A novel circulating tumor cell subpopulation for treatment monitoring and molecular characterization in biliary tract cancer. Issue 12 (19th December 2019)

• Record Type: Journal Article
• Authors: Reduzzi, Carolina; Vismara, Marta; Silvestri, Marco; Celio, Luigi; Niger, Monica; Peverelli, Giorgia; De Braud, Filippo; Daidone, Maria G.; Cappelletti, Vera
• Is Part Of: International journal of cancer. Volume 146:Issue 12(2020)
• Page Start: 3495
• Page End: 3503
• Publication Date: 2019-12-19
• Subjects: biliary tract cancer -- liquid biopsy -- single cell -- WGS -- copy number alterations; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.32822
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : In biliary tract cancer (BTC), tissue biopsies to guide treatment are rarely feasible, thus implementing liquid biopsy approaches to improve patient management represents a priority. So far, studies on circulating tumor cells (CTCs) in BTC are insufficient to promote their use in patient clinical management and are limited to EpCAM‐enriched CTCs evaluated with the CellSearch. We applied a single‐cell protocol allowing identification not only of epithelial CTCs (eCTCs), but also of nonconventional CTCs (ncCTCs) lacking epithelial and leukocyte markers, but presenting aberrant genomes as confirmed by copy number alterations and therefore representing a distinct subpopulation of bona fide CTCs. In 41 blood samples longitudinally collected from 21 patients with advanced‐stage BTC, addition of ncCTC to classic eCTC led to a CTC‐positivity increase from 19% to 83%. Patients presenting with at least 1 eCTC/10 ml of blood at baseline prior to treatment start had a significantly shorter median disease‐specific survival (DSS) compared to those lacking eCTCs (9 months vs . 19 months, p = 0.03 by log‐rank test). No differences in DSS were observed according to ncCTC‐positivity, conversely, variations in ncCTC counts during, and at the end of treatment, were associated with the RECIST response supporting their role in treatment monitoring. Moreover, in 88 ncCTCs collected at different times during treatment, unsupervised clustering evidenced segregation of cells by patient's best response, allowing identification of genomic regions possibly involved in resistance mechanisms. The presence of ncCTCs beside eCTCs opens the way to exploiting liquid biopsy for optimizing clinical management in BTC. Abstract : What's new? Late diagnosis of advanced biliary tract cancer (BTC) limits tissue biopsy for molecular analyses, resulting in missed opportunities for personalized therapy. Meanwhile, circulating tumor cells (CTCs) are promising tissue surrogates, but current CTC‐based methods detect only a fraction of BTC patients. Here, using unbiased CTC‐enrichment, coupled with identification and recovery of single cells, the authors identify a novel CTC subpopulation detectable in all BTC patient samples prior to treatment. The presence of even a single epithelial CTC was associated with reduced disease‐specific survival. This novel approach to CTC detection could be useful for treatment‐response monitoring and molecular characterization in BTC.