ]. Moreover, CTC detection after neoadjuvant chemotherapy is associated with worst survival for early triple-negative breast cancer with residual disease after preoperative chemotherapy [ 12 ]. No data exist concerning CTC value to assess bevacizumab efficacy for early non-inflammatory breast cancer.…”