Circulating Tumor Cells in Patients with Breast Cancer Dormancy

Abstract

Purpose: The purpose of this study was to test the hypothesis that circulating tumor cells (CTCs) are present in patients many years after mastectomy without evidence of disease and that these CTCs are shed from persisting tumor in patients with breast cancer dormancy.Experimental Design: We searched for CTCs in 36 dormancy candidate patients and 26 age-matched controls using stringent criteria for cytomorphology, immunophenotype, and aneusomy.Results: Thirteen of 36 dormancy candidates, 7 to 22 years after mastectomy and without evidence of clinical disease, had CTCs, usually on more than one occasion. Only 1 of 26 controls had a possible CTC (no aneusomy). The statistical difference of these two distributions was significant (exact P ‫؍‬ 0.0043). The CTCs in patients whose primary breast cancer was just removed had a half-life measured in 1 to 2.4 hours. Conclusions:The CTCs that are dying must be replenished every few hours by replicating tumor cells somewhere in the tissues. Hence, there appears to be a balance between tumor replication and cell death for as long as 22 years in dormancy candidates. We conclude that this is one mechanism underlying tumor dormancy.

Single CpG hypermethylation, allele methylation errors, and decreased expression of multiple tumor suppressor genes in normal body cells of mutation‐negative early‐onset and high‐risk breast cancer patients

“…Single CpG methylation in TS genes even ranged from 2% to >15%. Although we cannot exclude BC dormancy or early‐stage second tumors, circulating tumor cells in these patients occur at very low concentrations of one tumor cell in the background of millions of blood cells and have an average half‐life of only 1–3 h after separation 40, 41. Similarly, cell‐free circulating DNA has a half‐life of approximately 14 h and is rapidly cleared from blood, if not replenished from apoptotic/necrotic cells every few hours 42.…”

The Interrelating Dynamics of Hypoxic Tumor Microenvironments and Cancer Cell Phenotypes in Cancer Metastasis

“…When hypoxic cells experience reoxygenation, ROS induced DNA damage may result in apoptosis [90,92]. Indeed the half-life of CTC ranges between 1 to 2.4 h, and after 24 h the number of CTC detection events reaches background levels [76]. However, the hypoxic microenvironmental conditions of the bone marrow fit well to an observed hypoxic CTC phenotype [46,86,93].…”

“…After their passage through the blood followed by settlement into the bone marrow, a subset of DTC are assumed to be able to survive in the hypoxic microenvironment of the bone marrow even for decades [76]. It is possible that these cells can then undergo the reverse reaction of EMT-mesenchymal epithelial transition (MET)-, remain as epithelial phenotypes or acquire a dormant state in the bone marrow and can contribute later to the pool of bone marrow metastases [2,77].…”

« Je te tiens, tu me tiens »… Dormance tumorale : un équilibre instable ?

“…La détection des cellules tumorales dormantes chez les patients en rémission complète est extrêmement difficile, mais a pu être rapportée dans quelques travaux. Par exemple, des cellules néoplasiques circulantes ont été identifiées chez des patientes en rémission complète jusqu'à 22 ans après le diagnostic initial de cancer du sein [2]. Toutefois, la plupart de nos connaissances dans ce domaine proviennent de modèles expérimen-taux où l'on s'efforce d'induire un état d'équilibre entre l'hôte et les cellules malignes.…”