title: Circulating tumor cells: exploring intratumor heterogeneity of colorectal cancer.
abstract: The hypothesis of the "liquid biopsy" using circulating tumor cells (CTCs) emerged as a minimally invasive alternative to traditional tissue biopsy to determine cancer therapy. Discordance for biomarkers expression between primary tumor tissue and circulating tumor cells (CTCs) has been widely reported, thus rendering the biological characterization of CTCs an attractive tool for biomarkers assessment and treatment selection. Studies performed in metastatic colorectal cancer (mCRC) patients using CellSearch, the only FDA-cleared test for CTCs assessment, demonstrated a much lower yield of CTCs in this tumor type compared with breast and prostate cancer, both at baseline and during the course of treatment. Thus, although attractive, the possibility to use CTCs as therapy-related biomarker for colorectal cancer patients is still limited by a number of technical issues mainly due to the low sensitivity of the CellSearch method. In the present study we found a significant discordance between CellSearch and AdnaTest in the detection of CTCs from mCRC patients. We then investigated KRAS pathway activating mutations in CTCs and determined the degree of heterogeneity for KRAS oncogenic mutations between CTCs and tumor tissues. Whether KRAS gene amplification may represent an alternative pathway responsible for KRAS activation was further explored. KRAS gene amplification emerged as a functionally equivalent and mutually exclusive mechanism of KRAS pathway activation in CTCs, possibly related to transcriptional activation. The serial assessment of CTCs may represent an early biomarker of treatment response, able to overcome the intrinsic limit of current molecular biomarkers represented by intratumor heterogeneity.
authors: Dipartimento Medicina Molecolare; Sapienza Università di Roma; Rome, Italy.
authors: Cristina
authors: C
authors: Raimondi
authors: Dipartimento Medicina Molecolare; Sapienza Università di Roma; Rome, Italy.
authors: Chiara
authors: C
authors: Nicolazzo
authors: Dipartimento Medicina Molecolare; Sapienza Università di Roma; Rome, Italy.
authors: Angela
authors: A
authors: Gradilone
authors: Dipartimento Medicina Molecolare; Sapienza Università di Roma; Rome, Italy.
authors: Giuseppe
authors: G
authors: Giannini
authors: Dipartimento di Scienze Medico-Chirurgiche, Sapienza Università di Roma Polo Pontino; Rome, Italy.
authors: Elena
authors: E
authors: De Falco
authors: Dipartimento di Scienze Medico-Chirurgiche, Sapienza Università di Roma Polo Pontino; Rome, Italy.
authors: Isotta
authors: I
authors: Chimenti
authors: Diachem s.r.l.; Naples, Italy.
authors: Elisa
authors: E
authors: Varriale
authors: Adnagen GmbH; Langenhagen, Germany.
authors: Siegfried
authors: S
authors: Hauch
authors: Adnagen GmbH; Langenhagen, Germany.
authors: Linda
authors: L
authors: Plappert
authors: Dipartimento Scienze Radiologiche, Oncologiche ed Anatomopatologiche; Sapienza Università di Roma; Rome, Italy.
authors: Enrico
authors: E
authors: Cortesi
authors: Dipartimento Medicina Molecolare; Sapienza Università di Roma; Rome, Italy.
authors: Paola
authors: P
authors: Gazzaniga
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005784:Gene Amplification; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating / Q000378:metabolism / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: KRAS; biomarker; circulating tumor cells; colorectal cancer; tumor heterogeneity