Detection of KRAS Oncogene in Peripheral Blood as a Predictor of the Response to Cetuximab Plus Chemotherapy in Patients with Metastatic Colorectal Cancer
ABSTRACT Previously we developed membrane-arrays as a promising tool to detect circulating tumor cells (CTC) with KRAS oncogene in patients with malignancies. This study was conducted to determinate the predictive values of CTCs with KARS mutation by membrane-arrays for metastatic colorectal cancer patients treated with cetuximab plus chemotherapy.
Seventy-six metastatic colorectal cancer patients receiving cetuximab plus FOLFIRI or FOLFOX-4 chemotherapy were enrolled. KRAS mutation status in the peripheral blood of these patients was analyzed using membrane-arrays, and KRAS mutation status in tumors was analyzed by DNA sequencing.
Among 76 metastatic colorectal cancer patients, KRAS mutations in tumors and in peripheral blood were identified in 33 (43.4%) and 30 (39.5%) patients, respectively. The detection sensitivity, specificity, and accuracy of membrane-arrays for CTCs with KRAS oncogene were 84.4%, 95.3%, and 90.8%, respectively, and indeed a highly significant correlation to KRAS mutations in tumors (P < 0.0001) was observed. Forty-five (59.2%) patients responded to cetuximab plus chemotherapy, and 41 and 40 were wild-type KRAS in tumors and peripheral blood, respectively (both P < 0.0001). Patients with tumors that harbor wild-type KRAS are more likely to have a better progression-free survival and overall survival when treated with cetuximab plus chemotherapy (P < 0.0001). Likewise, patients with CTCs of wild-type KRAS in peripheral blood express a better progression-free survival and overall survival when treated with cetuximab plus chemotherapy (P < 0.0001).
These findings provide evidence that detection of KRAS mutational status in CTCs, by gene expression array, has potential for clinical application in selecting metastatic colorectal cancer patients most likely to benefit from cetuximab therapy.
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ABSTRACT: We have investigated the anticancer effects of the dietary isothiocyanate sulforaphane (SFN) on colorectal cancer (CRC), using primary cancer cells lines isolated from five Taiwanese colorectal cancer patients as the model for colorectal cancer. SFN-treated cells accumulated in metaphase (SFN 6.25 μM) and subG1 (SFN 12.5 and 25 μM) as determined by flow cytometry. In addition, treated cells showed nuclear apoptotic morphology that coincided with an activation of caspase-3, and loss of mitochondrial membrane potential (ΔΨm). Incubations at higher SFN doses (12.5 and 25 μM) resulted in cleavage of procaspase-3 and elevated caspase-2, -3, -8, and -9 activity, suggesting that the induction of apoptosis and the sulforaphane-induced mitosis delay at the lower dose are independently regulated. Daily SFN s.c. injections (400 micromol/kg/d for 3 weeks) in severe combined immunodeficient mice with primary human CRC (CP1 to CP5) s.c. tumors resulted in a decrease of mean tumor weight by 70% compared with vehicle-treated controls. Our findings suggest that, in addition to the known effects on cancer prevention, sulforaphane may have antitumor activity in established colorectal cancer.Evidence-based Complementary and Alternative Medicine 01/2012; 2012:415231. DOI:10.1155/2012/415231 · 1.88 Impact Factor
- Biomedical Engineering, Trends, Research and Technologies, 01/2011; , ISBN: 978-953-307-514-3
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ABSTRACT: The anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies cetuximab and panitumumab have been demonstrated to be new therapeutic options for metastatic colorectal cancer (mCRC). Oncogenic activation of intracellular signalling pathways downstream of EGFR has a major role in colorectal carcinogenesis but has also been reported to be an important mechanism of resistance to anti-EGFR antibodies. Among the activating mutations found in colorectal cancers, tumour KRAS mutations, which are found in approximately 40% of the cases, have been widely demonstrated as a major predictive marker of resistance to cetuximab or panitumumab, therefore, opening the way to individualized treatment for patients with mCRC. Other oncogenic mutations, such as BRAF or PIK3CA mutations or loss of PTEN expression, may also be additional interesting predictive markers of response to anti-EGFR monoclonal antibodies but required further evaluation before being incorporated in clinical practice. The identification of these molecular markers involved in the resistance of anti-EGFR antibodies will allow the development of new therapies that should target 'escape mechanisms' used by tumours to circumvent a pathway that has been pharmacologically blocked by anti-EGFR.Oncogene 04/2010; 29(21):3033-43. DOI:10.1038/onc.2010.89 · 8.56 Impact Factor