Annals of Oncology Advance Access originally published online on November 12, 2007
Annals of Oncology 2008 19(3):508-515; doi:10.1093/annonc/mdm496
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gastrointestinal tumors |
KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab
1 Center for Human Genetics, Katholieke Universiteit Leuven, Leuven
2 Service de Gastro-entérologie, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels
3 Independent biostatistician, Mechelen
4 Department of Morphology and Molecular Pathology University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Leuven
5 Digestive Oncology Unit, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Leuven
6 Department of Gastroenterology, Gastro-Intestinal Cancer Unit, Erasme University Hospital, Université Libre de Bruxelles, Brussels
7 Digestive Oncology Unit, Ghent University Hospital, Ghent
8 Clinique des Pathologies Tumorales du Côlon et du Rectum, Centre du Cancer, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
* Correspondence to: Prof. S. Tejpar, Digestive Oncology Unit, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. Tel: +32-16-344218; Fax: +32-16-344419; E-mail: sabine.tejpar{at}uz.kuleuven.be
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Abstract |
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 Top Abstract introductionpatients and methodsresultsdiscussionfundingsupplementary dataappendix 1AcknowledgementsReferences |
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Background: KRAS mutation status is a candidate marker for predicting survival in patients with metastatic colorectal cancer (mCRC) treated with cetuximab (CTX).
Patients and methods: 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.
Results: 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)].
Conclusions: 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.
Key words: cetuximab, colorectal cancer, EGFR, KRAS, survival
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingsupplementary dataappendix 1AcknowledgementsReferences |
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A recent advance in oncology is the targeting of the epidermal growth factor receptor (EGFR) in the treatment of many tumor types. Cetuximab (CTX) (Erbitux®, Merck KGaA, Darmstadt, Germany) is a chimeric immunoglobulin G1 monoclonal antibody which binds the EGFR with high affinity and competitively inhibits ligand binding [1]. This prevents activation of downstream signalling pathways such as the PI3K/Akt, RAS/Erk and STAT pathways, resulting in the inhibition of cellular proliferation and in the induction of apoptosis. However, for many tumor types including metastatic colorectal cancer (mCRC), it is not clear what proportion of tumors are dependent on EGFR signalling for their survival, nor how additional molecular alterations present in the tumor may influence primary or secondary resistance to EGFR inhibitors. CTX is approved for irinotecan-resistant mCRC expressing EGFR by immunohistochemistry (IHC). Response rates in this group however only amount to 23% in combination with chemotherapy and about 10% in monotherapy [2, 3]. Increased response rates in the combination arm did not translate into increased survival. As yet no clinical or molecular markers are available to identify those patients with a longer overall survival (OS). Predictive markers of response and survival benefit after CTX are urgently required to allow the rational and effective use of these drugs.
In a small series, Lièvre et al. [4] have shown objective response (OR) to CTX to be excluded in KRAS-mutated CRC and most importantly, showed an increase in OS for the KRAS wild-type (WT) patients. We retrospectively studied the ability of KRAS mutations and tumor regression on computerized tomography (CT) to predict OR, progression-free survival (PFS) and OS benefit in a large series of mCRC patients treated with CTX.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingsupplementary dataappendix 1AcknowledgementsReferences |
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patient characteristics
We included 113 irinotecan refractory mCRC patients with positive IHC for EGFR derived from four clinical trials (EVEREST, BOND, SALVAGE and BABEL) from four Belgian centers [2, 5, 6] (Appendix 1; Table 1 and Table 2, the latter being available online). Patients were included according to availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue. This retrospective study was carried out after approval of the Ethics Review Board.
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DNA extraction and mutation analysis
Tumor DNA was extracted from FFPE sections after macrodissection. The presence of KRAS and BRAF mutations was determined by an allelic discrimination assay on a 7500HT Real Time PCR System (Applied Biosystems, Foster City, CA). KRAS mutations located within the codon 12 (n = 6) and 13 (n = 1) and the BRAF mutation at codon 600 were screened for. All mutations were confirmed by direct sequencing. Probes and conditions were developed together with P. Laurent-Puig and are available upon request [4].
evaluation of OR, PFS and OS
Tumor response was evaluated by CT every 6 weeks until week 24, 30 or 36 and from then on every 12 weeks. Response Evaluation Criteria in Solid Tumors (RECIST) were used to classify tumor response in complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) [7]. PFS was calculated from start of CTX to either progression of disease, death from any cause or last radiological assessment. OS was defined as the period from start of CTX until death.
changes in tumor size
For 102 patients, tumor measurements carried out during the clinical trial were available at baseline, week 6 and every consecutive evaluation. The sum of the longest dimensions of the selected lesions in each patient was calculated, and the relative change of this sum from baseline was computed at every time point.
skin toxicity
Skin toxicity was graded according to National Cancer Institute–Common Toxicity Criteria (version 2.0) [8]. The highest grade of skin toxicity observed was used.
statistical analysis
Differences in OR rates between patients with and without KRAS mutations were evaluated by means of a two-sided Fisher's exact test. Relative changes in tumor size at each time point between tumors with and without KRAS mutations were compared using the Student's t-test. A multiple logistic regression was carried out to determine the impact of covariates on OR. The PFS and the OS were estimated by the Kaplan–Meier method and compared with use of the log-rank test. A Cox regression analysis with backward Wald stepwise elimination procedure for the PFS and the OS was built. The significance level for the removal of a covariate from the model was 0.10. The assumption of normality (t-test) was checked using the Kolmogorov–Smirnov test, the assumption of proportional hazards (Cox regression) via Schoenfeld residuals. A P value of <0.05 was considered to indicate statistical significance. Analyses were carried out using SAS version 8.2 and SPSS for Windows 14.0.
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingsupplementary dataappendix 1AcknowledgementsReferences |
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patient characteristics
The baseline and treatment characteristics of the patients are represented in Table 1. There was no imbalance between patients with and without a KRAS mutation.
mutations
KRAS mutations were detected in 46 of 113 (40.7%) tumors (Table 2, available online).
The BRAF V600E mutation was found in 6 (5.6%) of 107 assessable patients. No patient had tumors carrying both BRAF and KRAS mutations (Fisher's exact test, P = 0.050) (Table 2, available online).
mutation status versus OR
In five patients, OR could not be assessed due to dropout before first evaluation. OR (CR + PR) was observed exclusively in the KRAS WT group. KRAS mutations were absent in the 27 OR patients and found in 42 of 81 (51.9%) in nonresponders (SD + PD) (Fisher's exact test, P = 0.0000001). In SD and PD, KRAS mutations were present in 31 of 59 (52.5%) and 11 of 22 (50.0%) cases, respectively. OR rate was 27 of 66 (41%) in KRAS WT versus 0 of 42 (0%) in KRAS mutants (Table 3). The impact of the KRAS mutation state on OR rate was found both in the combination and the monotherapy group (Fisher's exact test: combination therapy, P = 0.000001; monotherapy, P = 0.126).
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The OR rate was not significantly different in BRAF mutants (1 of 6 (16.6%)) versus WT (26 of 98 (26.5%)) (Fisher's exact test, P = 1).
survival analysis
In univariate analysis, the median PFS was different between KRAS WT and mutants but did not reach statistical significance in the whole study population {24 weeks [95% confidence interval (CI) 17.0–31.0] in WT versus 12 weeks (95% CI 7.2–16.8) in mutants (log-rank test, P = 0.074)} (Figure 1A, available online). However, median PFS in the combination therapy group was significantly different between WT [34 weeks (95% CI 28.5–40.0) and mutants [12 weeks (95% CI 5.4–18.7)] (log-rank test, P = 0.016)] but not in the monotherapy group [WT 12 weeks (95% CI 4.2–20.0) versus mutants 12 weeks (95% CI 7.0–17.0) (log-rank test, P = 0.351)] (Figure 1B and C, available online). The median OS was significantly different between KRAS WT and mutants in the whole study population [43.0 weeks (95% CI 35.5–50.5) versus 27.3 weeks (95% CI 11.9–42.6) (log-rank test, P = 0.020)] (Figure 2A) and in the combination therapy group [44.7 weeks (95% CI 28.4–61.0) versus 27.3 weeks (95% CI 9.5–45.0) (log-rank test, P = 0.003)], but not in the monotherapy group [27 weeks (95% CI 8.9–45.1) versus 25.3 weeks (95% CI 0.0–70.0) (log-rank test, P = 0.330)] (Figure 2B and C) Table 4, available online).
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changes in tumor size
All patients had to have documented radiological progression before starting CTX. For 102 patients, tumor measurements were available at baseline and at least at the first evaluation at 6 weeks. Four had no measurements available to us, two had measurements outside the predefined time points and five stopped the clinical trial before 6 weeks [death (n = 1), biochemical reasons (n = 1), bowel obstruction (n = 1), bowel ischemia (n = 1) or dyspnoea (n = 1)].
The decrease in tumor sizes was more pronounced at all time points in WT patients compared with mutants. The mean relative change in tumor size was: –13.73% (95% CI –20.19 to –7.27) in KRAS WT versus 2.27% (95% CI –1.86 to 6.41) in KRAS mutants (P = 0.00038) at week 6, –24.5% (95% CI –32.02 to –16.99) versus 1.99% (95% CI –3.64 to 7.62) (P = 0.000006) at week 12 and –41.2% (95% CI –50.47 to –31.94) versus 6.09% (95% CI –2.80 to 14.98) (P = 0.0000002) at week 24, respectively (Figure 3). When we used bidimensional (World Health Organization) instead of unidimensional (RECIST) measurements, the difference remained equally significant (data not shown). Subgroup analysis restricted to SD patients, revealed a similar effect of KRAS status on tumor shrinkage. The differences were statistically significant at week 18: –8.84% (95% CI –19.23 to 1.54) in WT versus 4.19% (95% CI –4.17 to 12.55) (P = 0.044) in mutants and at week 24: –14.27% (95% CI –21.90 to –6.63) in WT versus 6.09% (95% CI –2.80 to 14.95) (P = 0.0010) in mutants.
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We carried out a sensitivity analysis to identify the best cut-off, to use the first radiological measurement at 6 weeks as a predictor variable for PFS and OS. OR patients had a median survival of 80.36 weeks (95% CI 64.5–108.63). We used the lower limit of the 95% CI of the OS to categorize the state variable and generated a Receiver Operating Characteristics (ROC) curve testing the relative decrease of the tumor size at 6 weeks. The area under the ROC curve was 0.813 (95% CI 0.725–0.901). Cut-off value –9.66% generated the optimal combination of sensitivity (75%) and specificity (74%). There is a clear association between KRAS mutation status and relative decrease of tumor size >9.66% at week 6 (Fisher's exact test, P = 0.0000095) (Table 5, available online).
We found a significant difference in median PFS and OS between patients with or without relative decrease of tumor size >9.66% at week 6 [median PFS: 36 weeks (95% CI 34.6–37.4) in early responders versus 12 weeks (95% CI 10.0–14.0) in early nonresponders (log-rank test, P = 0.0000011); median OS: 65.9 weeks (95% CI 41.3–90.4)] in early responders versus 31.3 weeks (95% CI 22.9–39.7) in early nonresponders (log-rank test, P = 0.000014)].
predictors of OR
In the logistic regression analysis, using age, sex, KRAS mutation status, skin toxicity, the number of previous lines of chemotherapy and treatment regimen as covariates, we found KRAS status (hazard ratio unavailable because constant in responders) and skin toxicity [hazard ratio (per increase in one grade): 2.35 (95% CI 0.93–5.93; P = 0.070)] being predictive of OR.
predictors of survival
A Cox regression analysis looked at the independent factors (age, sex, KRAS mutation status, skin toxicity, the number of previous lines of chemotherapy and treatment regimen) influencing PFS and OS. PFS was found to be determined by skin toxicity [hazard ratio (per increase in one grade): 0.543 (95% CI 0.387–0.762); (P = 0.00040)]. OS was determined by skin toxicity [hazard ratio (per increase in one grade): 0.477 (95% CI 0.339–0.671); (P = 0.00002)] and KRAS mutation status [hazard ratio: 0.620 (95% CI 0.41–0.921); (P = 0.018)].
When the Cox regression analyses were carried out replacing KRAS mutation status with relative decrease of tumor size >9.66% at week 6, we found PFS being determined by skin toxicity [hazard ratio (per increase in one grade): 0.690 (95% CI 0.480–0.993); (P = 0.046) and by relative decrease of tumor size >9.66% at week 6 (hazard ratio: 2.392 (95% CI 1.530–3.740); (P = 0.00013) and OS by the same variables (hazard ratios: 0.594 (95% CI 0.416–0.849); (P = 0.004) and 2.391 (95% CI 1.540–3.712); (P = 0.00073), respectively]. A model combining KRAS mutation status and early radiological response, together with all the other clinical variables, was not possible to elaborate due to important interaction between both variables.
interaction between KRAS mutation status and early radiological changes in predicting outcome
We analyzed the interaction of KRAS and early radiological response on tumor behavior. For each patient the smallest tumor size and the tumor size at progression were plotted against their time of occurrence (Figure 4). Patients were grouped according to their KRAS and early radiological response status. In patients with early radiological response, we observed that only KRAS WT patients (Figure 4 panel A versus C) showed further decrease in tumor size beyond 6 weeks and achieved the largest tumor size reductions. In addition, these are the patients that show delayed occurrence of progression. Within the KRAS WT patients, only those patients with an early radiological response (Figure 4 panel A versus B) continued to decrease over time and had delayed time to progression. In patients without regression at week 6, no subsequent tumor reduction or delayed occurrence of progression was observed even in KRAS WT patients. Lastly, in rare KRAS mutant patients delayed time to progression was observed, which was not associated to a tumor reduction.
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The interaction of KRAS and early radiological response was also analyzed on the OS. In KRAS WT patients OS was significantly better in patients with an initial decrease compared with those without [median OS: 74.9 weeks (95% CI 55.8–93.9) versus 30.6 weeks (95% CI 19.7–41.5) (log-rank test: P = 0.00000012)]. In contrast, in KRAS mutant patients, OS is similar, whether initial tumor decrease is observed or not [median OS: 17.6 weeks (95% CI 15.7–19.4) versus 32 weeks (95% CI 13.4–50.6) (log-rank test, P = 0.664)] (Figure 5). When comparing OS of patients with KRAS WT status and early tumor size reduction to all others we found a profound survival benefit [median OS: 74.9 weeks (95% CI 55.8–93.9) versus 30.6 weeks (95% CI 22.5–38.7) (log-rank test: P = 0.0000025)].
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingsupplementary dataappendix 1AcknowledgementsReferences |
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The KRAS mutation state of the tumor has been proposed as a promising marker of response to CTX in mCRC [4]. In the setting of irinotecan refractory patients we confirm the clear relationship between KRAS WT state and OR, and demonstrate that KRAS WT is a strong predictor of a significant increase in PFS and OS in these patients.
The ideal biomarker should identify responders and patients with improved survival with high sensitivity and specificity. However, the KRAS status of a tumor may still fall short in this respect, as not all WT patients respond or have improved survival and some mutant patients experience long-term disease control.
Despite the encouraging hazard ratios for survival (0.62) seen in KRAS WT patients as a group, half of these patients will not benefit. In an attempt to further stratify these patients we looked at the additional predictive value of early tumor size reduction on survival. The time point of 6 weeks, at first evaluation, was chosen to avoid selection bias due to dropouts for progression. The early tumor size reduction was shown to be a strong predictor of survival in a Cox regression analysis (hazard ratio: 0.42). There was a correlation between early tumor size reduction and the KRAS mutation status. Both parameters in conjunction were found to predict tumor behavior at later time points. This is demonstrated by the observation that early tumor size reduction will only translate in longlasting and more profound tumor control in KRAS WT patients and only KRAS WT patients with initial tumor decrease will have further and sustained tumor reduction. This translates into survival benefit as shown by the Kaplan–Meier analysis where only KRAS WT patients with an early tumor size reduction had a significantly improved survival. We attempted to build a Cox regression model for predicting survival, including all the clinical variables, KRAS mutation status and early tumor size reduction. The magnitude of the interaction between the KRAS mutation status and early tumor size reduction precluded reliable modeling.
Skin toxicity, a well-known predictor of response, was one of the predictor variables in our models. It was found to impact independently on all outcome parameters: OR, PFS and OS. In univariate log-rank analysis, we found a trend for an impact of skin toxicity on PFS and OS, only in patients with KRAS WT status and early radiological response (data not shown). We would like to point out that skin toxicity remains a difficult parameter to use as a response predictor in general, because of the lack of appropriate toxicity criteria specifically tailored to the effect of EGFR inhibitors. Also, the time point at which the skin toxicity should be graded to maximally reflect its predictive value has not been determined. These issues need to be specifically addressed in the future.
Selecting patients with both KRAS WT status and early tumor size reduction identifies a subgroup with a median OS of 74.9 weeks in comparison to 38.7 weeks for the whole study population or 43.0 weeks for all KRAS WT patients. If the end point were to identify patients surviving longer than 64.5 weeks, our combined parameters would yield a positive predictive value of 57% and a negative predictive value of 88%. The false-positive patients however, still had a clinically relevant survival comparable to that of the whole KRAS WT group (median 43 weeks). The false-negative patients (8) consisted of one WT patient with an initial tumor size decrease of 9.63% whereas the cut-off was set at 9.66% and seven mutant patients. These patients, as shown in panel D of Figure 4, are characterized by the absence of tumor decrease and a long time to progression and OS. This suggests that in KRAS mutant tumors some of the proliferation may still be driven by EGFR signalling and inhibition will result in tumor stabilization. This idea was reinforced when we studied tumor growth rates in KRAS mutant patients before and following initiation of CTX treatment. A clear decrease in tumor growth rates was observed (data not shown). This suggests there may be a subgroup of KRAS mutant patients who may benefit from long-term disease stabilization upon CTX treatment. Lastly, there has been a report on two KRAS mutant patients with an OR on CTX [9, 10]. In our own series, we identified some KRAS mutant patients with tumor shrinkage approaching the 30% cut-off (Figure 3). The mutual exclusion of KRAS mutations and OR may therefore not stand in larger patient sets, however, we found that those KRAS mutant patients who had tumor size decrease had no increased survival (Figure 4C and D).
To be considered for clinical use the molecular and radiological markers presented will need prospective validation. Our model necessitates the combination of a molecular marker and an early response marker that can only be assessed after 6 weeks of treatment. This is not common practice. However, there are clinical scenarios in which our data could already be put to use. In those patients where no tumor material is available, or determination of KRAS status is not feasible, we have shown that early response at 6 weeks is independently associated to longer survival. Alternatively, KRAS status alone could be used to select those patients in which to initiate treatment, but a stopping rule depending on the response at 6 weeks could be introduced. It is our opinion however that in the current paucity of therapeutic options after failing irinotecan- or oxaliplatin- based regimens, the median OS seen in KRAS mutants may be considered clinically relevant. This may represent the biggest barrier to clinical implementation.
We show that the KRAS mutation state impacts significantly on three fundamental aspects of the mCRC treated with CTX: tumor decrease, PFS and OS. Our series consisted mostly of combination therapy patients and no valid conclusions could be drawn for the monotherapy patients due to the small sample size. Kathamba-Ford et al. [11], focussing solely on 80 monotherapy patients, showed a significant association between the KRAS status with both OR and PFS. However, in addition, our series shows the significant association between KRAS status and better OS. A similar trend observed in a smaller series of patients (n = 81) was recently presented [12]. Improved response rates do not always correlate with survival [13]. In our series, the correlation between PFS and OS was good both in the KRAS WT and mutant patients (data not shown), suggesting all the OS benefit derived from the response to therapy. Another recent paper, also found a significant difference in time to progression according to KRAS mutation status in 59 patients [14].
Purely prognostic effects of the KRAS status cannot be excluded without a randomized trial [15]. In two studies of resected liver metastasis no prognostic effect of the KRAS mutations status could be demonstrated nor was there a proliferative advantage for KRAS mutant over WT metastases [16, 17]. A strong prognostic effect of KRAS in mCRC is unlikely, as the RASCAL study could only demonstrate a significant prognostic effect of KRAS in Dukes’ C but not Dukes’ D patients [18].
In the current models, KRAS is regarded as the main effector of the EGFR signalling cascade and may represent a bottleneck in the signalling pathway. Mutations of KRAS will constitutively activate the pathway and render it resistant to upstream inhibitors. If this model holds true, KRAS mutations may be negative predictors of response even in the presence of supra-normal upstream activation such as seen with EGFR amplifications or increased ligand expression [11].
In conclusion, patients characterized by the WT state and initial tumor regression tumor represent a subgroup with the largest survival benefit. The challenge lies in identifying the molecular markers that type these subgroups, so they can be identified early on in the therapeutic approach. In this regard, the recently published data [11] on high EGFR ligand expression in tumors responding to CTX is promising. We believe our work and that of others represent significant steps towards the optimal use of EGFR-targeting therapies.
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funding |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingsupplementary dataappendix 1AcknowledgementsReferences |
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Belgian Foundation against Cancer (SCIE2005-24); Unrestricted grant, Merck KGaA, Darmstadt, Germany.
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supplementary data |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingsupplementary dataappendix 1AcknowledgementsReferences |
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Figure 1 and Tables 2, 4 and 5 are available online to subscribers.
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appendix 1 |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingsupplementary dataappendix 1AcknowledgementsReferences |
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Centers having provided tumor samples and patient data:
University Hospital Gasthuisberg, Leuven, Belgium; Ghent University Hospital, Ghent, Belgium; Cliniques universitaires St-Luc, Brussels, Belgium; Hôpital Erasme, Brussels, Belgium.
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Acknowledgements |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingsupplementary dataappendix 1AcknowledgementsReferences |
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The authors wish to thank Liesbeth Lemmens, Hilde Marsé, Martine Crabbé, Dimphna Van Reijen (clinical trial coordinators, University Hospital Gasthuisberg, Leuven, Belgium), Muriel De Cooman (clinical trial coordinator, Cliniques universitaires St-Luc, Brussels, Belgium) and Nancy Van Damme (Universiteit Gent) for the data collection. ST had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. ST and EVC are Senior Clinical Investigator of the Fund for Scientific Research—Flanders (Belgium) (Fonds Wetenschappelijk Onderzoek – Vlaanderen). The research sponsor (University Hospital Gasthuisberg) had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; or preparation, review, or approval of the manuscript.
Received for publication June 26, 2007. Revision received September 12, 2007. Accepted for publication September 14, 2007.
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References |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingsupplementary dataappendix 1AcknowledgementsReferences |
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1. Harding J, Burtness B. Cetuximab: an epidermal growth factor receptor chimeric human-murine monoclonal antibody. Drugs Today (2005) 41:107–127.[CrossRef][Medline]
2. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med (2004) 351:337–345.
3. 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 (2004) 22:1201–1208.
4. Lièvre A, Bachet JB, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res (2006) 66:3992–3995.
5. 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 (2006) 24:4914–4921.
6. Tejpar S, Peeters M, Humblet Y, et al. Dose-escalation study using up to twice the standard dose of cetuximab in patients with metastatic colorectal cancer (mCRC) with no or slight skin reactions on cetuximab standard dose treatment (EVEREST study): preliminary data. J Clin Oncol (2006) 24:159S. (Abstr 3554).
7. 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 (2000) 92:205–216.
8. Common Toxicity Criteria v2.0 (CTC). Cancer Therapy Evaluation Program (1999) National Cancer Institute. http://ctep.cancer.gov/reporting/ctc.html (13 July 2006, date last accessed).
9. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, et al. Oncogenic activation of the RAS/RAF signalling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res (2007) 67:2643–2648.
10. 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 (2005) 6:279–286.[CrossRef][Web of Science][Medline]
11. Khambata-Ford S, Garrett CR, Clark EA, et al. Expression of epiregulin and amphiregulin and K-Ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol (2007) 25:3230–3237.
12. Finocchiaro G, Cappuzzo F, Jänne PA, et al. EGFR, HER2 and Kras as predictive factors for cetuximab sensitivity in colorectal cancer. 2007 ASCO Annual Meeting Proceedings Part I. J Clin Oncol. 25 (18 Suppl): 2007 (Abstr 4021).
13. Buyse M, Thirion P, Carlson RW, et al. Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis. Lancet (2000) 356:373–378.[CrossRef][Web of Science][Medline]
14. Di Fiore F, Blanchard F, Charbonnier F, et al. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br J Cancer (2007) 96:1166–1169.[CrossRef][Web of Science][Medline]
15. Jonker DJ, Karapetis CS, Moore M, et al. Randomized Phase III Trial of Cetuximab Monotherapy Plus Best Supportive Care (BSC) Versus BSC Alone in Patients with Pretreated Metastatic Epidermal Growth Factor Receptor (EGFR)-Positive Colorectal Carcinoma: A Trial of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) and the Australasian Gastro-Intestinal Trials Group (AGITG) [Abstract]. Presented at the American Association for Cancer Research Annual Meeting, Los Angeles, CA, 14–18 April 2007.
16. Kastrinakis WV, Ramchurren N, Maggard M, et al. K-ras status does not predict successful hepatic resection of colorectal cancer metastasis. Arch Surg (1995) 130:9–14.
17. Petrowsky H, Sturm I, Graubitz O, et al. Relevance of Ki-67 antigen expression and K-ras mutation in colorectal liver metastases. Eur J Surg Oncol (2001) 27:80–87.[CrossRef][Web of Science][Medline]
18. Andreyev HJ, Norman AR, Cunningham D, et al. Kirsten ras mutations in patients with colorectal cancer: the multicenter "RASCAL" study. J Natl Cancer Inst (1998) 90:675–684.
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K. Klinghammer, M. Knodler, A. Schmittel, V. Budach, U. Keilholz, and I. Tinhofer Association of Epidermal Growth Factor Receptor Polymorphism, Skin Toxicity, and Outcome in Patients with Squamous Cell Carcinoma of the Head and Neck Receiving Cetuximab-Docetaxel Treatment Clin. Cancer Res., January 1, 2010; 16(1): 304 - 310. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Eng The Evolving Role of Monoclonal Antibodies in Colorectal Cancer: Early Presumptions and Impact on Clinical Trial Development Oncologist, January 1, 2010; 15(1): 73 - 84. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Laurent-Puig, A. Cayre, G. Manceau, E. Buc, J.-B. Bachet, T. Lecomte, P. Rougier, A. Lievre, B. Landi, V. Boige, et al. Analysis of PTEN, BRAF, and EGFR Status in Determining Benefit From Cetuximab Therapy in Wild-Type KRAS Metastatic Colon Cancer J. Clin. Oncol., December 10, 2009; 27(35): 5924 - 5930. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. E. Mancl, J. M. Kolesar, and L. C. Vermeulen Clinical and economic value of screening for Kras mutations as predictors of response to epidermal growth factor receptor inhibitors Am. J. Health Syst. Pharm., December 1, 2009; 66(23): 2105 - 2112. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Luthra and Z. Zuo COLD-PCR Finds Hot Application in Mutation Analysis Clin. Chem., December 1, 2009; 55(12): 2077 - 2078. [Full Text] [PDF]
|
|
|
|
|
|
S. Ogino, J. A. Meyerhardt, N. Irahara, D. Niedzwiecki, D. Hollis, L. B. Saltz, R. J. Mayer, P. Schaefer, R. Whittom, A. Hantel, et al. KRAS Mutation in Stage III Colon Cancer and Clinical Outcome Following Intergroup Trial CALGB 89803 Clin. Cancer Res., December 1, 2009; 15(23): 7322 - 7329. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Whitehall, K. Tran, A. Umapathy, F. Grieu, C. Hewitt, T.-J. Evans, T. Ismail, W. Q. Li, P. Collins, P. Ravetto, et al. A Multicenter Blinded Study to Evaluate KRAS Mutation Testing Methodologies in the Clinical Setting J. Mol. Diagn., November 1, 2009; 11(6): 543 - 552. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Jacobs, W. De Roock, H. Piessevaux, R. Van Oirbeek, B. Biesmans, J. De Schutter, S. Fieuws, J. Vandesompele, M. Peeters, J.-L. Van Laethem, et al. Amphiregulin and Epiregulin mRNA Expression in Primary Tumors Predicts Outcome in Metastatic Colorectal Cancer Treated With Cetuximab J. Clin. Oncol., October 20, 2009; 27(30): 5068 - 5074. [Abstract] [Full Text] [PDF]
|
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|
|
 |
|
 S. Siena, A. Sartore-Bianchi, F. Di Nicolantonio, J. Balfour, and A. Bardelli Biomarkers Predicting Clinical Outcome of Epidermal Growth Factor Receptor-Targeted Therapy in Metastatic Colorectal Cancer J Natl Cancer Inst, October 7, 2009; 101(19): 1308 - 1324. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E S K Ma, C L P Wong, F B F Law, W-K Chan, and D Siu Detection of KRAS mutations in colorectal cancer by high-resolution melting analysis J. Clin. Pathol., October 1, 2009; 62(10): 886 - 891. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Mittmann, H.-J. Au, D. Tu, C. J. O'Callaghan, P. K. Isogai, C. S. Karapetis, J. R. Zalcberg, W. K. Evans, M. J. Moore, J. Siddiqui, et al. Prospective Cost-Effectiveness Analysis of Cetuximab in Metastatic Colorectal Cancer: Evaluation of National Cancer Institute of Canada Clinical Trials Group CO.17 Trial J Natl Cancer Inst, September 2, 2009; 101(17): 1182 - 1192. [Abstract] [Full Text] [PDF]
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|
|
|
|
C. L.H. Snozek, D. J. O'Kane, and A. Algeciras-Schimnich Pharmacogenetics of Solid Tumors: Directed Therapy in Breast, Lung, and Colorectal Cancer: A Paper from the 2008 William Beaumont Hospital Symposium on Molecular Pathology J. Mol. Diagn., September 1, 2009; 11(5): 381 - 389. [Abstract] [Full Text] [PDF]
|
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|
 |
|
 H. Piessevaux, M. Buyse, W. De Roock, H. Prenen, M. Schlichting, E. Van Cutsem, and S. Tejpar Radiological tumor size decrease at week 6 is a potent predictor of outcome in chemorefractory metastatic colorectal cancer treated with cetuximab (BOND trial) Ann. Onc., August 1, 2009; 20(8): 1375 - 1382. [Abstract] [Full Text] [PDF]
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L.-C. Yen, Y.-S. Yeh, C.-W. Chen, H.-M. Wang, H.-L. Tsai, C.-Y. Lu, Y.-T. Chang, K.-S. Chu, S.-R. Lin, and J.-Y. Wang Detection of KRAS Oncogene in Peripheral Blood as a Predictor of the Response to Cetuximab Plus Chemotherapy in Patients with Metastatic Colorectal Cancer Clin. Cancer Res., July 1, 2009; 15(13): 4508 - 4513. [Abstract] [Full Text] [PDF]
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|
A. Debucquoy, K. Haustermans, A. Daemen, S. Aydin, L. Libbrecht, O. Gevaert, B. De Moor, S. Tejpar, W. H. McBride, F. Penninckx, et al. Molecular Response to Cetuximab and Efficacy of Preoperative Cetuximab-Based Chemoradiation in Rectal Cancer J. Clin. Oncol., June 10, 2009; 27(17): 2751 - 2757. [Abstract] [Full Text] [PDF]
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|
|
F. Loupakis, L. Pollina, I. Stasi, A. Ruzzo, M. Scartozzi, D. Santini, G. Masi, F. Graziano, C. Cremolini, E. Rulli, et al. PTEN Expression and KRAS Mutations on Primary Tumors and Metastases in the Prediction of Benefit From Cetuximab Plus Irinotecan for Patients With Metastatic Colorectal Cancer J. Clin. Oncol., June 1, 2009; 27(16): 2622 - 2629. [Abstract] [Full Text] [PDF]
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B. Nordlinger, E. Van Cutsem, T. Gruenberger, B. Glimelius, G. Poston, P. Rougier, A. Sobrero, M. Ychou, and on behalf of the European Colorectal Metastases Tr Combination of surgery and chemotherapy and the role of targeted agents in the treatment of patients with colorectal liver metastases: recommendations from an expert panel Ann. Onc., June 1, 2009; 20(6): 985 - 992. [Abstract] [Full Text] [PDF]
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|
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K. -L. Garm Spindler, N. Pallisgaard, A. A. Rasmussen, J. Lindebjerg, R. F. Andersen, D. Cruger, and A. Jakobsen The importance of KRAS mutations and EGF61A>G polymorphism to the effect of cetuximab and irinotecan in metastatic colorectal cancer Ann. Onc., May 1, 2009; 20(5): 879 - 884. [Abstract] [Full Text] [PDF]
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H. Prenen, J. De Schutter, B. Jacobs, W. De Roock, B. Biesmans, B. Claes, D. Lambrechts, E. Van Cutsem, and S. Tejpar PIK3CA Mutations Are Not a Major Determinant of Resistance to the Epidermal Growth Factor Receptor Inhibitor Cetuximab in Metastatic Colorectal Cancer Clin. Cancer Res., May 1, 2009; 15(9): 3184 - 3188. [Abstract] [Full Text] [PDF]
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|
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|
C. J. Allegra, J. M. Jessup, M. R. Somerfield, S. R. Hamilton, E. H. Hammond, D. F. Hayes, P. K. McAllister, R. F. Morton, and R. L. Schilsky American Society of Clinical Oncology Provisional Clinical Opinion: Testing for KRAS Gene Mutations in Patients With Metastatic Colorectal Carcinoma to Predict Response to Anti-Epidermal Growth Factor Receptor Monoclonal Antibody Therapy J. Clin. Oncol., April 20, 2009; 27(12): 2091 - 2096. [Abstract] [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. Health-Related Quality of Life in Patients With Advanced Colorectal Cancer Treated With Cetuximab: Overall and KRAS-Specific Results of the NCIC CTG and AGITG CO.17 Trial J. Clin. Oncol., April 10, 2009; 27(11): 1822 - 1828. [Abstract] [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. Cetuximab and Chemotherapy as Initial Treatment for Metastatic Colorectal Cancer N. Engl. J. Med., April 2, 2009; 360(14): 1408 - 1417. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Levy, G. Sycz, J. M. Arriaga, M. M. Barrio, E. M. von Euw, S. B. Morales, M. Gonzalez, J. Mordoh, and M. Bianchini Cetuximab-mediated cellular cytotoxicity is inhibited by HLA-E membrane expression in colon cancer cells Innate Immunity, April 1, 2009; 15(2): 91 - 100. [Abstract] [PDF]
|
|
|
|
|
|
S. Staal, M. J. O'Connell, and C. J. Allegra The Marriage of Growth Factor Inhibitors and Chemotherapy: Bliss or Bust? J. Clin. Oncol., April 1, 2009; 27(10): 1545 - 1548. [Full Text] [PDF]
|
|
|
|
 |
|
 R. F. Morton and E. H. Hammond ASCO Provisional Clinical Opinion: KRAS, Cetuximab, and Panitumumab--Clinical Implications in Colorectal Cancer J. Oncol. Pract, March 1, 2009; 5(2): 71 - 72. [Full Text] [PDF]
|
|
|
|
|
|
A. Jimeno, W. A. Messersmith, F. R. Hirsch, W. A. Franklin, and S. G. Eckhardt KRAS Mutations and Sensitivity to Epidermal Growth Factor Receptor Inhibitors in Colorectal Cancer: Practical Application of Patient Selection J. Clin. Oncol., March 1, 2009; 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. Impact of Fc{gamma}RIIa-Fc{gamma}RIIIa Polymorphisms and KRAS Mutations on the Clinical Outcome of Patients With Metastatic Colorectal Cancer Treated With Cetuximab Plus Irinotecan 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. Epidermal growth factor receptor gene copy number, K-ras mutation and pathological response to preoperative cetuximab, 5-FU and radiation therapy in locally advanced rectal cancer Ann. Onc., March 1, 2009; 20(3): 469 - 474. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Marchetti, G. Gasparini, M. Albitar, C. Yeh, W. Ma, W. De Roock, D. Lambrechts, S. Tejpar, T. Winder, W. Scheithauer, et al. K-ras Mutations and Cetuximab in Colorectal Cancer N. Engl. J. Med., February 19, 2009; 360(8): 833 - 836. [Full Text] [PDF]
|
|
|
|
|
|
P. Laurent-Puig, A. Lievre, and H. Blons Mutations and Response to Epidermal Growth Factor Receptor Inhibitors 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. Fluorouracil, Leucovorin, and Oxaliplatin With and Without Cetuximab in the First-Line Treatment of Metastatic Colorectal Cancer 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. Chemotherapy, Bevacizumab, and Cetuximab in Metastatic Colorectal Cancer 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 Can Epidermal Growth Factor Receptor-Fluorescent in Situ Hybridization Predict Clinical Benefit From Cetuximab Treatment in Patients With Non-Small-Cell Lung Cancer? J. Clin. Oncol., January 20, 2009; 27(3): 464 - 465. [Full Text] [PDF]
|
|
|
|
|
|
S. Velho, C. Oliveira, and R. Seruca KRAS Mutations and Anti-Epidermal Growth Factor Receptor Therapy in Colorectal Cancer With Lymph Node Metastases 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]
|
|
|
|
|
|
M. Peeters, T. Price, and J.-L. Van Laethem Anti-Epidermal Growth Factor Receptor Monotherapy in the Treatment of Metastatic Colorectal Cancer: Where Are We Today? Oncologist, January 1, 2009; 14(1): 29 - 39. [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. 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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
L. Quaye, S. A. Gayther, S. J. Ramus, R. A. Di Cioccio, V. McGuire, E. Hogdall, C. Hogdall, J. Blaakr, D. F. Easton, B. A.J. Ponder, et al. The Effects of Common Genetic Variants in Oncogenes on Ovarian Cancer Survival Clin. Cancer Res., September 15, 2008; 14(18): 5833 - 5839. [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]
|
|
|
|
|
|
D. Arnold, T. Hohler, C. Dittrich, F. Lordick, T. Seufferlein, J. Riemann, E. Woll, T. Herrmann, A. Zubel, and H.-J. Schmoll Cetuximab in combination with weekly 5-fluorouracil/folinic acid and oxaliplatin (FUFOX) in untreated patients with advanced colorectal cancer: a phase Ib/II study of the AIO GI Group Ann. Onc., August 1, 2008; 19(8): 1442 - 1449. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Borner, D. Koeberle, R. Von Moos, P. Saletti, D. Rauch, V. Hess, A. Trojan, D. Helbling, B. Pestalozzi, C. Caspar, et al. Adding cetuximab to capecitabine plus oxaliplatin (XELOX) in first-line treatment of metastatic colorectal cancer: a randomized phase II trial of the Swiss Group for Clinical Cancer Research SAKK Ann. Onc., July 1, 2008; 19(7): 1288 - 1292. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Lievre and P. Laurent-Puig In Reply J. Clin. Oncol., May 20, 2008; 26(15): 2601 - 2602. [Full Text] [PDF]
|
|
|
|
|
|
A. de Reynies, V. Boige, G. Milano, J. Faivre, and P. Laurent-Puig KRAS Mutation Signature in Colorectal Tumors Significantly Overlaps With the Cetuximab Response Signature J. Clin. Oncol., May 1, 2008; 26(13): 2228 - 2230. [Full Text] [PDF]
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