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Journal of Clinical Oncology, Vol 26, No 9 (March 20), 2008: pp. 1427-1434 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.4602
Pharmacogenetic Profiling for Cetuximab Plus Irinotecan Therapy in Patients With Refractory Advanced Colorectal Cancer
From the Medical Oncology Unit, Hospital of Pesaro, Pesaro; Institute of Biochemistry "G. Fornaini," and Institute of Biotechnology, University of Urbino, Urbino; Medical Oncology Unit, Azienda USL-6 Livorno, Livorno; University of Pisa, Istituto Toscano Tumori, Pisa; Medical Oncology Unit, University Campus Biomedico, Rome; Medical Oncology Unit, Hospital of Fermo, Fermo; Medical Oncology Unit, Hospital of Macerata, Macerata; Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy; and Cancer Genetics Laboratory, University of Otago, Otago, New Zealand Corresponding author: Francesco Graziano, MD, Medical Oncology Unit, Hospital of Urbino, via Bonconte da Montefeltro, 61029, Urbino, Italy; e-mail: frada{at}tin.it
Purpose Regulation of epidermal growth factor receptor (EGFR) signaling pathways may play a relevant role in determining the activity of cetuximab therapy in patients with metastatic colorectal cancer (MCRC). We investigated possible associations between genetic variants and clinical outcomes of MCRC patients treated with cetuximab-irinotecan salvage therapy. Patients and Methods Patients who underwent cetuximab-irinotecan salvage therapy after disease progression during or after first-line bolus/infusional fluorouracil, leucovorin, and oxaliplatin chemotherapy and a second-line irinotecan-based regimen were considered eligible for analysis of polymorphisms with putative influence on cetuximab-related pathways. Epidermal growth factor (EGF) 61A>G, EGF receptor (EGFR) 216G>T, EGFR 497G>A, EGFR intron-1 (CA)n dinucleotide short (S)/long (L) variant, cyclin-D1 870A>G, immunoglobulin-G fragment-C receptors RIIIa 158G>T, and RIIa 131G>A were studied for a possible association with overall survival (OS) as the primary end point. Additional analyses were addressed at possible associations among polymorphisms and EGFR expression, toxicity, and response.
Results In 110 assessable patients, significant association with favorable OS was observed for EGFR intron-1 S/S and EGF 61 G/G genotypes. In the multivariate model, EGFR intron-1 S/S and EGF 61 G/G genotypes showed a hazard ratio of 0.41 (95% CI, 0.21 to 0.78; P = .006) and 0.44 (95% CI, 0.23 to 0.84; P = .01), respectively. EGFR intron-1 S/S carriers showed more frequent G2-G3 skin toxicity ( Conclusion Although additional studies are required for confirmation, our findings could optimize the use of cetuximab in MCRC patients.
Cetuximab is a chimeric immunoglobulin G1 monoclonal antibody that targets the epidermal growth factor receptor (EGFR) extracellular domain.1 It competitively inhibits endogenous epidermal growth factor (EGF)/transforming growth factor binding, thereby inhibiting EGFR activation.2 Cetuximab has shown activity in metastatic colorectal cancer (MCRC)3 and has been approved for use in conjunction with irinotecan in irinotecan-refractory patients. The approval is currently restricted to patients with EGFR-expressing tumors (by immunohistochemistry, approximately 70% of colorectal carcinomas). Notably, this restriction results from the choice of excluding EGFR-negative patients in clinical trials, which led to this approval. In fact, an affordable marker for selecting patients who benefit from cetuximab therapy has not yet been identified.2,3 One possibility for optimizing monoclonal antibody therapy may be the application of pharmacogenetics.4,5
A polymorphic (CA)n-repeat variant in EGFR gene intron-1, a G>A single nucleotide polymorphism (SNP) in EGFR codon 497 (extracellular subdomain IV), and the –216G>T EGFR promoter SNP within the Sp-1 binding site (Sp-1 is a key regulator of the EGFR promoter activity) are three functional EGFR variants that have been associated with EGFR regulation.5-11 Modulation of the EGFR ligand EGF and of the downstream EGFR signaling, including the cyclin-D1 gene, also may play a role in modulating cetuximab activity. Functional variants have been described in the EGF 5'-untranslated region (EGF 61G>A),12 and in exon 4 of the cyclin-D1 gene (870A>G).13,14 Finally, monoclonal antibodies may exert an indirect antitumor activity by recruiting cytotoxic host effector cells such as monocytes and natural-killer cells,15 thus determining an antibody-dependent cell-mediated cytotoxicity (ADCC). As observed in experimental models, cetuximab also mediates ADCC against cancer cells.16 The effectiveness of ADCC may depend on the degree of activation of effector cells after immunoglobulin-G fragment-C receptors (Fc We studied these genetic variants (Table 1) in patients who underwent cetuximab-irinotecan therapy after disease progression during or after bolus/infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) and a second-line irinotecan-based regimen. The primary end point of this study was the association between genetic variants and overall survival (OS). Additional analyses were addressed at possible associations between polymorphisms and progression-free survival (PFS), EGFR expression, toxicity, and response.
Study Population Patients with MCRC who were enrolled prospectively onto a pharmacogenetic study for first-line FOLFOX chemotherapy19 also were considered for a second analysis of genetic variants with putative influence on cetuximab-related pathways. In this population,19 patients undergoing cetuximab-irinotecan salvage therapy after disease progression during or after FOLFOX and a second-line irinotecan-based regimen were considered eligible for this study. Additional eligibility criteria were EGFR-expressing colorectal cancer (Cytomation kit; DAKO, Carpinteria, CA), cytologically or histologically confirmed metastatic disease, presence of at least one bidimensionally measurable lesion, Karnofsky performance score (KPS) 70. Pretreatment evaluation included complete medical and clinical-physical examination; KPS evaluation; assessment of metastatic disease based on computed tomography scans, x-ray, or other radiographic means; serum chemistries; and carcinoembryonic antigen. The Response Evaluation Criteria in Solid Tumors were adopted for evaluating response.20 Patients' characteristics and outcomes were unknown to the investigators performing the genetic analyses. The study was approved by local ethics committees, and the patients provided signed informed consent forms.
Analysis of Genetic Variants
In vitro and in vivo data indicate that the length of the EGFR intron-1 (CA)n repeat inversely correlates with transcription activity, mRNA amount, and EGFR expression.5-9 Given the trimodal distribution of the EGFR intron-1 (CA)n-repeat alleles in the white population,5,7 and the experimental data indicating enhanced EGFR levels with alleles having less than 17 CA repeats,5,8,9 EGFR intron-1 less than (CA)17 and
Statistical Analyses
Linkage disequilibrium (LD) and haplotype analyses were performed to further define possible clinical effects of genetic variants.23 Haplotype frequencies were reconstructed in the study population, which was dichotomized according to the median value (below and above) of a given clinical parameter (eg, OS). LD exists between two SNPs of a haplotype if their variants appear together more often than expected (nonrandom inheritance). LD was estimated using r2, with r2 = 1 indicating complete LD and r2 = 0 indicating absence of LD. The SHEsis software platform23 (http://202.120.7.14/analysis/myAnalysis.php) was used to estimate haplotype frequencies and the presence of LD. Global association of haplotypes with clinical parameters was estimated by comparing haplotype distributions among dichotomized patients using a
Study Population One hundred ten white patients were studied (Table 2). After second-line, irinotecan-based chemotherapy,25 irinotecan with weekly cetuximab (400 mg/m2 loading dose followed by 250 mg/m2) was administered as weekly (90 to 100 mg/m2) or every 2 weeks (180 mg/m2) infusion in 33 patients and 77 patients, respectively.
In Table 1, the frequencies of the genotypes (no deviation from the HWE) are compared with those reported in previous studies in whites. EGFR intron-1 variant (CA)n-repeat alleles ranged from 14 to 22 repeats (predominance of 16, 18, and 20 repeats). Patients received at least two cetuximab infusions. Neither severe anaphylactic reactions nor treatment-related deaths occurred. The overall response rate was 24.5%, with one complete and 26 partial responses. Stable disease and progression occurred in 43 (39%) and 40 (37%) patients, respectively. Skin toxicity occurred in 86% of patients (no grade 4). At last data analysis in March 2007, 99 patients (90%) had disease progression and 83 patients (75%) had died. Median PFS and OS were 4.4 and 9.4 months, respectively. C value for completeness of follow-up was 99%.
Survival and Genotypes
Haplotype and LD Analysis of the EGFR Gene EGFR haplotypes showed a global association with OS (P < .04). In general, haplotypes containing EGFR intron-1 variants were more frequent in the patient group with OS below the patient median. In contrast, haplotypes with S variants were more frequent in the patient group with OS above the median. A significantly different distribution was observed for the T-L-A haplotype (Table 4). However, LD was not observed for the three possible pairs of SNPs (r2 < 0.01), suggesting that the EGFR intron-1 (CA)n variant is associated with the clinical parameters independently of the other EGFR SNPs. To estimate the effects of the EGFR haplotypes on OS at the individual level, the two most likely haplotypes were imputed for each patient, and the patients were subdivided into groups corresponding to one of the eight possible EGFR haplotypes. A log-rank test confirmed the global association of EGFR haplotypes with OS (P < .005). Haplotypes containing L-repeat variants were associated with shorter OS (P < .03) compared with those containing S variants. Again, the T-L-A haplotype conferred the worst survival among the EGFR haplotypes. Corresponding survival curves are shown in Figure 1C.
Treatment Response, Skin Toxicity, EGFR Expression, and Genotypes All variants were studied for association with skin toxicity, EGFR expression, and treatment response. No significant association was found except for the EGFR intron-1 (CA)n. Carriers of the EGFR intron-1 S/S genotype (96% relative dose-intensity of cetuximab) were more prone to be responsive to treatment and to suffer from grade 2 to 3 skin toxicity than L/L carriers (99% relative dose-intensity of cetuximab). Table 5 lists the results for EGFR/EGF variants.
In experimental models,6 the transcription of the EGFR gene was found to be inhibited by approximately 80% in (CA)21-repeat alleles of the EGFR intron-1 variant, whereas decreasing the number of CA pairs down to (CA)12 enhances transcription as much as five-fold. Head and neck cancer cells with a lower number of the EGFR intron-1 (CA)n showed higher EGFR expression and greater sensitivity to anti-EGFR therapy.9 Han et al26 and Liu et al27 found that a low number of the EGFR intron-1 (CA)n variant was associated with gefitinib responsiveness in non–small-cell lung cancer (NSCLC) patients. Therefore, a plausible mechanism for explaining the EGFR intron-1 variant influence on cetuximab activity is EGFR upregulation, which in turn is a determinant for the activity of anti-EGFR therapeutics.6,9,28 The lack of association between EGFR intron-1 variant and EGFR expression29 is likely be related to methodologic issues regarding the use of poorly validated30 and nonqualitative immunohistochemistry methods for EGFR analysis in vivo. In this regard, it is important to mention that measuring EGFR mRNA levels by reverse transcription PCR from microdissected tumor tissue may be a more reliable predictive marker to EGFR inhibitors.5,31 Also, the analysis of low-/high-affinity EGFR32 or activated/phosphorylated EGFR33 may supply more precise predictive information. The occurrence of skin toxicity was found to be a reliable indicator of cetuximab efficacy.34,35 This adverse effect was found to be associated with the presence of the EGFR intron-1 short (CA)n allele in the present as well as in a previous analysis of colorectal cancer patients.9 EGFR homodimers seem to be the predominant human epidermal growth factor receptor dimer pair in normal primary keratinocytes and in normal skin tissue.36 Preliminary data suggest that EGFR dimerization in human skin and inhibition of EGFR homodimer signaling rather than EGFR/HER-2 heterodimer signaling may be a key molecular event determining dermatologic toxicity.36 Germline EGFR intron-1 S/S status resulting in EGFR upregulation in tissues may trigger this molecular predisposing condition for skin toxicity. The median number of cetuximab infusions was 12 in EGFR intron-1 L/L carriers (range, six to 36 infusions) and 18 in EGFR intron-1 S/S carriers (range, four to 52 infusions). Cetuximab-induced skin toxicity occurs early,34 and it is therefore unlikely that the observed grade 2 to 3 skin toxicity in EGFR intron-1 S/S carriers is simply the expression of the patients' longer treatment period. Notably, grade 2 to 3 skin toxicity in EGFR intron-1 S/S carriers may explain the slightly lower relative dose-intensity of cetuximab with respect to EGFR intron-1 L/L carriers. The strong association between high-grade skin toxicity and favorable OS obscured the impact of the other variables, including genotypes. However, it should be considered that skin toxicity is not a baseline feature for a possible selection of patients before cetuximab onset. In perspective, the assessment of the EGFR intron-1 status might be considered for planning innovative treatment strategies, such as cetuximab dose escalation according to the entity of the observed skin toxicity.37 The EGF 61G allele is transcriptionally more active than the A allele and is found to be associated with upregulated EGF levels. EGF signaling may promote a number of regulatory factors, which enhance tumor aggressiveness38; therefore, the observed favorable effect of the EGF 61G/G genotype may be counterintuitive. Furthermore, the EGF-ERBB system displays complex tunings and the presence of alternative negative signaling regulators.39-41 At specific concentrations that vary between experimental systems, EGF has been shown to induce apoptosis and growth inhibition rather than the usual growth-promoting effect.42-46 According to such findings, it cannot be ruled out that a functional EGF genotype, which upregulates EGF levels, may play a favorable prognostic rather than predictive influence. Indeed, in the present study, the EGF 61G/G genotype was associated with improved OS and not with improved PFS or response rate/skin toxicity. Notably, similar findings have been reported recently by Ali-Osman et al,47 who analyzed EGF 61A>G in 332 astrocytoma patients, with the G/G carriers having significantly better survival rates than the A/A carriers.
It is not surprising that our findings are in conflict with results from two previous investigations that include 39 patients from a phase II multicenter trial of cetuximab.48,49 In these studies, Zhang et al found preliminary associations for Fc We found frequencies of the EGFR intron-1 genotypes that are comparable to those reported in the literature, with short (CA)n alleles more common in white than in Asian populations and long (CA)n alleles are less common in white than in Asian populations.7 Even if different genetic backgrounds may represent a limitation for reproducibility and applicability of our findings, the EGFR intron-1 S/S genotype seems to confirm its favorable role,26,27 TK-EGFR with identification of subsets of responsive patients, as domain mutations allowed in gefitinib-treated NSCLC patients.1 Pharmacokinetic factors do not appear to have influenced our findings; all patients showed progression after second-line irinotecan-based chemotherapy, no apparent pharmacokinetic interactions between cetuximab and irinotecan were described,55 and the studied polymorphisms should not influence cetuximab activation/excretion pathways. A control arm would have been helpful for defining the predictive role of the studied polymorphisms. In reality, EGFR expression is detectable in the majority of colorectal carcinomas and almost all patients with EGFR-expressing tumors receive cetuximab. Therefore, it is difficult to plan an association analysis that includes controls. When we studied EGF and EGFR genotypes in patients treated with first-line FOLFOX chemotherapy19 and the previously studied genetic variants19 in the present population of cetuximab-treated patients, no significant association with clinical outcomes was observed (data not shown). These observations may at least in part sustain a predictive effect of the EGFR intron-1 genotype when cetuximab is added in the course of treatments. In conclusion, the present findings deserve further research; they may represent a valuable tool for optimizing the use of the anti-EGFR cetuximab in MCRC.
The author(s) indicated no potential conflicts of interest.
Conception and design: Francesco Graziano, Annamaria Ruzzo, Fotios Loupakis, Mauro Magnani Financial support: Mauro Magnani Administrative support: Annamaria Ruzzo, Mauro Magnani Provision of study materials or patients: Francesco Graziano, Annamaria Ruzzo, Fotios Loupakis, Daniele Santini, Vincenzo Catalano, Renato Bisonni, Umberto Torresi, Gaia Schiavon, Alfredo Falcone, Lucio Giustini, Giuseppe Tonini, Andrea Fontana, Gianluca Masi Collection and assembly of data: Francesco Graziano, Annamaria Ruzzo, Emanuele Canestrari, Irene Floriani, Francesca Andreoni Data analysis and interpretation: Francesco Graziano, Annamaria Ruzzo, Emanuele Canestrari, Irene Floriani, Eliana Rulli, Bostjan Humar, Mauro Magnani Manuscript writing: Francesco Graziano, Annamaria Ruzzo, Fotios Loupakis, Irene Floriani, Bostjan Humar, Mauro Magnani Final approval of manuscript: Francesco Graziano, Annamaria Ruzzo, Fotios Loupakis, Daniele Santini, Vincenzo Catalano, Renato Bisonni, Umberto Torresi, Irene Floriani, Gaia Schiavon, Paolo Maltese, Eliana Rulli, Bostjan Humar, Alfredo Falcone, Lucio Giustini, Giuseppe Tonini, Andrea Fontana, Gianluca Masi, Mauro Magnani
Supported by Consorzio Interuniversitario per le Biotecnologie and Fanoateneo. F.G. and A.R. contributed equally to this study. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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