Circulating tumor DNA and circulating tumor cells in metastatic triple negative breast cancer patients

Abstract

Circulating tumor DNA (ctDNA) is a new circulating tumor biomarker which might be used as a prognostic biomarker in a way similar to circulating tumor cells (CTCs). Here, we used the high prevalence of TP53 mutations in triple negative breast cancer (TNBC) to compare ctDNA and CTC detection rates and prognostic value in metastatic TNBC patients. Forty patients were enrolled before starting a new line of treatment. TP53 mutations were characterized in archived tumor tissues and in plasma DNA using two next generation sequencing (NGS) platforms in parallel. Archived tumor tissue was sequenced successfully for 31/40 patients. TP53 mutations were found in 26/31 (84%) of tumor samples. The same mutation was detected in the matched plasma of 21/26 (81%) patients with an additional mutation found only in the plasma for one patient. Mutated allele fractions ranged from 2 to 70% (median 5%). The observed correlation between the two NGS approaches (R 2 5 0.903) suggested that ctDNA levels data were quantitative. Among the 27 patients with TP53 mutations, CTC count was 1 in 19 patients (70%) and 5 in 14 patients (52%). ctDNA levels had no prognostic impact on time to progression (TTP) or overall survival (OS), whereas CTC numbers were correlated with OS (p 5 0.04) and marginally with TTP (p 5 0.06). Performance status and elevated LDH also had significant prognostic impact. Here, absence of prognostic impact of baseline ctDNA level suggests that mechanisms of ctDNA release in metastatic TNBC may involve, beyond tumor burden, biological features that do not dramatically affect patient outcome.Triple negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancer cases and are defined by a lack of both estrogen and progesterone receptors expression, and the absence of HER2 amplification. 1 Notwithstanding high molecular heterogeneity within this breast cancer subtype, TNBCs frequently display TP53 inactivating mutations, and adverse clinico-pathological features. 2 At the metastatic stage, TNBC is associated with worse prognosis than hormone receptor-positive or HER2-amplified metastatic breast cancers. Conventional systemic chemotherapy is the only therapeutic option for most metastatic TNBC patients as there are no validated targetable molecular alterations. 3 In the absence of a predictive biomarker of response to chemotherapy, current treatment management consists of radiological evaluation of metastases burden at regular intervals. In this clinical setting, blood-borne dynamic biomarkers with

Cell-Free DNA and Circulating Tumor Cells: Comprehensive Liquid Biopsy Analysis in Advanced Breast Cancer

“…The results of our study confirm that CTCs levels at baseline are predictors of both PFS and OS and confirm that the detection of 5 cells per 7.5 mL of blood is the best cutoff point to stratify the patients' prognosis (22,32). In MBC, whereas the prognostic power of CTCs increases according to the number of cells, quantification of tumor-specific mutations in ctDNA has been shown to correlate significantly with tumor burden (33).…”

Clinical Applications of Circulating Tumor Cells and Circulating Tumor DNA as Liquid Biopsy

“…However, the dropout rate was considerable, and the analyses were restricted to a small cohort of patients. Recently, Madic and colleagues performed another comparative evaluation of CTCs and ctDNA in patients with triple-negative breast cancer ( 98 ). TP53 mutations were found in more than 80% of tumor and ctDNA samples.…”

Short report: Monitoring ESR1 mutations by circulating tumor DNA in aromatase inhibitor resistant metastatic breast cancer

“…17 The use of dPCR for ctDNA analysis has been reported previously for MBC, but only after deep sequencing of the primary tumor to define the non-recurrent driver mutations of TP53, PI3KCA or PTEN. 13,17,20,21 For ESR1, few activating mutations confined to codons 537 and 538 in exon 8 represent 74% of the described mutations, limiting the number of contributing designs 8 and the requirement for sequencing metastases. A more complex and non-invasive method for the determination of the ESR1 mutational status using a culture of circulating tumor cells has been described previously.…”