Journal of Clinical Oncology, Vol 26, No 3 (January 20), 2008: pp. 374-379
© 2008 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2007.12.5906
KRAS Mutations As an Independent Prognostic Factor in Patients With Advanced Colorectal Cancer Treated With Cetuximab
Astrid Lièvre,
Jean-Baptiste Bachet,
Valérie Boige,
Anne Cayre,
Delphine Le Corre,
Emmanuel Buc,
Marc Ychou,
Olivier Bouché,
Bruno Landi,
Christophe Louvet,
Thierry André,
Fréderic Bibeau,
Marie-Danièle Diebold,
Philippe Rougier,
Michel Ducreux,
Gorana Tomasic,
Jean-François Emile,
Frédérique Penault-Llorca,
Pierre Laurent-Puig
From the L'Institut National de la Santé et de la Recherche Médicale; Université Paris-Descartes; Assistance Publique–Hôpitaux de Paris, Hôpital Européen Georges Pompidou; Assistance Publique–Hôpitaux de Paris, Hôpital Saint-Antoine; Assistance Publique–Hôpitaux de Paris, Hôpital Tenon, Paris; Assistance Publique–Hôpitaux de Paris, Hôpital Ambroise Paré, Boulogne-Billancourt; Université de Versailles Saint-Quentin-en-Yvelines, Versailles; Institut Gustave Roussy, Villejuif; Centre Jean Perrin; Université Auvergne; Centre Hospitalier Universitaire (CHU) Clermont-Ferrand, Service Chirurgie Digestive, Clermont-Ferrand; Centre Val d'Aurelle, Montpellier; and CHU Robert Debré, Reims, France
Corresponding author: Pierre Laurent-Puig, MD, PhD, L'Institut National de la Santé et de la Recherche Médicale U775, Université Paris-Descartes, 45 rue des Saints-Pères, 75006 Paris, France; e-mail: pierre.laurent-puig{at}univ-paris5.fr
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ABSTRACT
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Purpose 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.
Patients and Methods 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.
Results 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.
Conclusion 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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INTRODUCTION
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Colorectal cancer (CRC) is the second cause of cancer death both in the United States and in the European Union, where more than 300,000 new patients are diagnosed each year. In the last decade, significant improvements have been made in response rates, progression-free survival (PFS), and overall survival (OS).1-4 These significant improvements are mainly a result of the development of new combinations of standard chemotherapy including fluorouracil, irinotecan, and oxaliplatin and also new therapeutic agents targeting molecular events involved in colorectal carcinogenesis.
One of the most promising targets is the epidermal growth factor receptor (EGFR), which is activated in colorectal carcinogenesis by the binding of a ligand on the extracellular part of it. The autophosphorylation of the intracellular tyrosine kinase domain of the EGFR activates downstream signaling pathways, including the Ras/raf/mitogen-activated protein kinase pathway, the phosphatidylinositol 3-kinase/Akt pathway, and the signal transduction and activator of transcription pathway, which interfere with apoptosis, cell proliferation, angiogenesis, and the metastatic process.
Monoclonal antibodies represent one of the most important options to inhibit the EGFR. The chimeric immunoglobulin G1 monoclonal antibody cetuximab (Erbitux; Merck, Lyon, France), which binds to EGFR with a high specificity and blocks ligand-induced phosphorylation of the receptor, has proven to be active in irinotecan-resistant metastatic CRC expressing EGFR by immunohistochemistry (IHC) in two phase II studies.5,6 However, only a small proportion (8% to 23%) of patients achieves an objective response and benefit from cetuximab. It is now clear that there is no significant correlation between EGFR expression based on IHC and response to cetuximab5,6 and that objective response can be obtained with cetuximab in CRC that does not express EGFR,7,8 suggesting the existence of other predictive markers of response to this targeted therapy.
In a series of 30 patients with CRC treated with cetuximab, we previously reported that the presence of a tumor KRAS mutation was significantly associated with resistance to cetuximab and a lower OS.9 Our hypothesis is that activating KRAS mutation could be responsible for an acquired activation of the Ras/mitogen-activated protein kinase pathway independently of the ligand-induced activation of the EGFR and, therefore, induces a resistance to cetuximab treatment. The aim of this retrospective multicenter study was to validate the prognostic value of KRAS mutations on response to cetuximab and survival in an independent and larger series of metastatic CRC patients treated with this targeted therapy.
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PATIENTS AND METHODS
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Patients
First, we assessed an independent series of 89 metastatic CRC patients (44 males; mean age, 59.2 ± 11.3 years) treated with cetuximab in six centers (Groupe Hospitalier Universitaire-West Paris, Groupe Hospitalier Universitaire-East Paris, Gustave-Roussy Institute, Clermont-Ferrand Hospital, Val d'Aurelle Institute, and Reims Hospital). Then, we analyzed the pooled series including these 89 patients with the patients of our previous study.9 The 114 patients of this pooled series were obtained from a total of 234 metastatic CRC patients treated with cetuximab in the six centers until December 31, 2005. Among them, a tumor tissue block was available for 135 patients. We then selected only the patients who were treated by cetuximab according to the US Food and Drug Administration guidelines and who were assessable for tumor response (see Appendix, online only). All of these patients had a histologically proven metastatic colorectal adenocarcinoma. Tumor samples were obtained from primary colorectal tumor (n = 83) or metastatic tissue (n = 31). An analysis of EGFR expression was performed by IHC on at least one tumor fragment, and tumor was considered EGFR positive if at least 1% malignant cells stained (Zymed Laboratories Inc, San Francisco, CA or Dako Cytomation, Glostrup, Denmark). This retrospective study was performed according to the Ethic French laws.
Two patients received cetuximab monotherapy, 78 patients received cetuximab combined with irinotecan, and nine patients received cetuximab combined with irinotecan plus fluorouracil and folinic acid. Cetuximab was administered as second-line, third-line, fourth-line, or fifth-line therapy or more in eight, 37, 29, and 15 patients, respectively. The median follow-up time was 9.5 months.
Skin toxicity grading was collected retrospectively from the patient data file according to National Cancer Institute Common Toxicity Criteria (version 2.0). Skin toxicity data were missing from only one patient.
Tumor response was evaluated by computerized tomodensitometry according to the Response Evaluation Criteria in Solid Tumors.10 For the analysis, patients with complete or partial response were classified as responders, and those with stable or progressive disease were classified as nonresponders.
DNA Extraction and Mutation Analysis
DNA was extracted from frozen or paraffin-embedded CRC samples using QIAmp DNA Mini Kit (Qiagen, Courtaboeuf, France) after a histologic control of the presence of tumor cells (> 70%) in each tumor sample by HES coloration. KRAS mutation status was assessed before the treatment with cetuximab.
The presence of KRAS mutation was determined by an allelic discrimination assay on an ABI 7900HT Sequence Detection System (Applied Biosystems, Foster City, CA). The seven KRAS mutations located within codons 12 (n = 6) and 13 (n = 1) were screened. Specific probes for each allele (mutated and nonmutated alleles) were labeled with the fluorescence reporter dyes FAM and VIC at their 5'-end (sequences available on request), respectively. Briefly, reactions were performed in 5 µL comprising 10 ng of DNA, 1x of specific primers and probes, and 1x TaqMan Universal PCR Master Mix (Applied Biosystems). DNA was then submitted to the following cycle conditions: 95°C for 15 minutes; 40 cycles, 95°C for 15 seconds; and 60°C for 1 minute. Data were analyzed with SDS2.0 software (Applied Biosystems). Each mutation detected by allelic discrimination was checked by direct sequencing of exon 2 of the KRAS gene.9
We tested the sensitivity of the probes to detect KRAS mutation by the use of one CRC cell line with a KRAS mutation in codon 13, the HCT-116 cell line (with G38A mutation). We mixed the mutated DNA with nonmutated DNA extracted from normal colon tissue according to the following proportions: 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, and 0%. A KRAS mutation was detected when the mix contained at least 20% of DNA extracted from mutated cell lines, which represents a cutoff of one mutated DNA copy for a total of nine nonmutated copies.
Statistical Analysis
The  2 test was used to calculate the P value for association between KRAS mutation, skin toxicity, and response to cetuximab. PFS was calculated as the period from the first day of cetuximab treatment to the date of tumor progression, to the date of death from any cause, or to the date of the last follow-up, at which point data were censored. OS was calculated as the period from the first day of cetuximab treatment until death from any cause or until the date of the last follow-up, at which point data were censored. Data on survival were available for all but one patient who was lost of follow-up. Both PFS and OS were estimated using the Kaplan-Meier method and compared using the log-rank test. A multivariate Cox model was used to estimate the effect of KRAS mutation and skin toxicity on survival after adjustment for age, sex, and number of chemotherapy lines. Analysis was carried out using the STATA software (STATA Corp, College Station, TX). The level of significance was set at P = .05.
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RESULTS
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Twenty-six (29%) of the 89 patients responded to cetuximab. Median duration of response was 35 weeks (range, 7 to 98 weeks). Skin reactions were observed in 85% of the 89 patients, among whom 33 (43%) had grade 1, 37 (49%) had grade 2, and six (8%) had grade 3 skin reactions. A KRAS mutation was found in 24 tumors (27%).
KRAS mutation was significantly associated with lack of response to cetuximab (Appendix Table A1, online only). None of the 24 patients with a KRAS mutation had a response to cetuximab, whereas 26 of the 65 nonmutated patients were responders (0% v 40%, respectively; P < .001). In the 88 patients assessable for survival, PFS and OS times of patients without KRAS mutation were significantly longer compared with the PFS and OS times of mutated patients (median PFS: 31.4 weeks [95% CI, 19.4 to 36 weeks] v 10.1 weeks [95% CI, 8 to 16 weeks], respectively; P = .0001; median OS: 14.3 months [95% CI, 9.4 to 20 months] v 10.1 months [95% CI, 5.1 to 13 months], respectively; P = .026; Figs 1A and 1B).
In the pooled analysis of 114 patients (Table 1), no responder was observed among the 36 patients with a KRAS mutation compared with 34 responders among the 78 patients without KRAS mutation (0% v 43.6%, respectively; P < 3 x 10–6). In the 113 patients assessable for survival, both PFS and OS strongly correlated with KRAS mutation status. The median PFS time was 32 weeks (95% CI, 20 to 34.4 weeks) for patients without KRAS mutation and 9 weeks (95% CI, 8 to 15.6 weeks) for patients with mutation (P = 1.4 x 10–7), and the median OS time was 14.3 months (95% CI, 10.5 to 20.8 months) for nonmutated patients compared with 10.1 months (95% CI, 5.6 to 10.7 months) for mutated patients (P = .0017; Figs 2A and 2B). The severity of skin toxicity was significantly associated with response to cetuximab and survival, with a higher overall response rate (Appendix Table A2, online only) and a longer OS time for the patients with grade 2 to 3 skin toxicity versus grade 0 to 1 skin toxicity (median OS: 13.9 v 8.2 months, respectively; P = .029; Appendix Fig A1, online only). The PFS time for patients with grade 2 to 3 skin toxicity (median PFS: 28.8 weeks; 95% CI, 18.4 to 33.1 weeks) was also longer compared with patients with grade 0 to 1 toxicity (median PFS: 12 weeks; 95% CI, 8 to 29.7 weeks), but the difference did not reach the statistical significance (P = .146). No correlation was found between skin toxicity and KRAS mutation (P = .34). Median PFS time was 33.1 and 19.4 weeks for KRAS nonmutated patients with and without severe skin toxicity, respectively, and 11 and 8 weeks for KRAS mutated patients with and without severe skin toxicity, respectively (P = 4.8 x 10–6). A multivariate Cox model adjusted for age, sex, and number of previous chemotherapy lines was performed. Patients with a KRAS mutation showed a higher risk of disease progression than patients without KRAS mutation, whereas skin toxicity was not an independent risk factor (Table 2). Similarly, a significant difference was observed between groups for OS according to KRAS mutation status and skin toxicity (P = .002; see Appendix), and in a multivariate Cox model for OS, KRAS mutation and skin toxicity were found to be independent risk factors for death (Table 2). Therefore, in a combined analysis of skin toxicity and KRAS mutation status, patients with two favorable prognostic factors (severe skin toxicity and no KRAS mutation) had a median OS time of 15.6 months (95% CI, 10.9 to 22 months) compared with 10.7 months (95% CI, 8.3 to 16.3 months) for patients with one favorable prognostic factor (severe skin toxicity or nonmutated KRAS) and 5.6 months (95% CI, 2.8 to 10.6 months) for patients with no favorable prognostic factors (P = .0008; Fig 3).
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Table 2. Multivariate Analysis With HRs for Overall and Progression-Free Survival According to KRAS Mutation Status and the Severity of Skin Toxicity*
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[PowerPoint Slide for Teaching]
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Fig 3. Overall survival according to the number of favorable prognostic factors (112 patients). Two favorable prognostic factors: no KRAS mutation and grade 2 to 3 skin toxicity; one favorable prognostic factor: no KRAS mutation or grade 2 to 3 skin toxicity; zero favorable prognostic factors (P = .0008).
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DISCUSSION
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Cetuximab has proven to be active in patients with irinotecan-resistant metastatic CRC in phase II clinical trials5,6 and, more recently, in patients refractory to irinotecan, oxaliplatin, and fluoropyrimidine.11 However, even if cetuximab is active in irinotecan-resistant patients, the response rate with the combination of cetuximab and irinotecan is only 23%, and the PFS time is 4.1 months.5 It is necessary to better define the subpopulation of patients who truly benefit from cetuximab because cetuximab is associated with an increase in treatment costs,12 frequent trips to therapeutic centers, and specific toxicity. Therefore, the identification of markers allowing the selection of patients who are likely to benefit from this novel targeted therapy is an important challenge.
There is no significant association between EGFR expression based on IHC, either as the percentage of EGFR-positive tumor cells or as the maximal staining intensity per cell, and response to cetuximab,5,6,13 and response can be obtained in CRCs that do not express EGFR by IHC in 25% of patients.7,8 There are several explanations for the lack of correlation between response to cetuximab and EGFR expression by IHC. First, the rate of positive-staining colorectal tumors with the different EGFR kits available remains variable (between 75% and 93%, with a cutoff value of 1% positive cells) according to the type of kit used.14 Second, intratumoral heterogeneity of EGFR expression has been demonstrated. Third, the existence of both high- and low-affinity EGFR has been reported,15 and the over-representation of low-affinity EGFR compared with high-affinity EGFR could explain the lack of association between the cetuximab response rate and EGFR expression because the low affinity for the ligands includes that for cetuximab. However, Moroni et al16 reported that EGFR copy number, measured by fluorescent in situ hybridization, is related to the response to cetuximab or to the fully human monoclonal antibody panitumumab. Although EGFR amplification, assessed by chromogenic in situ hybridization, was not as frequent in our study as previously reported by Moroni et al16 (10% v 31%, respectively), we also found a significant association between EGFR amplification and response to cetuximab.9 In contrast, Lenz et al11 reported no association between EGFR gene copy number, assessed by quantitative polymerase chain reaction, and response to cetuximab or PFS, although it was significantly correlated with OS (P = .03). However, the association between low EGFR mRNA expression and longer OS of the patients treated by cetuximab observed in another study published by the same group17 is conflicting with this previous result. Because of these discrepant results, there is a need of a strong standardization effort of EGFR expression measuring (at RNA level and protein level) before it can be used in routine practice.
In the present study, we validated the prognostic relevance of KRAS mutation status in an independent series of 89 patients treated with cetuximab. Patients with a tumor KRAS mutation were resistant to cetuximab and had shorter PFS and OS times compared with patients without mutation. Our finding of a strong prognostic importance of KRAS mutation in cetuximab-treated patients thus suggests that KRAS may actually be predictive for cetuximab responsiveness, as opposed to strictly prognostic, although this requires further validation. Numerous studies have tried to determine whether the presence of a KRAS mutation correlates with response to adjuvant therapy or survival in CRC, but to date, they have yielded conflicting results.18 Furthermore, KRAS mutations seem not to influence prognosis in patients with stage IV CRC, although few data are available.19 The G12V mutation has been reported to be more aggressive than other KRAS mutations.20 We did not find any influence of the mutation type (ie, codon 12 v codon 13 or G12V mutation v other mutations; data not shown) on response rate or prognosis.
In our study, response to cetuximab and OS were also significantly correlated with skin toxicity. These findings are consistent with those of several previous studies.5,6,11,13,17 In a phase II study including 346 CRC patients, who were refractory to irinotecan, oxaliplatin, and fluoropyrimidines, treated with cetuximab, a partial response occurred in 7%, 17%, and 20% of patients with grade 1, 2, and 3 skin rash, respectively.11 In the BOND trial, response rates were also significantly higher in patients with skin toxicity compared with patients without skin toxicity (25.8% v 6.3%, respectively, in the combination therapy group, P = .005).5 In both studies, as in the one published by Saltz et al,6 the OS of the patients with a severe skin rash was significantly higher than the OS of patients without rash. We analyzed simultaneously the prognostic value of KRAS mutation and skin toxicity in CRC patients treated with cetuximab and their impact on response to cetuximab in a multivariate analysis. The presence of a KRAS mutation remains a marker of poor prognosis, independently of skin toxicity. Our results even suggest that KRAS mutation status is more powerful to predict the resistance to cetuximab because no patient with KRAS mutation had an objective response to cetuximab compared with 13 (23.2%) of the 56 patients with grade 0 to 1 skin rash. Moreover, the multivariate analysis showed a strong correlation between KRAS mutation and both PFS and OS, whereas skin toxicity was only associated with OS, although there was a trend toward a higher PFS for patients with severe skin toxicity. However, the absence of a significant difference may be a result of the small sample size. One of the major advantages of KRAS mutation compared with skin toxicity is that KRAS mutation status can be determined before the initiation of cetuximab treatment and, thus, could be included in the algorithm of treatment decision. Moreover, the relevance of skin toxicity remains to be confirmed because the recent results of the EVEREST study showed no OS or PFS benefit from cetuximab dose escalation in patients who did not have skin rash after the first 3 weeks of treatment despite a higher response rate.21 In the present study, there was no association between KRAS mutation and skin toxicity. However, this result requires confirmation in a prospective series.
Several studies have focused their search on other molecular changes affecting EGFR intracellular signal transducers. In one series, BRAF mutations were found to be important when associated with KRAS mutations because they were associated with a shorter time to progression in patients receiving cetuximab or panitumumab.22 In our series, only two tumors were found to be mutated on BRAF codon 600 (V600E). These two patients did not have a KRAS mutation, and one of the two patients was a responder (data not shown). To date, no correlation has been found between PI3KCA gene mutations and response to cetuximab.
To our knowledge, we showed for the first time a correlation between the response rate and survival of CRC patients treated with an anticancer drug as second-line therapy and a molecular marker. Furthermore, our results show that skin toxicity is insufficient to predict outcome in patients treated with cetuximab and that KRAS mutation status provides supplementary information.
The results of the present study warrant an analysis of KRAS mutations in a randomized trial comparing an experimental arm containing cetuximab with a control arm without this targeted therapy to confirm their impact on survival and evaluate their potential predictive value on response to cetuximab. Complementary studies are required to explore mechanisms of resistance in patients without KRAS mutation who do not respond to cetuximab and also to better understand the mechanisms of resistance in patients with KRAS mutation to develop new therapeutic approaches with other agents blocking alternate intracellular pathways.
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AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory Role: Philippe Rougier, Merck Lipha Sante (C) Stock Ownership: None Honoraria: Astrid Lièvre, Merck Lipha Sante; Valérie Boige, Merck Lipha Sante; Marc Ychou, Merck Lipha Sante, Pfizer Inc; Olivier Bouché, Merck Lipha Sante, Pfizer Inc; Christophe Louvet, Pfizer Inc; Thierry André, Merck Lipha Sante, Pfizer Inc; Fréderic Bibeau, Merck Lipha Sante; Philippe Rougier, Merck Lipha Sante; Michel Ducreux, Merck Lipha Sante; Frédérique Penault-Llorca, Merck Lipha Sante; Pierre Laurent-Puig, Merck Lipha Sante, Pfizer Inc Research Funding: Frédérique Penault-Llorca, Merck Lipha Sante Expert Testimony: None Other Remuneration: Astrid Lièvre, Merck Lipha Sante; Marc Ychou, Merck Lipha Sante; Olivier Bouché, Pfizer Inc, Merck Lipha Sante; Thierry André, Pfizer Inc; Frédérique Penault-Llorca, Merck Lipha Sante
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AUTHOR CONTRIBUTIONS
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Conception and design: Astrid Lièvre, Marc Ychou, Olivier Bouché, Bruno Landi, Philippe Rougier, Michel Ducreux, Jean-François Emile, Frédérique Penault-Llorca, Pierre Laurent-Puig
Administrative support: Pierre Laurent-Puig
Provision of study materials or patients: Astrid Lièvre, Jean-Baptiste Bachet, Valérie Boige, Emmanuel Buc, Marc Ychou, Olivier Bouché, Christophe Louvet, Thierry André, Fréderic Bibeau, Marie-Danièle Diebold, Philippe Rougier, Michel Ducreux, Gorana Tomasic, Jean-François Emile, Frédérique Penault-Llorca, Pierre Laurent-Puig
Collection and assembly of data: Astrid Lièvre, Jean-Baptiste Bachet, Valérie Boige, Anne Cayre, Delphine Le Corre, Emmanuel Buc, Marc Ychou, Olivier Bouché, Bruno Landi, Christophe Louvet, Thierry André, Fréderic Bibeau, Philippe Rougier, Michel Ducreux, Frédérique Penault-Llorca, Pierre Laurent-Puig
Data analysis and interpretation: Astrid Lièvre, Jean-Baptiste Bachet, Valérie Boige, Anne Cayre, Delphine Le Corre, Bruno Landi, Jean-François Emile, Frédérique Penault-Llorca, Pierre Laurent-Puig
Manuscript writing: Astrid Lièvre, Valérie Boige, Olivier Bouché, Philippe Rougier, Frédérique Penault-Llorca, Pierre Laurent-Puig
Final approval of manuscript: Astrid Lièvre, Jean-Baptiste Bachet, Valérie Boige, Anne Cayre, Delphine Le Corre, Emmanuel Buc, Marc Ychou, Olivier Bouché, Bruno Landi, Christophe Louvet, Thierry André, Fréderic Bibeau, Marie-Danièle Diebold, Philippe Rougier, Michel Ducreux, Gorana Tomasic, Jean-François Emile, Frédérique Penault-Llorca, Pierre Laurent-Puig
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Appendix
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Patients and Methods
The patients of the previously published series and the independent validation series were selected using the same procedure. The figures provided in the next paragraph relate to the 114 patients of the pooled series.
All six centers (Groupe Hospitalier Universitaire [GHU]-West Paris, GHU-East Paris, Institut Gustave-Roussy, Clermont-Ferrand Hospital, Val d'Aurelle Institute of Montpellier, and Reims Hospital) were contacted by phone and mail. We selected all of the patients receiving cetuximab for advanced colorectal cancer up to December 31, 2005. A group of 238 patients were identified. The referent pathologist of each center was contacted to collect tissues (primary or metastatic tumor) from all patients. Frozen or paraffin-embedded tissues were only available for a subset of patients because these centers are reference centers where patients were referred only for chemotherapy treatment. Tumor tissues were available for 135 patients (56.7%) as follows: for the GHU-West Paris center, 39 tumors (72%) were collected out of 54 total patients; for the GHU-East center, five tumors (22%) were collected out of 25 patients; for the Institut Gustave-Roussy, 32 tumors (41%) were collected out of 77 patients; for Clermont-Ferrand Hospital, 22 tumors (85%) were collected out of 25 patients; for Reims Hospital, 18 tumors (93%) were collected out of 19 patients; and for Val d'Aurelle Institute of Montpellier, 19 tumors (54%) were collected out of 35 patients.
Clinical and follow-up data were then collected in each center, and only assessable patients were retained (ie, patients receiving cetuximab after progression under an irinotecan-based chemotherapy regimen and patients with a first morphologic evaluation after cetuximab therapy [6 to 8 weeks]). After applying these criteria, 114 (47.9%) of the 135 preselected patients with available tumor tissues were retained. The KRAS mutation assay worked for all 114 patients.
The sample size was determined with the following parameters: an overall response rate to cetuximab of 25%, a KRAS mutation prevalence of 40%, and an odds ratio of 5 for response in the group of patients with a non–KRAS-mutated tumor compared with the group of patient with a KRAS-mutated tumor. Follow-up data were kept on each center until the results of KRAS were provided by the laboratory.
Results
Median OS times were 15.4 and 11.4 months for KRAS nonmutated patients with and without severe skin toxicity, respectively, and 10.7 and 5.6 months for KRAS mutated patients with and without severe skin toxicity, respectively (P = .002).
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Table A1. Response to Cetuximab According to the Presence or Absence of KRAS Mutation in the Independent Series of 89 Patients
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ACKNOWLEDGMENTS
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We thank Jean-François Côté for his help and advice in pathologic interpretation.
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NOTES
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Supported by the Ligue Nationale de Lutte Contre le Cancer and the Institut National du Cancer (PL06_119).
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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REFERENCES
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1. de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938-2947, 2000[Abstract/Free Full Text]2. Douillard JY, Cunningham D, Roth AD, et al: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicentre randomised trial. Lancet 355:1041-1047, 2000[CrossRef][Medline] 3. Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23-30, 2004[Abstract/Free Full Text] 4. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer: Irinotecan Study Group. N Engl J Med 343:905-914, 2000[Abstract/Free Full Text] 5. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004[Abstract/Free Full Text] 6. Saltz LB, Meropol NJ, Loehrer PJ Sr, et al: Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22:1201-1208, 2004[Abstract/Free Full Text] 7. Chung KY, Shia J, Kemeny NE, et al: Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 23:1803-1810, 2005[Abstract/Free Full Text] 8. Hebbar M, Wacrenier A, Desauw C, et al: Lack of usefulness of epidermal growth factor receptor expression determination for cetuximab therapy in patients with colorectal cancer. Anticancer Drugs 17:855-857, 2006[CrossRef][Medline] 9. Lievre A, Bachet JB, Le Corre D, et al: KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66:3992-3995, 2006[Abstract/Free Full Text] 10. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000[Abstract/Free Full Text] 11. Lenz HJ, Van Cutsem E, Khambata-Ford S, et al: Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol 24:4914-4921, 2006[Abstract/Free Full Text] 12. Schrag D: The price tag on progress: Chemotherapy for colorectal cancer. N Engl J Med 351:317-319, 2004[Free Full Text] 13. Zhang W, Gordon M, Press OA, et al: Cyclin D1 and epidermal growth factor polymorphisms associated with survival in patients with advanced colorectal cancer treated with cetuximab. Pharmacogenet Genomics 16:475-483, 2006[Medline] 14. Penault-Llorca F, Cayre A, Arnould L, et al: Is there an immunohistochemical technique definitively valid in epidermal growth factor receptor assessment? Oncol Rep 16:1173-1179, 2006[Medline] 15. Francoual M, Etienne-Grimaldi MC, Formento JL, et al: EGFR in colorectal cancer: More than a simple receptor. Ann Oncol 17:962-967, 2006[Abstract/Free Full Text] 16. Moroni M, Veronese S, Benvenuti S, et al: Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: A cohort study. Lancet Oncol 6:279-286, 2005[CrossRef][Medline] 17. Vallbohmer D, Zhang W, Gordon M, et al: Molecular determinants of cetuximab efficacy. J Clin Oncol 23:3536-3544, 2005[Abstract/Free Full Text] 18. McDermott U, Longley DB, Johnston PG: Molecular and biochemical markers in colorectal cancer. Ann Oncol 13:235-245, 2002 (suppl 4)[Free Full Text] 19. Andreyev HJ, Norman AR, Cunningham D, et al: Kirsten ras mutations in patients with colorectal cancer: The multicenter "RASCAL" study. J Natl Cancer Inst 90:675-684, 1998[Abstract/Free Full Text] 20. Andreyev HJ, Norman AR, Cunningham D, et al: Kirsten ras mutations in patients with colorectal cancer: The ‘RASCAL II’ study. Br J Cancer 85:692-696, 2001[CrossRef][Medline] 21. Tejpar S, Peeters M, Humblet Y, et al: Phase I/II study of cetuximab dose-escalation in patients with metastatic colorectal cancer (mCRC) with no or slight skin reactions on cetuximab standard dose treatment (EVEREST): Pharmacokinetic (PK), pharmacodynamic (PD) and efficacy data. J Clin Oncol 25:172s, 2007 (suppl, abstr 4037) 22. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, et al: Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res 67:2643-2648, 2007[Abstract/Free Full Text]
Submitted May 16, 2007;
accepted October 25, 2007.
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|
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
|
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|
|
|
|
|
|
|
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April 15, 2009;
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[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Vilar, B. Mukherjee, R. Kuick, L. Raskin, D. E. Misek, J. M.G. Taylor, T. J. Giordano, S. M. Hanash, E. R. Fearon, G. Rennert, et al.
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April 15, 2009;
15(8):
2829 - 2839.
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[Full Text]
[PDF]
|
|
|
|
|
|
|
H.-J. Au, C. S. Karapetis, C. J. O'Callaghan, D. Tu, M. J. Moore, J. R. Zalcberg, H. Kennecke, J. D. Shapiro, S. Koski, N. Pavlakis, et al.
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27(11):
1822 - 1828.
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[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Van Cutsem, C.-H. Kohne, E. Hitre, J. Zaluski, C.-R. Chang Chien, A. Makhson, G. D'Haens, T. Pinter, R. Lim, G. Bodoky, et al.
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360(14):
1408 - 1417.
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[Full Text]
[PDF]
|
|
|
|
|
|
|
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|
|
|
|
|
|
|
S. Staal, M. J. O'Connell, and C. J. Allegra
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27(10):
1545 - 1548.
[Full Text]
[PDF]
|
|
|
|
|
|
|
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J. Clin. Oncol.,
March 20, 2009;
27(9):
1477 - 1484.
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[Full Text]
[PDF]
|
|
|
|
|
|
|
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March 1, 2009;
5(2):
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[Full Text]
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|
|
|
|
|
|
|
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J. Clin. Oncol.,
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27(7):
1130 - 1136.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Bibeau, E. Lopez-Crapez, F. Di Fiore, S. Thezenas, M. Ychou, F. Blanchard, A. Lamy, F. Penault-Llorca, T. Frebourg, P. Michel, et al.
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J. Clin. Oncol.,
March 1, 2009;
27(7):
1122 - 1129.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Bengala, S. Bettelli, F. Bertolini, S. Salvi, S. Chiara, C. Sonaglio, L. Losi, N. Bigiani, G. Sartori, C. Dealis, et al.
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Ann. Onc.,
March 1, 2009;
20(3):
469 - 474.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Laurent-Puig, A. Lievre, and H. Blons
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Clin. Cancer Res.,
February 15, 2009;
15(4):
1133 - 1139.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Bokemeyer, I. Bondarenko, A. Makhson, J. T. Hartmann, J. Aparicio, F. de Braud, S. Donea, H. Ludwig, G. Schuch, C. Stroh, et al.
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J. Clin. Oncol.,
February 10, 2009;
27(5):
663 - 671.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Tol, M. Koopman, A. Cats, C. J. Rodenburg, G. J.M. Creemers, J. G. Schrama, F. L.G. Erdkamp, A. H. Vos, C. J. van Groeningen, H. A.M. Sinnige, et al.
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N. Engl. J. Med.,
February 5, 2009;
360(6):
563 - 572.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. A. Pantaleo, M. Nannini, A. Maleddu, S. Fanti, C. Nanni, S. Boschi, F. Lodi, G. Nicoletti, L. Landuzzi, P. L. Lollini, et al.
Experimental results and related clinical implications of PET detection of epidermal growth factor receptor (EGFr) in cancer
Ann. Onc.,
February 1, 2009;
20(2):
213 - 226.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Takano, S. Ota, A. Hori, N. Seki, and K. Eguchi
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J. Clin. Oncol.,
January 20, 2009;
27(3):
464 - 465.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Velho, C. Oliveira, and R. Seruca
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J. Clin. Oncol.,
January 1, 2009;
27(1):
158 - 159.
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Perrone, A. Lampis, M. Orsenigo, M. Di Bartolomeo, A. Gevorgyan, M. Losa, M. Frattini, C. Riva, S. Andreola, E. Bajetta, et al.
PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients
Ann. Onc.,
January 1, 2009;
20(1):
84 - 90.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H.-J. Lenz
Established Biomarkers for Colon Cancer
ASCO Educational Book,
January 1, 2009;
2009(1):
215 - 219.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. I. Hurwitz, J. Yi, W. Ince, W. F. Novotny, and O. Rosen
The Clinical Benefit of Bevacizumab in Metastatic Colorectal Cancer Is Independent of K-ras Mutation Status: Analysis of a Phase III Study of Bevacizumab with Chemotherapy in Previously Untreated Metastatic Colorectal Cancer
Oncologist,
January 1, 2009;
14(1):
22 - 28.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Di Nicolantonio, M. Martini, F. Molinari, A. Sartore-Bianchi, S. Arena, P. Saletti, S. De Dosso, L. Mazzucchelli, M. Frattini, S. Siena, et al.
Wild-Type BRAF Is Required for Response to Panitumumab or Cetuximab in Metastatic Colorectal Cancer
J. Clin. Oncol.,
December 10, 2008;
26(35):
5705 - 5712.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. M. Sturgeon, M. J. Duffy, U.-H. Stenman, H. Lilja, N. Brunner, D. W. Chan, R. Babaian, R. C. Bast Jr., B. Dowell, F. J. Esteva, et al.
National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for Use of Tumor Markers in Testicular, Prostate, Colorectal, Breast, and Ovarian Cancers
Clin. Chem.,
December 1, 2008;
54(12):
e11 - e79.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Milano, M.-C. Etienne-Grimaldi, L. Dahan, M. Francoual, J.-P. Spano, D. Benchimol, M. Chazal, C. Letoublon, T. Andre, F.-N. Gilly, et al.
Epidermal growth factor receptor (EGFR) status and K-Ras mutations in colorectal cancer
Ann. Onc.,
December 1, 2008;
19(12):
2033 - 2038.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Lurje, F. Nagashima, W. Zhang, D. Yang, H. M. Chang, M. A. Gordon, A. El-Khoueiry, H. Husain, P. M. Wilson, R. D. Ladner, et al.
Polymorphisms in Cyclooxygenase-2 and Epidermal Growth Factor Receptor Are Associated with Progression-Free Survival Independent of K-ras in Metastatic Colorectal Cancer Patients Treated with Single-Agent Cetuximab
Clin. Cancer Res.,
December 1, 2008;
14(23):
7884 - 7895.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Santini, F. Loupakis, B. Vincenzi, I. Floriani, I. Stasi, E. Canestrari, E. Rulli, P. E. Maltese, F. Andreoni, G. Masi, et al.
High Concordance of KRAS Status Between Primary Colorectal Tumors and Related Metastatic Sites: Implications for Clinical Practice
Oncologist,
December 1, 2008;
13(12):
1270 - 1275.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. M. Ellis and D. G. Haller
Bevacizumab Beyond Progression: Does This Make Sense?
J. Clin. Oncol.,
November 20, 2008;
26(33):
5313 - 5315.
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. A. Pratilas, A. J. Hanrahan, E. Halilovic, Y. Persaud, J. Soh, D. Chitale, H. Shigematsu, H. Yamamoto, A. Sawai, M. Janakiraman, et al.
Genetic Predictors of MEK Dependence in Non-Small Cell Lung Cancer
Cancer Res.,
November 15, 2008;
68(22):
9375 - 9383.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Tahara, K. Shirao, N. Boku, K. Yamaguchi, Y. Komatsu, Y. Inaba, T. Arai, N. Mizunuma, T. Satoh, H. Takiuchi, et al.
Multicenter Phase II Study of Cetuximab Plus Irinotecan in Metastatic Colorectal Carcinoma Refractory to Irinotecan, Oxaliplatin and Fluoropyrimidines
Jpn. J. Clin. Oncol.,
November 1, 2008;
38(11):
762 - 769.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. J. Riely and M. Ladanyi
KRAS Mutations: An Old Oncogene Becomes a New Predictive Biomarker
J. Mol. Diagn.,
November 1, 2008;
10(6):
493 - 495.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Duffy and J. Crown
A Personalized Approach to Cancer Treatment: How Biomarkers Can Help
Clin. Chem.,
November 1, 2008;
54(11):
1770 - 1779.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. S. Karapetis, S. Khambata-Ford, D. J. Jonker, C. J. O'Callaghan, D. Tu, N. C. Tebbutt, R. J. Simes, H. Chalchal, J. D. Shapiro, S. Robitaille, et al.
K-ras Mutations and Benefit from Cetuximab in Advanced Colorectal Cancer
N. Engl. J. Med.,
October 23, 2008;
359(17):
1757 - 1765.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. H. Chau, O. Rixe, H. McLeod, and W. D. Figg
Validation of Analytic Methods for Biomarkers Used in Drug Development
Clin. Cancer Res.,
October 1, 2008;
14(19):
5967 - 5976.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. R. Alberts and L. D. Wagman
Chemotherapy for Colorectal Cancer Liver Metastases
Oncologist,
October 1, 2008;
13(10):
1063 - 1073.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. H. O'Neil and R. M. Goldberg
Innovations in Chemotherapy for Metastatic Colorectal Cancer: An Update of Recent Clinical Trials
Oncologist,
October 1, 2008;
13(10):
1074 - 1083.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Personeni, S. Fieuws, H. Piessevaux, G. De Hertogh, J. De Schutter, B. Biesmans, W. De Roock, A. Capoen, M. Debiec-Rychter, J.-L. Van Laethem, et al.
Clinical Usefulness of EGFR Gene Copy Number as a Predictive Marker in Colorectal Cancer Patients Treated with Cetuximab: A Fluorescent In situ Hybridization Study
Clin. Cancer Res.,
September 15, 2008;
14(18):
5869 - 5876.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Artale, A. Sartore-Bianchi, S. M. Veronese, V. Gambi, C. S. Sarnataro, M. Gambacorta, C. Lauricella, and S. Siena
Mutations of KRAS and BRAF in Primary and Matched Metastatic Sites of Colorectal Cancer
J. Clin. Oncol.,
September 1, 2008;
26(25):
4217 - 4219.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. M. Carethers
Review: Systemic treatment of advanced colorectal cancer: Tailoring therapy to the tumor
Therapeutic Advances in Gastroenterology,
July 1, 2008;
1(1):
33 - 42.
[Abstract]
[PDF]
|
|
|
|
|
|
|
B. Vincenzi, D. Santini, S. Galluzzo, A. Russo, F. Fulfaro, M. Silletta, F. Battistoni, L. Rocci, B. B. Zobel, V. Adamo, et al.
Early Magnesium Reduction in Advanced Colorectal Cancer Patients Treated with Cetuximab Plus Irinotecan as Predictive Factor of Efficacy and Outcome
Clin. Cancer Res.,
July 1, 2008;
14(13):
4219 - 4224.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. C. Garassino, G. Farina, A. Rossi, O. Martelli, and V. Torri
Should KRAS Mutations Be Considered an Independent Prognostic Factor in Patients With Advanced Colorectal Cancer Treated With Cetuximab?
J. Clin. Oncol.,
May 20, 2008;
26(15):
2600 - 2600.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Lievre and P. Laurent-Puig
In Reply
J. Clin. Oncol.,
May 20, 2008;
26(15):
2601 - 2602.
[Full Text]
[PDF]
|
|
|
|
|
|
|
Cetuximab Therapy Is Inactive in Colorectal Cancer Patients with KRAS Mutations
Journal Watch Oncology and Hematology,
February 19, 2008;
2008(219):
3 - 3.
[Full Text]
|
|
|
|
|
|
|
J. V. Melo and C. Chuah
Novel Agents in CML Therapy: Tyrosine Kinase Inhibitors and Beyond
Hematology,
January 1, 2008;
2008(1):
427 - 435.
[Abstract]
[Full Text]
[PDF]
|
|
|
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TOP
ABSTRACT
INTRODUCTION
