KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: The OPUS experience

Bokemeyer, Carsten; Bondarenko, Igor; Hartmann, Jörg T.; Braud, Filippo G. De; Volovăţ, Constantin; Nippgen, Johannes; Stroh, Christopher; Çelik, I.; Koralewski, P.

doi:10.1200/jco.2008.26.15_suppl.4000

Cited by 182 publications

(125 citation statements)

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“…The appearance of pERK1/2 probably coincides with activation of KRAS, probably only in the tip of the colon epithelial cells and not in the initiation of tumor growth at the stroma, as was demonstrated in the present work, which would suggest different genetic alteration in the latter site of tumor progression (29)(30)(31)(32)(33)(34).…”

Section: Discussionsupporting

confidence: 60%

Two initiation sites of early detection of colon cancer, revealed by localization of pERK1/2 in the nuclei or in aggregates at the perinuclear region of tumor cells

et al. 2011

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Abstract.We have used human specimens and antibodies to pERK1/2 to detect early development of colon cancer, using indirect immunocytochemistry. Two distinct sites were stained; one at the tip of the colon villi and the other in the stromal tissue, associated with the colon tissue. These foci represent early stages of colon cancer initiation, as established by enhanced KRAS, and lack of p53 staining. It should be noted, however, that the enhanced KRAS coincides with the initiation of tumor growth revealed by pERK1/2 only in the tip of the colon villi but not in the stromal initiation site of the colon tumors. Interestingly, foci of pERK1/2 staining were also detected within 50% of stromal tissue and tips of colon villi, that were classified as normal tissues, distal from the malignant one according to general morphology. The staining of pERK1/2 at the stromal foci of this apparently non-malignant tissue appeared as aggregates at the perinuclear region, while at the colon epithelium, it appeared at the cell nuclei. At low-grade of colon cancer, that was still free of induced mutated p53, staining of pERK1/2 was prominent at the cell nuclei both at the stroma tissue and the tip of the colon villi. In intermediate stage, that exhibited a significant p53 staining, only a fraction of p53-free tumor cells was labeled with pERK1/2 antibody, while in high-grade tumors, all cells of tumors were labeled with antibodies to p53, but not with pERK1/2. We also found that the cytoplasm of low-grade tumors was positive for epiregulin, while this labeling decreased in high-grade tumors. Interestingly, we found that the tumors initiating from the stroma demonstrated poor structural differentiation, while the tumors initiating from the epithelial cells of the colon demonstrated high structural differentiation. It is concluded that pERK1/2 is a sensitive early marker of colon cancer, which disappears at later stages of cancer development. Moreover, pERK1/2 staining can distinguish between tumor cells originated from the tip of the colon villi and those originated in the stroma, associated with the colon tissue, and thus can assist in selecting the appropriate therapy.

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Section: Discussionsupporting

confidence: 60%

Two initiation sites of early detection of colon cancer, revealed by localization of pERK1/2 in the nuclei or in aggregates at the perinuclear region of tumor cells

et al. 2011

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“…K-ras wild-type cancers (Bokemeyer et al, 2008;Van Cutsem et al, 2008). In contrast, the addition of cetuximab to FOLFOX-4 had a detrimental effect on response and progression-free survival in K-ras mutant tumours in the OPUS trial (Bokemeyer et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Biomarker analysis of cetuximab in colorectal cancer has identified potential biomarkers such as EGFR gene amplification and K-ras mutations that may guide treatment decisions (Moroni et al, 2005;Khambata-Ford et al, 2007;Sartore-Bianchi et al, 2007;Zhang et al, 2007;Bokemeyer et al, 2008;Cappuzzo et al, 2008;Lievre et al, 2008;Van Cutsem et al, 2008;Tejpar et al, 2008b). The additional activity of cetuximab combined with chemotherapy was limited to K-ras wild-type colorectal cancers (Bokemeyer et al, 2008;Van Cutsem et al, 2008). Other potential biomarkers of cetuximab activity in colorectal cancer include EGFR ligands (epiregulin and amphiregulin) and polymorphisms in EGFR, EGF, and Fc fragment of IgG receptor (Khambata-Ford et al, 2007;Zhang et al, 2007;Graziano et al, 2008;Tejpar et al, 2008a).…”

mentioning

confidence: 99%

Phase II study and biomarker analysis of cetuximab combined with modified FOLFOX6 in advanced gastric cancer

Han

et al. 2009

Br J Cancer

131

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This prospective study was conducted with the Korean Cancer Study Group to evaluate the efficacy and safety of cetuximab combined with modified FOLFOX6 (mFOLFOX6) as first-line treatment in recurrent or metastatic gastric cancer and to identify potential predictive biomarkers. Patients received cetuximab 400 mg m À2 at week 1 and 250 mg m À2 weekly thereafter until disease progression. Oxaliplatin (100 mg m À2 ) and leucovorin (100 mg m À2) were administered as a 2-h infusion followed by a 46-h continuous infusion of 5-fluorouracil (2400 mg m À2 ) every 2 weeks for a maximum of 12 cycles. Biomarkers potentially associated with efficacy were analysed. Among 38 evaluable patients, confirmed response rate (RR) was 50.0% (95% CI 34.1 -65.9). Median time-to-progression (TTP) was 5.5 months (95% CI 4.5 -6.5) and overall survival (OS) 9.9 months. Eleven patients having tumour EGFR expression by immunohistochemistry with low serum EGF and TGF-a levels showed a 100% RR compared to 37.0% in the remaining 27 patients (Po0.001). Moreover, ligand level increased when disease progressed in seven out of eight patients with EGFR expression and low baseline ligand level. No patient exhibited EGFR amplification or K-ras mutations. Gastric cancer patients with EGFR expression and low ligand levels had better outcomes with cetuximab/mFOLFOX6 treatment.

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“…110 Similarly, patients treated with FOLFOX chemotherapy with or without cetuximab in the first-line mCRC phase II OPUS study showed benefit in response and in PFS only for the subgroup of patients with WT KRAS (58%), whereas the other 42% with KRAS mutations did not gain from the addition of cetuximab. 111 Results from the phase III National Cancer Institute of Canada CTG CO.17 study (cetuximab and best supportive care (BSC) versus BSC in advanced pretreated CRC) were recently published by Karapetis et al 112 Likewise, the authors reported significant clinical and survival benefit in KRAS WT patients treated with cetuximab and BSC compared with that in KRAS mutant or BSC alone patients. KRAS mutations were observed in about 42% of studied patients.…”

Section: Egfr Inhibitorsmentioning

confidence: 99%

Pharmacogenetics and biomarkers in colorectal cancer

2009

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The prognosis of patients with colorectal cancer (CRC) is affected by various factors at the time of diagnosis, including location of the tumor, gender, age and overall performance status of the patient. Predicting response and limiting drug-induced toxicity for patients with CRC are also critical. Interpatient differences in tumor response and drug toxicity are common during chemotherapy. Genomic variability of key metabolic enzyme complexes, drug targets and drug transport molecules are important contributing factors. At present, there is inconsistent and rather low use of pharmacogenetic testing in the clinical setting because of a lack of robust evidence or of resources. Patients' selection and tailored treatments by the introduction of genetic testing will hopefully allow better response prediction and limit drug-induced toxicity leading to improved patient outcomes in the most cost-effective way. Here, we review the main genetic alterations observed in familial and sporadic CRC and their associations with the metabolism, efficacy and toxicities of drugs used in this disease.

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KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: The OPUS experience

Cited by 182 publications

References 0 publications

Two initiation sites of early detection of colon cancer, revealed by localization of pERK1/2 in the nuclei or in aggregates at the perinuclear region of tumor cells

Two initiation sites of early detection of colon cancer, revealed by localization of pERK1/2 in the nuclei or in aggregates at the perinuclear region of tumor cells

Phase II study and biomarker analysis of cetuximab combined with modified FOLFOX6 in advanced gastric cancer

Pharmacogenetics and biomarkers in colorectal cancer

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