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      Second-line panitumumab as a triweekly dose for patients with wild-type KRAS exon 2 metastatic colorectal cancer: a single-institution experience

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          Abstract

          Objective: Panitumumab administered as monotherapy in colorectal cancer (CRC) has shown response and disease stabilization rates of approximately 30%. The current study aimed to evaluate the progression-free survival (PFS) and overall survival (OS) of patients with metastatic colorectal cancer (mCRC) treated with panitumumab every 3 weeks as a second line treatment. Methods: This study is a retrospective analysis of 18 patients, aged more than 18 years, with wild-type KRAS exon 2 mCRC treated with panitumumab as a second-line single agent after progression on first-line chemotherapy. Results: The median number of courses received was 10 (range, 4-29), and the median duration of treatment was 30 weeks (range, 12-96 weeks). After a median follow-up period of 13 months, the median PFS was 6 months (range, 4.3-7.7 months) and the median OS was 11 months (range, 7.4-14.5 months). The median PFS was 4 months for patients with < grade 2 skin toxicity and 6 months (range, 4.5-7.5 months) for patients with ≥grade 2 skin rash ( P=0.05). The median OS was 9 months (range, 6.4-11.5 months) and 14 months (range, 11.6-16.3 months) for the two groups of patients ( P=0.002). Conclusions: Panitumumab given every 3 weeks is effective and well tolerated in patients with advanced CRC that progressed after standard chemotherapy.

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          KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab.

          Cetuximab is efficient in advanced colorectal cancer (CRC). We previously showed that KRAS mutations were associated with resistance to cetuximab in 30 CRC patients. The aim of this study was to validate, in an independent larger series of 89 patients, the prognostic value of KRAS mutations on response to cetuximab and survival. Eighty-nine metastatic CRC patients treated with cetuximab after treatment failure with irinotecan-based chemotherapy were analyzed for KRAS mutation by allelic discrimination on tumor DNA. The association between KRAS mutations and tumor response, skin toxicity, progression-free survival (PFS) and overall survival (OS) was analyzed. A KRAS mutation was present in 27% of the patients and was associated with resistance to cetuximab (0% v 40% of responders among the 24 mutated and 65 nonmutated patients, respectively; P < .001) and a poorer survival (median PFS: 10.1 v 31.4 weeks in patients without mutation; P = .0001; median OS: 10.1 v 14.3 months in patients without mutation; P = .026). When we pooled these 89 patients with patients from our previous study, the multivariate analysis showed that KRAS status was an independent prognostic factor associated with OS and PFS, whereas skin toxicity was only associated with OS. In a combined analysis, median OS times of patients with two, one, or no favorable prognostic factors (severe skin toxicity and no KRAS mutation) was of 15.6, 10.7, and 5.6 months, respectively. These results confirm the high prognostic value of KRAS mutations on response to cetuximab and survival in metastatic CRC patients treated with cetuximab.
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            Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies.

            Monoclonal antibodies (mAbs) against the extracellular domain of the epidermal growth factor receptor (EGFR) have been introduced for the treatment of metastatic colorectal cancer (mCRC). We have reported recently that increased copy number of the EGFR can predict response to anti-EGFR mAbs and that patients might be selected for treatment based on EGFR copy number. Here, we show that mutations activating the RAS/RAF signaling pathway are also predictive and prognostic indicators in mCRC patients, being inversely correlated with response to anti-EGFR mAbs. In cellular models of CRCs, activation of the RAS signaling pathway by introduction of an activated K-RAS allele (Gly(12)Val) impairs the therapeutic effect of anti-EGFR mAbs. In cancer cells carrying constitutively active RAS, the pharmacologic inhibition of the mitogen-activated protein kinase (MAPK) signaling cascade improves anti-EGFR treatment based on mAbs. These results have implications for the identification of patients who are likely to respond to anti-EGFR treatment. They also provide the rationale for combination therapies, targeted simultaneously to the EGFR and RAS/RAF/MAPK signaling pathways in CRC patients.
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              KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab.

              KRAS mutation status is a candidate marker for predicting survival in patients with metastatic colorectal cancer (mCRC) treated with cetuximab (CTX). We studied the KRAS mutation status of 113 patients with irinotecan refractory mCRC treated with CTX in clinical trials. A predictive model for objective response (OR), progression-free survival (PFS) and overall survival (OS) was constructed using logistic and Cox regression. OR was seen in 27 of 66 KRAS wild-type (WT) patients versus 0 of 42 in KRAS mutants. Median OS was significantly better in KRAS WT versus mutants (43.0 versus 27.3 weeks; P = 0.020). Decrease in tumor sizes was significantly larger at all time points in WT patients. KRAS WT patients with an initial relative decrease of tumor size >9.66% at week 6 had a significantly better median OS compared with all other patients (74.9 versus 30.6 weeks; P = 0.0000025). Within KRAS WT patients OS was significantly better in patients with an initial decrease compared with those without [median OS: 74.9 versus 30.6 weeks (P = 0.00000012)]. KRAS WT status is associated to survival benefit in CTX treated mCRC. This benefit is even more pronounced in those patients with early radiological response. These characteristics may be exploited for response prediction.
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                Author and article information

                Journal
                Cancer Biol Med
                Cancer Biol Med
                CBM
                Cancer Biology & Medicine
                Chinese Anti-Cancer Association (Tianjing China )
                2095-3941
                March 2016
                : 13
                : 1
                : 136-141
                Affiliations
                [1]Department of Radiation Oncology, Mansoura Faculty of Medicine, King Abdullah Medical City, Mecca 24246, Saudi Arabia
                Author notes
                Correspondence to: Mohamed A. Daoud E-mail: daoud1964@hotmail.com
                Article
                10.28092/j.issn.2095-3941.2015.0009
                4850122
                27144068
                ea7d0ccc-83d9-4202-bc1e-9a9dee82d897
                Copyright 2016 Cancer Biology & Medicine

                This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/

                History
                : 29 January 2015
                : 30 June 2015
                Categories
                Original Article

                metastatic colorectal carcinoma,panitumumab,second-line,kras

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