Identification of Atypical Circulating Tumor Cells with Prognostic Value in Metastatic Breast Cancer Patients.

Alexia Lopresti,Pascal Finetti,Olivier Cabaud,Jihane Pakradouni,Emilie Denicolai,Arnaud Guille,Anthony Goncalves,Anaïs Aulas,Claire Acquaviva,François Bertucci,Daniel Birnbaum,Laurys Boudin,Quentin Da Costa,Maria Lucia Liberatoscioli,Séverine Garnier,Emilie Mamessier,Alexandre De Nonneville

doi:10.3390/cancers14040932

Abstract

Simple SummaryIn this study we have isolated and analyzed atypical cells found in the blood of metastatic breast cancer patients using a micro-filtration technic. This technic, being very easy to implement, was also extremely useful for studying circulating tumors cells’ (CTCs) heterogeneity in cancer patients. We highlighted three subsets of CTCs, with different independent unfavorable prognostic values for progression-free and overall survival. We demonstrated that these cells can further be analyzed by immunofluorescence to narrow their molecular profiles and identify specific characteristics. Moreover, we identified a subset of CTCs, for which positivity might be a useful stratification tool to select patients more susceptible to benefit from early clinical trials testing novel therapeutics, which frequently enroll late-stage, already heavily pre-treated and thus poor-responder patients.Circulating tumor cells have a strong potential as a quasi-non-invasive tool for setting up a precision medicine strategy for cancer patients. Using a second-generation “filtration-based” technology to isolate CTCs, the Screencell™ technology (Sarcelles, France), we performed a large and simultaneous analysis of all atypical circulating tumor cells (aCTCs) isolated from the blood of metastatic breast cancer (mBC) patients. We correlated their presence with clinicopathological and survival data. We included 91 mBC patients from the PERMED-01 study. The median number of aCTCs was 8.3 per mL of blood. Three subsets of aCTCs, absent from controls, were observed in patients: single (s-aCTCs), circulating tumor micro-emboli (CTM), and giant-aCTCs (g-aCTCs). The presence of g-aCTCs was associated with shorter progression free survival and overall survival. This study highlights the heterogeneity of aCTCs in mBC patients both at the cytomorphological and molecular levels. In addition, it suggests the usefulness of the g-aCTC subset as a prognostic factor and a potential stratification tool to treat late-stage mBC patients and improve their chances of benefiting from early clinical trials.

Highlights

Metastases are responsible for more than 90% of cancer-associated mortality
Ninety-one metastatic breast cancer (mBC) patients enrolled in the PERMED-01 trial were included
CTshoefsh‐ayCbTriCdsEd/idMnsotat tsuhso(wg-aaCnTyCp0re+feEre/nMtia0l) pdaisttpelranyefodr a 6-month progression-free survival (PFS) of 71% vs. 17% for patients with both positive status (g-atypical circulating tumor cells (aCTCs) 1 + E/M 1) and 40% for patients not matching these classes (g-aCTC 0 + E/M 1 and giant-atypical CTC (g-aCTC) 1 + EM0) (p = 1.12 × 10−2, log-rank test)

Summary

Introduction

Metastases are responsible for more than 90% of cancer-associated mortality. Anticipating and understanding their evolution using simple and reliable biomarkers is paramount. CTC sampling is minimally invasive and can be repeated on demand. It represents an “easy” access to distant tumor lesions. In metastatic breast cancer (mBC) patients, variation in CTC counts during chemotherapy is predictive for disease progression and survival on a real-time basis, as therapy proceeds [3,4]. CTCs’ prognostic value has a poor added clinical utility in metastatic patients and remains unproven in non-metastatic patients [2,5]

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