Abstract
Evidence suggests that the DNA end-binding protein p53-binding protein 1 (53BP1) is down-regulated in subsets of breast cancer. Circulating tumor cells (CTCs) provide accessible “biopsy material” to track cell traits and functions and their alterations during treatment. Here, we prospectively monitored the 53BP1 status in CTCs from 67 metastatic breast cancer (MBC) patients with HER2- CTCs and known hormone receptor (HR) status of the primary tumor and/or metastases before, during, and at the end of chemotherapeutic treatment with Eribulin. Nuclear 53BP1 staining and genomic integrity were evaluated by immunocytochemical and whole-genome-amplification-based polymerase chain reaction (PCR) analysis, respectively. Comparative analysis of CTCs from patients with triple-negative and HR+ tumors revealed elevated 53BP1 levels in CTCs from patients with HR+ metastases, particularly following chemotherapeutic treatment. Differences in nuclear 53BP1 signals did not correlate with genomic integrity in CTCs at baseline or with nuclear γH2AX signals in MBC cell lines, indicating that 53BP1 detected features beyond DNA damage. Kaplan–Meier analysis revealed an increasing association between nuclear 53BP1-positivity and progression-free survival (PFS) during chemotherapy until the final visit. Our data suggest that 53BP1 detection in CTCs could be a useful marker to capture dynamic changes of chemotherapeutic responsiveness in triple-negative and HR+ MBC.
Highlights
Triple-negative breast cancer (TNBC), which is diagnosed in 10–15% of all metastatic breast cancer (MBC), affects younger patients and patients with a mutation in BRCA genes more frequently
Accumulating evidence has demonstrated that loss of 53BP1 expression in breast cancer is associated with poor prognosis, when focusing on TNBC patients [7,9]
We aimed at detecting 53BP1 in Circulating tumor cells (CTCs) of MBC patients with defined HER2 and hormone receptor (HR) status to explore its potential as a biomarker
Summary
Triple-negative breast cancer (TNBC), which is diagnosed in 10–15% of all MBCs, affects younger patients and patients with a mutation in BRCA genes more frequently. Often patients develop a resistance to first-line chemotherapy very rapidly, resulting in a median duration of first-line palliative chemotherapy of 11.9 weeks [1]. A mutation in BRCA1 or 2 is found in up to 20% of triple-negative metastatic patients [2]. The proteins encoded by BRCA genes are critically involved in DNA double-strand break (DSB) repair, in the error-free pathway of homologous recombination repair (HRR) [3]. In TNBC, a high prevalence of gene mutations as well as epigenetic changes result in BRCAness, compromising safe DNA repair through HRR [2,4,5]
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