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Year : 2011  |  Volume : 48  |  Issue : 1  |  Page : 47--54

Role of cetuximab and sorafenib in treatment of metastatic colorectal cancer

KM Galal1, Z Khaled2, Abdel Monem M Mourad3,  
1 Radiotherapy and Oncology Center (NEMROCK), Cairo University; Oncology Center, Saudi German Hospital
2 Oncology Center, Saudi German Hospital; Internal Medicine Department, Tanta University
3 Oncology Center, Saudi German Hospital; Radiology Department, Assiut University

Correspondence Address:
K M Galal
Radiotherapy and Oncology Center (NEMROCK), Cairo University; Oncology Center, Saudi German Hospital


Background: The relationship of epidermal growth factor receptors (EGFR) pathway, such as PI3K, K-ras, and B-raf, with response to EGFR-targeted antibodies is less well studied. Aim: To assess sorafenib with cetuximab in treating metastatic colorectal cancer. Settings and Design: Thirty-five patients with metastatic colorectal cancer were randomized to receive cetuximab with or without oral sorafenib. Patients and Methods: Patients received cetuximab IV weekly for four weeks and oral sorafenib twice daily on days 1 - 28, with recycling every four weeks. The primary end point was the response rate (partial and complete), while the secondary end points were the adverse effects, time to progression and overall survival. Statistical Analysis was made using the Statistical Product and Service Solutions, using SPSS 10.0, with estimation of both time to progression and overall survival time by the Kaplan-Meier method and comparing the two groups with the use of a log-rank test. Results: Partial response was higher in cetuximab-sorafenib (EN), which constituted 33.3% compared to 17.6% in the cetuximab group (P = 0.44). Progression-free survival had a statistically higher significant difference in wild K-ras compared to mutant K-ras cases (P = .0001). Median overall survival was seven and five months in the (EN) and (E) groups respectively (P = 0.49). Conclusion: K-ras and B-raf was a predictor of response, so genotyping of tumors was needed for defining the patient population that was likely to benefit from the targeted therapy. A combination of therapy that simultaneously targets K-ras and B-raf could be a useful approach to increase the number of patients who may benefit from anti-EGFR therapy.

How to cite this article:
Galal K M, Khaled Z, Mourad AM. Role of cetuximab and sorafenib in treatment of metastatic colorectal cancer.Indian J Cancer 2011;48:47-54

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Galal K M, Khaled Z, Mourad AM. Role of cetuximab and sorafenib in treatment of metastatic colorectal cancer. Indian J Cancer [serial online] 2011 [cited 2020 Dec 3 ];48:47-54
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Early stage colorectal cancer is frequently curable with surgery. However, unresectable metastatic disease is uniformly fatal. Once a patient's cancer becomes refractory to chemotherapy agents, there are essentially no established treatment options with demonstrated efficacy. Clearly, there is a desperate need for new and improved therapies for this lethal disease.[1] Recent advances in the identification of key tumorigenesis signaling pathways and protein kinases have led to the development of novel targeted anticancer therapies.[2] Previous trial on sorafenib was originally focused on patients with colorectal cancer.[3] The rationale of the study depends on blocking multiple cellular pathways with the use of different targeted treatments, which may influence the growth and metastatic potential of tumors.

 Patients and Methods

The rationale of the study depends on monoclonal antibodies, such as cetuximab, which can block the ability of tumor cells to grow and spread. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Sorafenib given together with cetuximab may kill more tumor cells. This phase II trial aims to study how well giving sorafenib together with cetuximab works in treating patients with metastatic colorectal cancer.

This randomized trial was conducted on 35 patients with metastatic colorectal cancer, referred to the Saudi German Hospital, Oncology Center, in the Kingdom of Saudi Arabia, from October, 2007 to June, 2009. All the patients signed a consent form. The study was approved by the hospital ethics committees. The study objective was to determine the response rate (partial and complete), as the primary end point for metastatic colorectal cancer patients with wild or mutant K-RAS tumors treated with sorafenib and cetuximab, while secondary end points included the incidence of adverse effects, time to progression, and overall survival time.

Inclusion criteria included age ≥ 18 years, Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2, life expectancy ≥ 3 months, histologically or cytologically confirmed metastatic colorectal cancer, evidence of disease recurrence or progression after at least one previous chemotherapy regimen for metastatic disease. Measurable disease was defined as a ≥ 1 unidimensionally measurable lesion, ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan. Tumor blocks or unstained slides from an archival pathological specimen were suitable for isolation of genomic DNA. The patients were not eligible for or refused tumor resection. No known brain metastases, unless stable for ≥ 6 months, without anticonvulsant or steroid therapy. Adequate blood counts, and hepatic and renal functions were needed; platelet count ≥ 100,000/mm^3; absolute neutrophil count ≥ 1,500/mm^3, AST and ALT ≤ 2.5 times upper limit of normal (ULN); bilirubin ≤ 1.5 times ULN; creatinine ≤ 1.5 times ULN or creatinine clearance ≥ 60 mL/min, PT/PTT ≤ 1.5 times ULN. Other inclusion criteria included systolic blood pressure of ≤ 150 mm Hg and a diastolic blood pressure of ≤ 90 mm Hg, with recovery from prior therapy at least four weeks since prior chemotherapy, radiotherapy or surgery, no prior sorafenib or cetuximab, and no concurrent therapeutic anticoagulation

Exclusion criteria were evidence of bleeding diathesis, uncontrolled illness (active serious infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia or hypertension, HIV positivity), and other malignancies within the past five years.

Patients were randomized to receive cetuximab with or without oral sorafenib. Patients received cetuximab IV over 1 - 2 hours on days 1, 8, 15, and 22 and oral sorafenib twice daily on days 1 - 28. Treatment was repeated every four weeks in the absence of disease progression or unacceptable toxicity. Cetuximab was given at an initial dose of 400 mg/m 2 , followed by weekly infusions of 250 mg/m 2 . A histamine-receptor antagonist diphenhydramine 50 mg was given intravenously as premedication before at least the first infusion. Sorafenib is available as 200-mg, film-coated tablets. The recommended dosage is 400 mg twice / day, at least one hour before or two hours after food intake. The patients were stratified according to tumor K-ras status (wild type vs. codon 12 / 13 mutations in K-ras) by DNA sequencing[4] . All patients were to be treated until disease progression or unacceptable toxic effects occurred. In case of disease progression, the patients assigned to the monotherapy group could continue to receive combined cetuximab and sorafenib.

The evaluation of patients was done. Blood samples were collected periodically for blood counts, hepatic, and renal functions. Tumor tissue collected prior to and during the study treatment was analyzed for K-ras mutations. Patients underwent weekly blood counts, and physical examinations were performed at every fourth week while on study. Patients should have their blood pressure checked weekly for the first eight weeks of therapy. Any hypertension should be treated appropriately. Tumor response was evaluated every eight weeks for the first 24 weeks, and thereafter, every three months, with the use of consistent imaging techniques (CT or MRI). Assessment was performed with the Response Evaluation Criteria in Solid Tumors (RECIST).[5] Toxic effects were assessed according to the National Cancer Institute Common Toxicity Criteria, version 2.[6] Modifications of the dose of cetuximab were made only in cases of toxic effects to the skin.

The study was conducted according to Simon's two-stage phase II design,[7] provided 80% power, and a 0.05 level of significance, given an unacceptable response probability of 5% (P0) versus the alternative hypothesis of at least 20% response (P1). Alpha and beta errors were set at 5 and 20%, respectively. The planned sample size was 34 patients, with 10 patients in the first stage. If one or more responses were seen in the first stage, the trial was continued. The primary end point was the rate of confirmed radiological tumor response in the intention-to-treat population. Differences in response rates between the two groups were evaluated by means of a two-sided Fisher's exact test. The P value of less than 0.05 indicated statistical significance. Secondary end points included time to progression, overall survival time, and incidence of adverse effects. The time to progression was calculated as the period from the date of randomization to the first observation of disease progression, or to death, from any cause, within 60 days after randomization or the most recent tumor assessment. Overall survival time was calculated as a period from the date of randomization until death from any cause or until the date of last follow-up, at which point the, data were censored. Statistical analysis was conducted by using the Statistical Product and Service Solutions, SPSS 10.0, with estimation of both time to progression and overall survival time by the Kaplan-Meier method [8] and comparing the two groups with the use of the log-rank test.[9]


Thirty-five patients from October 2007 to June 2009, diagnosed with metastatic colorectal carcinoma with tumor progression after previous first-line therapy were admitted into the study. The patients had progression on previous oxaliplatin or irinotecan-based chemotherapy. All patients were evaluable for response and toxicity. Patients' characteristics in [Table 1] show well-balanced data at baseline with no statistically significant difference between the treatment groups.{Table 1}

[Table 2]a shows that the partial response was higher in the combined cetuximab-sorafenib group compared to the cetuximab group (P = 0.44). [Table 2]b shows the response in both treatment groups, in relation to the K-ras status. Cases with mutant K-ras had disease progression in 35.3 and 38.9% in the (E) and (EN) groups respectively (P = 1). Response of treatment was stratified according to the K-ras status as shown in [Table 2]c. All cases of partial response had wild K-ras that constituted 40.9% compared to 0% in the mutant type (P = .013), while all cases of mutant K-ras (13 patients) had disease progression compared to 36.4% of wild type (P = .0001).{Table 2}

Univariate and multivariate analysis of different factors (age, gender, performance status, K-ras type, and treatment regimen) revealed that K-ras status had statistically significant P values (0.03 and 0.04, respectively) in progression-free survival as presented in [Table 3].{Table 3}

With a median period of follow-up, of 8.5 months (1.1 - 13.7 months), the current study showed that addition of sorafenib to cetuximab had higher median OS than the cetuximab group, but without a statistically significant difference (P = 0.49) as shown in [Table 4]a and [Figure 1].{Table 4}{Figure 1}

Progression-free survival had a statistically higher significant difference (P = .0001) in patients with wild K-ras patients of (E) and (EN) groups compared to mutant K-ras cases of both groups, respectively, as shown in [Table 4]b and [Figure 2]. Median OS was higher in wild K-ras patients in the (E) and (EN) groups compared to mutant K-ras patients of both groups, respectively, (P = .09) as shown in [Table 4]b and [Figure 3].{Figure 2}{Figure 3}

Toxicity of cetuximab (E) and combined cetuximab-sorafenib (EN) was nearly similar without astatistical significant difference, except for hand and foot syndrome, it was higher in the (EN) group than in the (E) group (P = 0.02) as presented in [Table 5].{Table 5}

The average cost of one cycle of four weeks of cetuximab was 35,960 ± 170 compared to 71,850 ± 130 Egyptian pounds for cetuximab - sorafenib regimen as shown in [Table 6].{Table 6}


The epidermal growth factor receptor (EGFR) is relevant in colorectal cancer because the upregulation of the EGFR gene occurs in 60 to 80% of the cases.[10],[11],[12] Dimerization activates the intracellular tyrosine kinase region of the EGFR, resulting in initiating a cascade of intracellular events[13] that regulate cell differentiation, proliferation, migration, angiogenesis, and apoptosis, all of which become deregulated in the cancer cells.[14]

Cetuximab (Erbitux) binds to the extracellular domain of EGFR, thus blocking the ligand-induced phosphorylation of EGFR.[15],[16] It is not clear if EGFR tyrosine kinase mutations really confer a greater susceptibility to EGFR-targeted antibodies.[17],[18] Mutations in other genes in the EGFR pathway, such as PI3K, K-ras, and B-raf, are more frequent in colorectal cancer, but their relationship with response to EGFR-targeted antibodies is less well studied and also conflicting.[19],[20],[21]

The current study has shown that K-ras mutations occurred in 37.1% of all patients in both groups, which was slightly higher than the results of Federica Di Nicolantonio and colleagues[22] who found it in 30% of the cases, while other studies[20],[23] reported that K-ras mutations occurred in 43% of the cases. These variable incidences of K-ras mutations could be attributed to different patient populations and sample size in different studies.

The current study has shown that K-ras mutation constituted 50% of all non-responding cases of all patients, whereas, 42.9 and 58.3% of the (E) and (EN) groups, respectively. Partial response occurred only in 40.9% of the wild K-ras patients, which reflected that the K-ras gene was not the only factor determining the response to treatment. Partial response was higher in wild K-ras patients of the (EN) group 6/11 (54.5%) compared to 3/11 (27.3%) of the (E) group, which revealed that addition of sorafenib had a beneficial effect in targeting factors other than K-ras, which matched the results of other studies [22],[24]. However, the response rates in the current study seem to be quite high, which could be attributed to the relatively small sample size.

The current study shows that partial response has a statistically higher significant incidence in wild K-ras compared to mutant K-ras cases that coincide with the studies[23],[25] that have found response rates to the EGFR antibodies, which were (6.3 versus 26.5%) and (17 versus 0%), for wild versus mutant K-ras groups, in both studies, respectively.

Blocking K-ras / B-raf pathways with cetuximab and sorafenib had partial response in only 33.3% of the cases, while disease progression occurred in 55.6% of the cases, which could be attributed to other signaling pathways.

Multiple cellular pathways influence the growth and metastatic potential of tumors. This creates heterogeneity, and the potential for tumors to bypass signaling pathway blockades, resulting in primary or acquired resistance. Therefore, targeting a single cell surface protein tyrosine kinase such as EGFR may not be enough to inhibit growth or survival signals. Thus, tumors may be primarily resistant or could become resistant. Combining therapies that inhibit different signaling pathways are more effective. Sorafenib (Nexavar), a multikinase inhibitor inhibits tumor growth and tumor angiogenesis by targeting Raf kinase, vascular endothelial growth factor receptor, platelet-derived growth factor receptor, tyrosine kinases, Fms-like tyrosine kinase-3 (Flt3), stem cell growth factor receptor (c-KIT), and p38a, a member of the MAP kinase family.[26],[27],[28],[29]

Although K-ras mutations may be a common genetic aberration involved in carcinogenesis, mutations of other genes, such as, B-raf, phosphatase, and tensin homolog (PTEN or PI3K) can lead to unrestricted growth of cancer cells. Loss of PTEN activity was associated with lack of efficacy of cetuximab, in patients with colorectal cancer.[30],[31]

Phosphatidylinositol 3-kinases (PI3Ks) are heterodimeric kinases composed of regulatory and catalytic subunits that are involved in the control of cell proliferation, survival, and motility. The PI3K catalytic subunit (PIK3CA) mutations are reported to be associated with resistance to EGFR-targeted monoclonal antibodies, with shorter PFS, in patients with metastatic colorectal cancer. [32],[33]

Cell lines with both PIK3CA mutant / PTEN null and Ras / BRAF mutant had significantly maximal resistance to cetuximab than cell lines without mutations in both these pathways. Mutation screening analysis of colon cancer cell lines revealed that 56% with Ras / BRAF mutations harbored a synchronous PIK3CA / PTEN mutation and 90% of the cell lines harboring PIK3CA / PTEN mutations contained synchronous Ras / BRAF mutations. [34],[35],[36],[37]

The current study revealed that progression-free and overall survival was statistically higher in wild K-ras patients than mutant K-ras cases, and the median overall survival was significantly higher in K-ras wild type versus mutants (43 versus 27.3 weeks) [38] that coincided with our results even though the median overall survival in the current study was statistically insignificant. The higher incidence of survivals in the cetuximab - sorafenib group than in the monotherapy cetuximab arm could be attributed to the extended target therapy toward B-raf as a beneficial effect with the addition of sorafenib.

The tolerability of cetuximab makes it an attractive option for combination with other cancer treatments. Sorafenib had no severe toxic effects on the heart or thyroid gland that coincided with the study, [39] which reported that serious adverse events including cardiac ischemia, infarction or hypertension occurred in 2% of the cases.

In conclusion, the study reflects that the mutation status of molecular markers such as K-ras and B-raf is a predictor of response. K-ras mutation has a significant effect on response and progression-free survival, so genotyping of tumors is needed for defining the patient population, which will probably benefit from targeted therapy. A combination of therapies that simultaneously target K-ras and B-raf can be useful approaches to increase the number of patients who may benefit from anti-EGFR therapy, however, large scale prospective randomized trials are needed to properly determine the patients who are best candidates for these targeted agents.


1Saltz LB, Meropol NJ, Loehrer PJ Sr, Needle MN, Kopit J, Mayer RJ. Phase II Trial of Cetuximab in Patients With Refractory Colorectal Cancer That Expresses the Epidermal Growth Factor Receptor. J Clin Oncol 2004;22:1201-8.
2Gollob JA, Wilhelm S, Carter C, Kelley SL. Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Semin Oncol 2006;33:392-406.
3Ratain MJ, Eisen T, Stadler WM, Flaherty KT, Kaye SB, Rosner GL, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2006;24:2505-12.
4Lopez-Crapez E, Livache T, Caillat P, Zsoldos D. Detection of K-ras Mutations by a Microelectronic DNA Chip, Methods in Molecular Medicine; Molecular Diagnosis of Cancer. Springer Science 2004;97:337-54.
5Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, 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 2000;92:205-16.
6Scharf O, Colevas AD. Adverse event reporting in publications compared with sponsor database for cancer clinical trials. J Clin Oncol 2006;24:3933-8.
7Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989;10:1-10.
8Dinse GE, Lagakos SW. Nonparametric estimation of lifetime and disease onset distributions from incomplete observations. Biometrics 1982;38:921-32.
9DiRienzo AG. Nonparametric comparison of two survival-time distributions in the presence of dependent censoring. Biometrics 2003;59:497-504.
10Messa C, Russo F, Caruso MG, Di Leo A. EGF, TGF-alpha and EGF-R in human colorectal adenocarcinoma. Acta Oncol 1998;37:285-9.
11Porebska I, Harlozinska A, Bojarowski T. Expression of the tyrosine kinase activity growth factor receptors (EGFR, ERB B2, ERB B3) in colorectal adenocarcinomas and adenomas. Tumour Biol 2000;21:105-15.
12Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995;19:183-32.
13Klapper LN, Kirschbaum MH, Sela M, Yarden Y. Biochemical and clinical implications of the ErbB/HER signaling network of growth factor receptors. Adv Cancer Res 2000;77:25-79.
14Ciardiello F, Tortora G. novel approach in the treatment of cancer: targeting the epidermal growth factor receptor. Clin Cancer Res 2001;7:2958-70.
15Fan Z, Masui H, Altas I, Mendelsohn J. Blockade of epidermal growth factor receptor function by bivalent and monovalent fragments of 225 anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res 1993;53:4322-8.
16Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337-45.
17Lenz HJ, Van Cutsem E, Khambata-Ford S, Mayer RJ, Gold P, Stella P, et al. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol 2006;24:4914-21.
18Ji H, Li D, Chen L, Shimamura T, Kobayashi S, McNamara K, et al. The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies. Cancer Cell 2006;9:485-95.
19Moroni M, Veronese S, Benvenuti S, Marrapese G, Sartore-Bianchi A, Di Nicolantonio F, et al. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to anti-EGFR treatment in colorectal cancer: a cohort study. Lancet Oncol 2005;6:279-86.
20Lievre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 2006;66:3992-5.
21Jimeno A, Messersmith WA, Hirsch FR, Franklin WA, Eckhardt SG. KRAS Mutations and Susceptibility to Cetuximab and Panitumumab in Colorectal Cancer. Cancer J 2009;15:110-13.
22Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, et al. Wild-Type BRAF Is Required for Response to Panitumumab or Cetuximab in Metastatic Colorectal Cancer. J Clin Oncol 2008;26:5705-12.
23Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008;26:1626-34.
24Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, Zanon C, Moroni M, Veronese S, 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 2007;67:2643-8.
25Cappuzzo F, Varella-Garcia M, Finocchiaro G, Skokan M, Gajapathy S, Carnaghi C, et al. Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients. Br J Cancer 2008;99:83-9.
26Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004;64:7099-109.
27Sridhar SS, Hedley D, Siu LL. Raf kinase as a target for anticancer therapeutics. Mol Cancer Ther 2005;4:677-85.
28Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 2006;5:835-44.
29Kupsch P, Henning BF, Passarge K, Richly H, Wiesemann K, Hilger RA, et al. Results of a phase I trial of sorafenib (BAY 43-9006) in combination with oxaliplatin in patients with refractory solid tumors, including colorectal cancer. Clin Colorectal Cancer 2005;5:188-96.
30Frattini M, Saletti P, Romagnani E, Martin V, Molinari F, Ghisletta M, et al. PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer 2007;97:1139-45.
31Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, et al. K-ras Mutations and Benefit from Cetuximab in Advanced Colorectal Cancer. NEJM 2008;359:1757-65.
32Sartore-Bianchi A, Martini M, Molinari F, Veronese S, Nichelatti M, Artale S, et al. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Research 2009;69:1851-7.
33Egloff AM, Grandis JR. Improving Response Rates to EGFR-Targeted Therapies for Head and Neck Squamous Cell Carcinoma: Candidate Predictive Biomarkers and Combination Treatment with Src Inhibitors. J Oncol 2009;2009:896407
34Jhawer M, Goel S, Wilson AJ, Montagna C, Ling YH, Byun DS, et al. PIK3CA Mutation/PTEN Expression Status Predicts Response of Colon Cancer Cells to the Epidermal Growth Factor Receptor Inhibitor Cetuximab. Cancer Research 2008;68:1953.
35Parsons DW, Wang TL, Samuels Y, Bardelli A, Cummins JM, DeLong L, et al. Colorectal cancer: mutations in a signaling pathway. Nature 2005;436:792.
36Velho S, Oliveira C, Ferreira A, Ferreira AC, Suriano G, Schwartz S Jr, et al. The prevalence of PIK3CA mutations in gastric and colon cancer. Eur J Cancer 2005;41:1649-54.
37Perrone F, Lampis A, Orsenigo M, Di Bartolomeo M, Gevorgyan A, Losa M, et al. PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Annals of Oncology 2009;20:84-90.
38Roock W, Piessevaux H, De Schutter J, Janssens M, De Hertogh G, Personeni N, et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol 2008;19:508-15.
39Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in advanced clear-cell renal-cell carcinomas. N Engl J Med 2007;356:125-34.