Heterogeneity of Epidermal Growth Factor Receptor Status and Mutations of KRAS/PIK3CA in Circulating Tumor Cells of Patients with Colorectal Cancer

Gasch, Christin; Bauernhofer, Thomas; Pichler, Martin; Langer-Freitag, Sabine; Reeh, Matthias; Seifert, Adrian M.; Mauermann, Oliver; Izbicki, Jakob R.; Pantel, Klaus; Riethdorf, Sabine

doi:10.1373/clinchem.2012.188557

Cited by 213 publications

(194 citation statements)

References 40 publications

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“…Here, we also observed that 33% of CTCs samples showed KRAS mutation. This result is similar to previous findings published by Gasch et al,20 that verified the presence of mutation in KRAS in 1 of the 5 CTCs of mCRC patient studied and the same mutation was observed in primary tumor.…”

Section: Discussionsupporting

confidence: 93%

“…Concerning this level of agreement found by our group and others 7,19,20 between CTCs and primary tumors, it has been hypothesized that the development of resistance to EGFR therapy is caused by rare cells with KRAS mutations that pre exist at low levels in mCRC with apparent KRAS wt. 22 Diaz et al 22 tested this hypothesis by analyzing 24 patients with mCRC, all of them with KRAS wt in primary tumor and resistant to anti-EGFR therapy.…”

Section: Discussionsupporting

confidence: 62%

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Detection of KRAS mutations in circulating tumor cells from patients with metastatic colorectal cancer

Buim

Fanelli

Souza

et al. 2015

Cancer Biology & Therapy

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Background: Quantification of Circulating Tumor Cells (CTCs) as a prognostic marker in metastatic colorectal cancer (mCRC) has already been validated and approved for routine use. However, more than quantification, qualification or characterization of CTCs is gaining importance, since the genetic characterization of CTCs may reflect, in a real time fashion, genetic profile of the disease. Objective: To characterize KRAS mutations (codon 12 and 13) in CTCs from patients with mCRC and to compare with matched primary tumor. Additionally, correlate these mutations with clinical and pathological features of patients. Methods: Blood samples were collected from 26 patients with mCRC from the AC Camargo Cancer Center (São Paulo-Brazil). CTCs were isolated by ISET technology (Isolation by Size of Epithelial Tumors; Rarecells Diagnostics, France) and mutations analyzes were performed by pyrosequencing (QIAGEN). Results: KRAS mutation was detected in 7 of the 21 cases (33%) of samples from CTCs. In matched primary tumors, 9 of the 24 cases (37.5%) were found KRAS mutated. We observed that 5 of the 9 samples with KRAS mutation in their primary tumor had also KRAS mutation in CTCs, meaning a concordance of 71% of matched cases (P D 0.017). KRAS mutation neither on primary tumor nor in CTCs was associated with clinical-pathological parameters analyzed. Conclusion: Faced with a polyclonal disease like colorectal cancer, which is often treated with alternating and successive lines of chemotherapy, real time genetic characterization of CTCs, in a fast and feasible fashion, can provide important information to clinical management of metastatic patients. Although our cohort was limited, it was possible to show a high grade of concordance between primary tumor and CTCs, which suggests that CTCs can be used as surrogate of primary tumors in clinical practice, when the knowledge of mutation profile is necessary and the primary tumor is not available.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 62%

Detection of KRAS mutations in circulating tumor cells from patients with metastatic colorectal cancer

Buim

Fanelli

Souza

et al. 2015

Cancer Biology & Therapy

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“…27 Few studies have explored in small series of mCRC patients the correlation between KRAS mutational status in primary or metastatic tumor and in CTCs, revealing further mutational discordance, possibly complicating the selection of patients candidate for anti-EGFR treatments. [28][29][30][31][32][33] Our results confirm a divergent KRAS status in a large proportion of cases, highlighting that KRAS wild-type CTCs are frequently detected in peripheral blood of patients harboring mutated primary tumors. As potential mechanism to explain the relative prevalence of wild type KRAS CTCs, 34 the generation of hypoxia in large advanced tumors or induced by treatments has been evoked.…”

Section: Discussionsupporting

confidence: 71%

Circulating tumor cells

Raimondi

Nicolazzo

Gradilone

et al. 2014

Cancer Biology & Therapy

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“…[23,[54][55][56][57] Another previous study demonstrated potentially clinical application in detection of KRAS mutational in CTCs for selecting metastatic colorectal cancer patients for cetuximab therapy. [58] In addition, recent development of molecular and genetic characterization of single-CTC demonstrated that there was intra-and inter-heterogeneity of EGFR expression and genetic alterations of EGFR, KRAS and PIK3CA, [59] Therefore, the information on the molecular status of CTCs might be useful for stratifi cation of molecular-directed therapy.…”

Section: Colorectal Cancermentioning

confidence: 99%

The clinical significance of circulating tumor cells in gastrointestinal cancer

Iwatsuki¹,

Kurashige²,

Ishimoto³

et al. 2015

J Cancer Metastasis Treat

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A B S T R A C TCirculating tumor cells (CTCs) are originated from the primary tumor lesion into the blood stream. CTCs could lead to recurrence of gastrointestinal (GI) cancers, even after a curative resection and colonizing in the distant organs to facilitate tumor distant metastasis; however, it has been challenging in clinic to detect CTCs for a long time, such as detection methodology or molecular markers for identifi cation of CTCs. This review discussed the recent technical advances and biomarkers in the detection of CTCs and the molecular mechanism of CTC in cancer progression and metastasis. Moreover, novel concepts, such as cancer stem cells and epithelial-mesenchymal transition, could lead to CTCs and tumor progression and metastasis. Nevertheless, the involvement of CTCs varies greatly among cancer types in the GI and much remains to be learned. Thus, further study will provide more insightful information from a clinical and translational viewpoint to use CTCs for cancer early diagnosis or prediction of tumor recurrence and investigation of tumor progression and metastasis as well.

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Heterogeneity of Epidermal Growth Factor Receptor Status and Mutations of KRAS/PIK3CA in Circulating Tumor Cells of Patients with Colorectal Cancer

Cited by 213 publications

References 40 publications

Detection of KRAS mutations in circulating tumor cells from patients with metastatic colorectal cancer

Detection of KRAS mutations in circulating tumor cells from patients with metastatic colorectal cancer

Circulating tumor cells

The clinical significance of circulating tumor cells in gastrointestinal cancer

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