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Epidermal Growth Factor Receptor Gene Copy Number and Clinical Outcome of Metastatic Colorectal Cancer Treated With Panitumumab

Andrea Sartore-Bianchi, Mauro Moroni, Silvio Veronese, Carlo Carnaghi, Emilio Bajetta, Gabriele Luppi, Alberto Sobrero, Carlo Barone, Stefano Cascinu, Giuseppe Colucci, Enrico Cortesi, Michele Nichelatti, Marcello Gambacorta, Salvatore Siena

From the Ospedale Niguarda Ca' Granda; Istituto Nazionale Tumori, Milan; Istituto Clinico Humanitas, Rozzano; Università Modena e Reggio Emilia, Modena; Ospedale San Martino, Genova; Policlinico Gemelli, Università Cattolica; Policlinico Umberto I, Università La Sapienza, Rome; Università Politecnica Marche, Ancona; and Istituto Tumori Giovanni Paolo II, Bari, Italy

Address reprint requests to Salvatore Siena, MD, Divisione Oncologia Falck, Ospedale Niguarda Ca' Granda, Piazza Ospedale Maggiore 3, 20162 Milan, Italy; e-mail: salvatore.siena{at}ospedaleniguarda.it

	ABSTRACT

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Purpose: In a previous cohort study, we proposed that responsiveness of metastatic colorectal cancer (mCRC) to anti–epidermal growth factor receptor (EGFR) monoclonal antibodies has a genetic basis, being associated with increased EGFR gene copy number (GCN) as measured by fluorescence in situ hybridization (FISH) in individual tumors. The present study was aimed at assessing the predictive role of EGFR GCN, in terms of clinical outcome, in patients treated with panitumumab.

Patients and Methods: Patients with mCRC refractory to standard therapies were a subset of patients from a phase III trial of panitumumab plus best supportive care (BSC; n = 58) versus BSC alone (n = 34) who were selected on the basis of availability of tumor samples adequate for FISH.

Results: In patients treated with panitumumab, a mean EGFR GCN of less than 2.5/nucleus or less than 40% of tumor cells displaying chromosome 7 polysomy within the tumor predicted for shorter progression-free survival (PFS; P = .039 and P = .029, respectively) and overall survival (P = .015 and P = .014, respectively). None of the treated patients with mean EGFR GCN of less than 2.47/nucleus or less than 43% of tumor cells displaying chromosome 7 polysomy obtained objective response compared with six of 20 and six of 19 patients with values greater than these cutoff limits, respectively (P = .0009 and P = .0007, respectively). Evaluation of BSC-treated patients showed no correlation between EGFR GCN or chromosome 7 polysomy status and PFS.

Conclusion: In a larger and more homogeneous series than in previous studies, present exploratory data suggest that mCRC patients with tumors distinguishable by FISH analysis of EGFR as homogenously disomic or with low chromosome 7 polysomy have a reduced likelihood of response to panitumumab.

	INTRODUCTION

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The anti–epidermal growth factor receptor (EGFR) monoclonal antibody (moAb) panitumumab is effective in prolonging survival in patients with metastatic colorectal cancer (mCRC) after failure of conventional chemotherapy.^1,2 Clinical evidence shows that approximately 10% of patients achieve objective tumor response to anti-EGFR moAbs.^1-3 The identification of patients who are likely to benefit from EGFR-targeted moAbs is increasingly crucial for improving therapeutic strategies, as well as for reducing the financial burden of health care systems.⁴

We previously reported that, in mCRC patients, objective tumor response to the EGFR-targeted moAbs cetuximab and panitumumab occurs in a fraction of patients whose tumors have increased gene copy number (GCN) of the EGFR, as assessed by fluorescent in situ hybridization (FISH).⁵ The predictive role of EGFR GCN in mCRC was then evaluated in subsequent studies, where an association with objective tumor response⁶ and overall survival (OS)⁷ was demonstrated after treatment with cetuximab. Nevertheless, because of partial discrepancies and difficult technical reproducibility,⁷ as well as because of the heterogeneity and paucity of evaluated patients, at the present time, no predictive assay has reached the clinical setting to select candidates to anti-EGFR moAb treatment.

The present study was performed to clarify the predictive role of EGFR GCN, in terms of objective response, progression-free survival (PFS), and OS, in patients treated with panitumumab monotherapy. In a larger and more homogeneous patient series than previously performed, we analyzed tumors from patients treated in a randomized phase III trial comparing panitumumab and best supportive care (BSC) with BSC only for treatment of mCRC after failure of regimens containing a fluoropyrimidine, oxaliplatin, and irinotecan.^1,2 The opportunity to also study patients treated with BSC only has allowed us to assess the role of EGFR GCN as a prognostic factor.

	PATIENTS AND METHODS

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Patients
We assessed tumor samples from 64 mCRC patients treated in nine institutions in Italy according to the panitumumab (Amgen, Thousand Oaks, CA) phase III, open-label, randomized 408 trial and the panitumumab open-label continuation 194 trial. Patients had mCRC progressing on or after standard treatments and expressed EGFR by immunohistochemistry, as reported elsewhere.^1,2

The subset of patients for the present study was selected among the 92 patients recruited in Italy based on the availability of tumor tissue adequate for further FISH analysis. Tumor response or resistance to therapy was confirmed radiologically by investigators according to Response Evaluation Criteria in Solid Tumors. Patients gave written informed consent for EGFR analysis and for receiving the study treatment. This study was authorized by the institutional ethical committee (amendment 4).

The association between EGFR GCN and objective tumor response, PFS, and OS was evaluated in 58 patients (33 men and 25 women; median age, 61 years; range, 44 to 78 years) who received panitumumab (408 trial or 194 continuation trial) and in 34 patients (21 men and 13 women; median age, 61 years; range, 44 to 76 years) who were initially randomly assigned to the BSC arm of the 408 trial. The latter group was evaluated for PFS only. Among the 58 patients who received panitumumab, 30 patients received panitumumab from the beginning, and 28 patients started in the BSC arm of the study and then, on progression, received panitumumab in the 194 trial. Among the 34 patients who were analyzed during BSC, six did not cross over to panitumumab. Thus, data from the 28 patients who crossed over to panitumumab treatment were analyzed twice regarding association between GCN and clinical outcome (ie, with and without panitumumab treatment; Fig 1). Total time at risk for calculating OS was 439 patient-months, and median follow-up time was 7.1 months (range, 0.8 to 17.7 months); cumulative time at risk for PFS was 183.5 months, with a median follow-up time of 1.8 months (range, 0.8 to 11.2 months).

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Patient disposition. Patients with metastatic colorectal cancer refractory to standard therapies evaluated in the present study were a subset of patients enrolled onto the 408 phase III trial of panitumumab plus best supportive care (BSC) versus BSC alone.1 Twenty-eight of 34 patients who were randomly assigned to the BSC arm of the study were allowed, at progression of disease (PD), to receive panitumumab in the 194 continuation study trial.2

FISH Analysis of EGFR GCN
Thin tissue sections (2 µm) were placed in a pretreatment solution for 10 minutes at 96°C, allowing them to cool in the same solution for 30 minutes at room temperature. After a wash in buffer solution, the slides were put into pepsin solution for 30 minutes at 37°C. Tissue sections were then stained with a propidium iodide solution (0.6 µg/mL; QBiogene, Irvine, CA) to verify whether nuclei of tumor cells were adequately digested for a subsequent optimal permeabilization of probes. If enzymatic digestion was considered incomplete, further steps of tissue digestion were performed at intervals of 15 minutes. Dual-color, dual-target FISH assays were performed as previously described.⁴ Analysis was performed with the Imager Z1 fluorescence microscope (Zeiss, Gottingen, Germany) and the ISIS FISH Imaging System (MetaSystems, Altlussheim, Germany) for acquisition and elaboration of images. EGFR gene, which is located on the short arm of chromosome 7, was visualized as a red signal with a tetramethylrhodamine isothiocyanate filter, whereas the -centromeric probe of chromosome 7 (CEP7) was visualized as a green signal with a fluorescein isothiocyanate filter, and nuclei were visualized as a blue signal with 4,6-diamidine-2-phenylindole filter. Representative images of samples were acquired by the CV-M4 digital double-speed megapixel progressive scan camera (Jai Europe, Copenhagen, Denmark) as monochromatic layers that were subsequently merged by the ISIS software. At least 200 nonoverlapping interphasic nuclei were scored for the number of EGFR and CEP7 copies at x400 magnification, after initial overlook at x200 magnification, to detect the pattern of fluorescence. EGFR gene status was scored as the average number of EGFR red signals per nucleus and as the ratio between EGFR red signals and CEP7 green signals. Normal controls consisted of a cultured retinal pigment epithelial cell line and healthy-appearing colorectal mucosa contiguous to the malignant component for each patient, whereas the positive control for amplified EGFR was the A431 cell line. Clinical outcome relative to 10 patients reported in a previous study⁴ using a different FISH methodology was known by pathologists before present analysis. Polysomy of EGFR gene consisted of an increase of EGFR red signals ( three signals per nucleus) paralleled by the same increase of chromosomes 7 (on which the EGFR gene is located) as measured by the number of CEP7 green signals per nucleus.

Statistical Analyses
The present study was promoted by the coordinating center of the 408 and 194 panitumumab trials in Italy. Participation was offered to 10 recruiting centers, and nine of these centers provided 64 samples of 92 total enrolled patients in Italy. Sample size of the study was determined by the highest number of patients collected based on availability of tumor specimens suitable for FISH analysis. All data were first analyzed and described by mean and standard deviation or by median and range, according to their distribution. Binomial end points have been analyzed by means of univariate logistic regression; models as a whole were evaluated by likelihood ratio test and by their pseudo-R² measure, whereas the significance of the single independent variables was evaluated by means of the Wald test. For binomial independent variables, a further cross-tabulation followed by the Fisher's exact test was also carried out. All statistical tests were two sided. Time-to-event analysis was performed using the Kaplan-Meier product-limit method; the equality of the survivor function was then evaluated using the log-rank test. For patients who received panitumumab, OS was defined as the time from random assignment onto the panitumumab arm of protocol 408 or, for those who crossed over, from the optional assignment onto protocol 194 until death from any cause, censoring patients who had not died at the date last known alive; PFS was defined as the time from assignment onto protocols until tumor progression. For patients treated with BSC only, PFS was defined as the time from random assignment onto the BSC arm of the 408 trial to progression.

Receiver operating characteristic (ROC) curve analysis was carried out to determine a possible cutoff point for the EGFR GCN continuous variable; for each value, sensitivity, specificity, and total accuracy were obtained as percentages. Statistical significance was set at P < .05 for each analysis; all analyses were carried out using STATA SE 9.2 software (STATA Corp, College Station, TX) running on a Windows XP machine (Microsoft, Redmond, WA).

	RESULTS

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Results of EGFR gene analysis by FISH in 58 patients with mCRC treated with panitumumab are listed in Table 1; mean values of EGFR GCN and the percentage of cells displaying chromosome 7 polysomy (EGFR gene/nucleus 3) and/or EGFR gene amplification (EGFR gene/CEP7 2) are reported. None of the tumors was found to show homogeneous amplification of the EGFR gene, whereas two patients showed focal areas of amplification in 5% of tumor area. Figure 2 shows representative patterns of EGFR gene signals evaluated by FISH. The hypothesis of an association between EGFR GCN and objective response to panitumumab was first evaluated with logistic regression, showing a statistically significant positive correlation between increase in mean GCN and probability of response (odds ratio = 5.62; 95% CI, 1.506 to 20.974). This model showed a 98.1% specificity (95% CI, 89.7% to 99.9%), and therefore, it seems particularly suited to identify nonresponders (89.5% negative predictive value; 95% CI, 78.5% to 96.0%).

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Representative fluorescence in situ hybridization (FISH) analyses showing the following microscopic patterns (magnification x200): (A) no gain in EGFR gene copy number, with a homogeneous disomic pattern (patient 48); (B) increase in EGFR gene copy number by polysomy of chromosome 7 (patient 4); and (C) EGFR gene focal amplification in less than 5% of tumor cells (patient 29).

View larger version (8K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Receiver operating characteristic analysis relative to logistic model based on mean (A) EGFR gene copy number or (B) fraction of cells displaying chromosome 7 polysomy, with objective tumor response to panitumumab as the end point. Both models achieve specificity of approximately 75% and maintain 100% sensitivity. AUC, area under the curve.

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Progression-free survival and overall survival in metastatic colorectal cancer patients treated with panitumumab according to the proposed cutoff values of (A and B) EGFR gene copy number (GCN)/nucleus < 2.5 (n = 39) versus 2.5 (n = 19) and (C and D) < 40% fraction of chromosome 7 polysomy (n = 36) versus 40% (n = 22) as evaluated by fluorescence in situ hybridization in individual tumor specimens.

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 5. Progression-free survival in patients treated with best supportive care without panitumumab according to the proposed cutoff value of < 2.5 EGFR gene copy number (GCN)/nucleus (n = 26) versus 2.5 (n = 8). The same patients harboring increased EGFR GCN ( 2.5 copies/nucleus) also displayed a fraction of chromosome 7 polysomy 40%, thus demonstrating no difference in progression-free survival according to both cutoff values (P = .6354).

	DISCUSSION

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The present study was carried out in a homogeneous series of patients receiving panitumumab and BSC or BSC only within a single clinical trial setting of mCRC after failure of regimens including irinotecan and oxaliplatin. Our data produced mean values of 2.5 EGFR GCN/nucleus and 40% chromosome 7 polysomy as suitable cutoff values to identify patients who are less likely to respond to panitumumab, thus generating the hypothesis that these tumors are probably not driven by (not addicted to) the EGFR pathway and thus less susceptible to respond to panitumumab. In our series, the objective response rate in patients with tumors with mean 2.5 EGFR GCN/nucleus or 40% chromosome 7 polysomy was three times higher than in the unselected population (ie, approximately 30% v 10%, respectively). None of the responsive patients had tumors with EGFR GCN less than these cutoff values. Consistent with response rates, analyses of PFS and OS confirmed better clinical outcome for patients harboring increased GCN as defined by these two parameters. Because of the limited patient number evaluated in the present study, these cutoff values should be considered as exploratory and possibly useful for larger studies. In particular, their validation could take place by a new ROC analysis on a wider sample, paralleled by the application of present cutoffs values to evaluate prospectively if their sensitivity and specificity are confirmed.

Interestingly, in patients treated with BSC only, analysis of PFS did not show differences between increased and not increased EGFR GCN, thus indicating a predictive, rather than prognostic, value of this biologic characteristic. Analysis of OS among patients treated with BSC only was not performed because the cross-over design of the study permitted subsequent treatment with panitumumab on progression.

Different studies have described the nonhomogenous EGFR GCN pattern by FISH in mCRC specimens, potentially hampering the reproducibility of results of this analysis.^8,9 FISH analysis of EGFR in mCRC turned out to be different from HER-2 evaluation in breast cancer, where specimens with increased copy number are mainly homogeneous and show clustered signals of HER-2 gene amplification.⁹ In our series, mCRC specimens with increased EGFR GCN frequently presented a nonhomogenous pattern, with variable ratios of chromosome 7 disomy versus polysomy and a low percentage of EGFR gene amplification that mainly occurred in focal areas (Fig 2). Given these features, in the attempt to improve technical quality and reproducibility of FISH results, we evaluated a high number of cells (at least 200 for each specimen) in thin sections of 2 µm to avoid overlapping of nuclei. Furthermore, we elected to evaluate specimens not only as mean EGFR GCN/nucleus but also in terms of fraction of chromosome 7 polysomy within the whole tumor specimen. Most of the tumors with nonincreased EGFR GCN displayed homogeneous disomy (26 of 58 patients had 100% chromosome 7 disomy), and according to our opinion, this pattern is more easily identifiable and assessable from a morphologic point of view. Because analysis of data revealed that the overall model is especially powerful to select patients less likely to respond to panitumumab by disomy, the clinical application of EGFR FISH analysis as predictive factor could be more effective than expected, mainly consisting of the detection of chromosome 7 disomy.

In our previous cohort study,⁵ we described the association of increased GCN with tumor response. The data presented in the present article confirm that nonincreased EGFR GCN is associated with failure of response to anti-EGFR moAb therapy. In contrast, new evidence is presented indicating that only a fraction of tumors with increased EGFR GCN achieves objective response. The discrepancy with our previous findings is likely a result of the clinical enrichment strategy that was conducted to evaluate responsive patients who consistently were found to have tumors with increased EGFR GCN. Furthermore, in our previous study, we reported higher prevalence of EGFR amplification than in this study. This is because the aforementioned nonhomogeneous pattern of focal amplification was, in some cases, previously scored as amplified. In the present study, the use of a more sensitive apparatus allowed pathologists to discriminate signals even at low magnification, thus ensuring the evaluation of the whole tissue section.

It was recently demonstrated that KRAS and/or BRAF mutations in mCRC are predictors of resistance to the anti-EGFR moAbs cetuximab and panitumumab and are associated with a worse prognosis.^5,6,10 These genes are indeed cellular effectors that act downstream of epidermal growth factor signaling, and their malignant activation caused by mutations can independently impair the inhibitory effect of anti-EGFR moAbs, as elucidated in a cellular model where transfection of the G12V KRAS mutation reverted sensitivity to cetuximab.¹⁰ In the future, the detection of KRAS and/or BRAF mutations in mCRC together with EGFR GCN could provide a better understanding of the molecular pathways that can be clinically exploited in individual mCRC patients for optimization of anti-EGFR moAb therapy.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Conception and design: Andrea Sartore-Bianchi, Mauro Moroni, Salvatore Siena

Financial support: Salvatore Siena

Provision of study materials or patients: Carlo Carnaghi, Gabriele Luppi, Emilio Bajetta, Alberto Sobrero, Carlo Barone, Stefano Cascinu, Giuseppe Colucci, Enrico Cortesi, Salvatore Siena

Collection and assembly of data: Andrea Sartore-Bianchi, Silvio Veronese

Data analysis and interpretation: Andrea Sartore-Bianchi, Mauro Moroni, Silvio Veronese, Michele Nichelatti, Marcello Gambacorta, Salvatore Siena

Manuscript writing: Andrea Sartore-Bianchi, Mauro Moroni, Salvatore Siena

Final approval of manuscript: Andrea Sartore-Bianchi, Mauro Moroni, Silvio Veronese, Carlo Carnaghi, Emilio Bajetta, Gabriele Luppi, Alberto Sobrero, Carlo Barone, Stefano Cascinu, Giuseppe Colucci, Enrico Cortesi, Michele Nichelatti, Marcello Gambacorta, Salvatore Siena

	ACKNOWLEDGMENTS

 
We are grateful to Alberto Bardelli for collaboration in the project on molecular predictors to targeted therapies in cancer, to Roberto Brusamolino for discussing fluorescent in situ hybridization (FISH) findings, to Cinzia Maisano for FISH technical assistance, and to Giovanna Marrapese and Ines Andreotti for coordinating study sample procurement.

	NOTES

 
Supported by research grants from Associazione Italiana Ricerca Cancro and Oncologia Ca' Granda ONLUS Fondazione.

A.S.-B., M.M., and S.V. contributed equally to this work.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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1. Van Cutsem E, Peeters M, Siena S, et al: Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25:1658-1664, 2007[Abstract/Free Full Text]

2. Van Cutsem E, Siena S, Humblet Y, et al: An open-label, single-arm study assessing safety and efficacy of panitumumab in patients with metastatic colorectal cancer refractory to standard chemotherapy. Ann Oncol 2007 (in press)

3. 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]

4. Schrag D: The price tag on progress: Chemotherapy for colorectal cancer. N Engl J Med 351:317-319, 2004[Free Full Text]

5. Moroni M, Veronese S, Benvenuti S, 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 6:279-286, 2005[CrossRef][Medline]

6. Liévre 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]

7. 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]

8. Shia J, Klimstra DS, Li AR, et al: Epidermal growth factor receptor expression and gene amplification in colorectal carcinoma: An immunohistochemical and chromogenic in situ hybridization study. Mod Pathol 18:1350-1356, 2005[CrossRef][Medline]

9. Ooi A, Takehana T, Li X, et al: Protein overexpression and gene amplification of HER-2 and EGFR in colorectal cancers: An immunohistochemical and fluorescent in situ hybridization study. Mod Pathol 17:895-904, 2004[CrossRef][Medline]

10. 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 EGFR antibody therapies. Cancer Res 67:2643-2648, 2007[Abstract/Free Full Text]

Submitted March 10, 2007; accepted May 8, 2007.

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