Abstract
BackgroundThe KRAS oncogene was one of the earliest discoveries of genetic alterations in colorectal and lung cancers. Moreover, KRAS somatic mutations might be used for predicting the efficiency of anti-EGFR therapeutic drugs. The purpose of this research was to improve Activating KRAS Detection Chip by using a weighted enzymatic chip array (WEnCA) platform to detect activated KRAS mutations status in the peripheral blood of non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC) patients in Taiwan.MethodsOur laboratory developed an Activating KRAS Detection Chip and a WEnCA technique that can detect activated KRAS mutation status by screening circulating cancer cells in the surrounding bloodstream. We collected 390 peripheral blood samples of NSCLC patients (n = 210) and CRC patients (n = 180) to evaluate clinical KRAS activation using this gene array diagnosis apparatus, an Activating KRAS Detection Chip and a WEnCA technique. Subsequently, we prospectively enrolled 88 stage III CRC patients who received adjuvant FOLFOX-4 chemotherapy with or without cetuximab. We compared the chip results of preoperative blood specimens and their relationship with disease control status in these patients.ResultsAfter statistical analysis, the sensitivity of WEnCA was found to be 93%, and the specificity was found to be 94%. Relapse status and chip results among the stage III CRC patients receiving FOLFOX-4 plus cetuximab (n = 59) and those receiving FOLFOX-4 alone (n = 29) were compared. Among the 51 stage III CRC patients with chip negative results who were treated with FOLFOX-4 plus cetuximab chemotherapy, the relapse rate was 33.3%; otherwise, the relapse rate was 48.5% among the 23 out of 88 patients with chip negative results who received FOLFOX-4 alone. Negative chip results were significantly associated to better treatment outcomes in the FOLFOX-4 plus cetuximab group (P = 0.047).ConclusionsThe results demonstrated that the WEnCA technique is a sensitive and convenient technique that produces easy-to-interpret results for detecting activated KRAS from the peripheral blood of cancer patients. We suggest that the WEnCA technique is also a potential tool for predicting responses in CRC patients following FOLFOX-4 plus cetuximab chemotherapy.
Highlights
The KRAS oncogene was one of the earliest discoveries of genetic alterations in colorectal and lung cancers
The association between weighted enzymatic chip array (WEnCA) and direct sequencing for activated KRAS detection in peripheral blood and tumor tissues To establish the capabilities of the WEnCA platform for the clinical detection of KRAS activation in blood samples, we collected 390 samples of peripheral blood from pathology-proven non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC) patients
Previous studies [24,25] showed that the benefits of the anti-EGFR mAb cetuximab among patients with metastatic colorectal cancer are limited to those patients who have colorectal tumor tissues with wild-type KRAS genes, and KRAS genes with mutations are essentially insensitive to EGFR inhibitors
Summary
The KRAS oncogene was one of the earliest discoveries of genetic alterations in colorectal and lung cancers. The purpose of this research was to improve Activating KRAS Detection Chip by using a weighted enzymatic chip array (WEnCA) platform to detect activated KRAS mutations status in the peripheral blood of non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC) patients in Taiwan. The activation of mutations of the ras family is among the most common genetic events of human tumorigenesis [6]. KRAS mutations are the most common in human tumors, including those arising from the colon and lungs [8]. The frequency of KRAS mutations across a broad range of human tumors suggests the potency of the oncogenic contribution of the constitutively active form of this protein
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