nach oben

Erschienen in:

09.08.2018 | Original Article

Prognostic significance of CEACAM5mRNA-positive circulating tumor cells in patients with metastatic colorectal cancer

verfasst von: Ippokratis Messaritakis, Maria Sfakianaki, Chara Papadaki, Asimina Koulouridi, Nikolaos Vardakis, Filippos Koinis, Dora Hatzidaki, Nefeli Georgoulia, Athina Kladi, Athanasios Kotsakis, John Souglakos, Vassilis Georgoulias

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 5/2018

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Τo evaluate the clinical relevance of CEACAM5mRNA-positive circulating tumor cells (CTCs) in patients with metastatic colorectal cancer (mCRC).

Methods

Peripheral blood was obtained from 436 patients with mCRC before the initiation of systemic therapy. A second sample was obtained on treatment assessment from 296 (67.9%) patients. The detection of CEACAM5mRNA-positive CTCs was performed using a real-time PCR assay.

Results

The patients’ median age was 67 years and PS (EGOG 0–1) 92%; KRAS exon 2 and BRAF^V600E mutated primary tumors were identified in 31.9% and 6.4% of the tested patients, respectively, whereas metastasectomy was performed in 17.7% of the patients. Circulating CEACAM5mRNA-positive CTCs were detected in 125 (28.7%) and 85 (28.7%) patients at baseline and on treatment assessment, respectively. The detection of CEACAM5mRNA-positive cells was revealed, in multivariate analysis, as an independent prognostic factor associated with decreased PFS (HR 1.6; 95% CI 1.1–2.5; p = 0.026) and OS (HR 2.2; 95% CI 1.3–3.2; p < 0.001). The detection of CEACAM5mRNA-positive CTCs in patients with KRAS and BRAF^V600E mutations was correlated with shorter PFS (p = 0.041 and p = 0.022, respectively). Moreover, OS was significantly shorter in patients with CEACAM5+/KRAS mutations compared to those with CEACAM5+/KRAS wt tumors (p = 0.023).

Conclusions

Detection of peripheral blood CEACAM5mRNA-positive CTCs is an adverse prognostic factor correlated with poor clinical outcome in patients with mCRC, especially in patients with KRAS and BRAF mutated tumors.

Nur mit Berechtigung zugänglich

Ries LA et al (2000) The annual report to the nation on the status of cancer, 1973–1997, with a special section on colorectal cancer. Cancer 88(10):2398–2424CrossRef

Jemal A et al (2010) Cancer statistics, 2010. CA Cancer J Clin 60(5):277–300CrossRef

Jemal A et al (2009) Cancer statistics, 2009. CA Cancer J Clin 59(4):225–249CrossRef

De Mattos-Arruda L, Dienstmann R, Tabernero J (2011) Development of molecular biomarkers in individualized treatment of colorectal cancer. Clin Colorectal Cancer 10(4):279–289CrossRef

Sun YF et al (2011) Circulating tumor cells: advances in detection methods, biological issues, and clinical relevance. J Cancer Res Clin Oncol 137(8):1151–1173CrossRef

Toss A et al (2014) CTC enumeration and characterization: moving toward personalized medicine. Ann Transl Med 2(11):108PubMedPubMedCentral

Cabinakova M et al (2015) Predictive factors for the presence of tumor cells in bone marrow and peripheral blood in breast cancer patients. Neoplasma 62(2):259–268CrossRef

Daskalaki A et al (2009) Detection of cytokeratin-19 mRNA-positive cells in the peripheral blood and bone marrow of patients with operable breast cancer. Br J Cancer 101(4):589–597CrossRef

Grobe A et al (2014) Prognostic relevance of circulating tumor cells in blood and disseminated tumor cells in bone marrow of patients with squamous cell carcinoma of the oral cavity. Clin Cancer Res 20(2):425–433CrossRef

10.

Hartkopf AD et al (2014) Tumor cell dissemination to the bone marrow and blood is associated with poor outcome in patients with metastatic breast cancer. Breast Cancer Res Treat 147(2):345–351CrossRef

11.

Kruck S, Gakis G, Stenzl A (2012) Circulating and disseminated tumor cells in the management of advanced prostate cancer. Adv Urol 2012:135281CrossRef

12.

Lin H et al (2011) Disseminated and circulating tumor cells: role in effective cancer management. Crit Rev Oncol Hematol 77(1):1–11CrossRef

13.

Cohen SJ et al (2006) Isolation and characterization of circulating tumor cells in patients with metastatic colorectal cancer. Clin Colorectal Cancer 6(2):125–132CrossRef

14.

Cristofanilli M et al (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351(8):781–791CrossRef

15.

Androulakis N et al (2012) Clinical relevance of circulating CK-19mRNA-positive tumour cells before front-line treatment in patients with metastatic breast cancer. Br J Cancer 106(12):1917–1925CrossRef

16.

Hou JM et al (2012) Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer. J Clin Oncol 30(5):525–532CrossRef

17.

Okegawa T, Nutahara K, Higashihara E (2009) Prognostic significance of circulating tumor cells in patients with hormone refractory prostate cancer. J Urol 181(3):1091–1097CrossRef

18.

Naito T et al (2012) Prognostic impact of circulating tumor cells in patients with small cell lung cancer. J Thorac Oncol 7(3):512–519CrossRef

19.

de Albuquerque A et al (2012) Prognostic and predictive value of circulating tumor cell analysis in colorectal cancer patients. J Transl Med 10:222CrossRef

20.

Matikas A et al (2017) Detection of KRAS exon 2 mutations in circulating tumor cells isolated by the ISET system from patients with RAS wild type metastatic colorectal cancer. Transl Oncol 10(4):693–698CrossRef

21.

Vardakis N et al (2011) Prognostic significance of the detection of peripheral blood CEACAM5mRNA-positive cells by real-time polymerase chain reaction in operable colorectal cancer. Clin Cancer Res 17(1):165–173CrossRef

22.

Liefers GJ et al (1998) Micrometastases and survival in stage II colorectal cancer. N Engl J Med 339(4):223–228CrossRef

23.

Schott A et al (1998) Isolated tumor cells are frequently detectable in the peritoneal cavity of gastric and colorectal cancer patients and serve as a new prognostic marker. Ann Surg 227(3):372–379CrossRef

24.

Stathopoulou A et al (2003) Real-time quantification of CK-19 mRNA-positive cells in peripheral blood of breast cancer patients using the lightcycler system. Clin Cancer Res 9(14):5145–5151PubMed

25.

Gerhard M et al (1994) Specific detection of carcinoembryonic antigen-expressing tumor cells in bone marrow aspirates by polymerase chain reaction. J Clin Oncol 12(4):725–729CrossRef

26.

Goeminne JC, Guillaume T, Symann M (2000) Pitfalls in the detection of disseminated non-hematological tumor cells. Ann Oncol 11(7):785–792CrossRef

27.

Burchill SA et al (1995) Detection of epithelial cancer cells in peripheral blood by reverse transcriptase-polymerase chain reaction. Br J Cancer 71(2):278–281CrossRef

28.

Mori M et al (1996) Molecular detection of circulating solid carcinoma cells in the peripheral blood: the concept of early systemic disease. Int J Cancer 68(6):739–743CrossRef

29.

Hampton R et al (2002) Differential expression of carcinoembryonic antigen (CEA) splice variants in whole blood of colon cancer patients and healthy volunteers: implication for the detection of circulating colon cancer cells. Oncogene 21(51):7817–7823CrossRef

30.

Ko Y et al (1998) Limitations of the reverse transcription-polymerase chain reaction method for the detection of carcinoembryonic antigen-positive tumor cells in peripheral blood. Clin Cancer Res 4(9):2141–2146PubMed

31.

Castells A et al (1998) Detection of colonic cells in peripheral blood of colorectal cancer patients by means of reverse transcriptase and polymerase chain reaction. Br J Cancer 78(10):1368–1372CrossRef

32.

Jung R et al (1998) Specificity of reverse transcriptase polymerase chain reaction assays designed for the detection of circulating cancer cells is influenced by cytokines in vivo and in vitro. Br J Cancer 78(9):1194–1198CrossRef

33.

Xenidis N et al (2009) Cytokeratin-19 mRNA-positive circulating tumor cells after adjuvant chemotherapy in patients with early breast cancer. J Clin Oncol 27(13):2177–2184CrossRef

34.

Saridaki Z et al (2011) Impact of KRAS, BRAF, PIK3CA mutations, PTEN, AREG, EREG expression and skin rash in ≥ 2 line cetuximab-based therapy of colorectal cancer patients. PLoS One 6(1):e15980CrossRef

35.

Douillard JY et al (2013) Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 369(11):1023–1034CrossRef

36.

Park YJ et al (1999) Prognostic factors in 2230 Korean colorectal cancer patients: analysis of consecutively operated cases. World J Surg 23(7):721–726CrossRef

37.

Souglakos J et al (2009) Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer. Br J Cancer 101(3):465–472CrossRef

38.

Saridaki Z, Papadatos-Pastos D, Tzardi M, Mavroudis D, Bairaktari E, Arvanity H, Stathopoulos E, Georgoulias V, Souglakos J (2010) BRAF mutations, microsatellite instability status and cyclin D1 expression predict metastatic colorectal patients’ outcome. Br J Cancer 102(12):1762–1768CrossRef

39.

Vlems FA et al (2003) Detection of disseminated tumour cells in blood and bone marrow samples of patients undergoing hepatic resection for metastasis of colorectal cancer. Br J Surg 90(8):989–995CrossRef

40.

Topal B et al (2005) Cancer cell dissemination during curative surgery for colorectal liver metastases. Eur J Surg Oncol 31(5):506–511CrossRef

41.

Seeberg LT et al (2015) Circulating tumor cells in patients with colorectal liver metastasis predict impaired survival. Ann Surg 261(1):164–171CrossRef

42.

Dienstmann R et al (2017) Prediction of overall survival in stage II and III colon cancer beyond TNM system: a retrospective, pooled biomarker study. Ann Oncol 28(5):1023–1031CrossRef

43.

Cao DD et al (2017) The impact of primary tumor location on efficacy of cetuximab in metastatic colorectal cancer patients with different Kras status: a systematic review and meta-analysis. Oncotarget 8:53631PubMedPubMedCentral

44.

Thomsen CEB et al (2017) The prognostic value of simultaneous tumor and serum RAS/RAF mutations in localized colon cancer. Cancer Med 6(5):928–936CrossRef

45.

Sastre J et al (2008) Circulating tumor cells in colorectal cancer: correlation with clinical and pathological variables. Ann Oncol 19(5):935–938CrossRef

46.

Cohen SJ et al (2008) Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol 26(19):3213–3221CrossRef

47.

Mani SA et al (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133(4):704–715CrossRef

48.

Yu M et al (2013) Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339(6119):580–584CrossRef

49.

El-Heliebi A et al (2018) In situ detection and quantification of AR-V7, AR-FL, PSA, and KRAS point mutations in circulating tumor cells. Clin Chem 64(3):536–546CrossRef

50.

Papadaki MA et al (2012) Analysis of the expression of stemness and epithelial-to-mesenchymal transition markers in circulating tumor cells of patients with breast cancer. Cancer Res 2012;72(8 Suppl):Abstract nr 2387. In: 103rd Annual Meeting of the American Association for Cancer Research, Chicago

51.

Kraan J et al (2011) External quality assurance of circulating tumor cell enumeration using the CellSearch((R)) system: a feasibility study. Cytom B Clin Cytom 80(2):112–118CrossRef

52.

Ignatiadis M et al (2014) International study on inter-reader variability for circulating tumor cells in breast cancer. Breast Cancer Res 16(2):R43CrossRef

53.

Pantel K, Alix-Panabieres C (2013) Real-time liquid biopsy in cancer patients: fact or fiction? Cancer Res 73(21):6384–6388CrossRef

54.

Kalikaki A et al (2014) KRAS genotypic changes of circulating tumor cells during treatment of patients with metastatic colorectal cancer. PLoS One 9(8):e104902CrossRef

55.

Voutsina A et al (2013) Combined analysis of KRAS and PIK3CA mutations, MET and PTEN expression in primary tumors and corresponding metastases in colorectal cancer. Mod Pathol 26(2):302–313CrossRef

Titel: Prognostic significance of CEACAM5mRNA-positive circulating tumor cells in patients with metastatic colorectal cancer
verfasst von: Ippokratis Messaritakis
Maria Sfakianaki
Chara Papadaki
Asimina Koulouridi
Nikolaos Vardakis
Filippos Koinis
Dora Hatzidaki
Nefeli Georgoulia
Athina Kladi
Athanasios Kotsakis
John Souglakos
Vassilis Georgoulias
Publikationsdatum: 09.08.2018
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 5/2018
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-018-3666-9

Springer Medizin

Prognostic significance of CEACAM5mRNA-positive circulating tumor cells in patients with metastatic colorectal cancer