Role of Anti-EGFR Therapy in Asian Cancer Patients
Authors: Yung-Jue Bang, Sae-Won Han, Tae-You Kim
Journal: Clinical Cancer Research (2007)

PL06-02   Epidermal growth factor receptor (EGFR) is frequently overexpressed in various malignancies which is often associated with poor prognosis. Its activation has important role in various steps of carcinogenesis and progression. Recently, efforts have been made to develop anti-cancer agents inhibiting EGFR activities which include small molecular tyrosine kinase inhibitor (TKI) and monoclonal antibody.  EGFR inhibition using small molecular TKI, gefitinib and erlotinib, has been most promising in non-small-cell lung cancer (NSCLC). EGFR TKI showed modest but meaningful activity with tolerable toxicity in pre-treated NSCLC. Interestingly, phase II studies and data from expanded access program of gefitinib showed that response rates were higher in patients with East-Asian ethnicity, female sex, adenocarcinoma or bronchioloalveolar carcinoma (BAC) histology, and never-smoking history. In the phase III trial of erlotinib (BR.21) which compared erlotinib with best supportive care in previously treated NSCLC, erlotinib treatment significantly prolonged survival. Response rates were also higher in females, adenocarcinomas, never-smokers and Asians although the survival benefit of erlotinib treatment was not limited to these subgroups. Although gefitinib failed to improve survival in the overall study population in the phase III gefitinib trial, Iressa Survival Evaluation in Lung Cancer (ISEL), planned subgroup analysis of ISEL showed significant survival benefit in never-smokers and Asians. Again, higher objective responses were seen in females, adenocarcinomas, never-smokers, and Asians. These findings suggest that patient selection is of great importance for optimized efficacy of EGFR TKI.  The mysterious link between the clinical predictors and the higher response to EGFR TKI can be partly explained by the presence of the activating EGFR tyrosine kinase domain mutations. EGFR mutations are more frequently found in Eastern Asians, adenocarcinomas, never-smokers, and females. EGFR mutant tumor comprises 30-50% of NSCLC from Asian patients in contrast to those from Caucasian patients of which around 10% harbor EGFR mutations. It is unclear what leads to the difference in mutational frequency, whether it be genetic or environmental.  EGFR mutation confers constitutive autophosphorylation and activation of the receptor and its downstream signal cascades. Moreover, the classic mutations (L858R and deletion in exon 19) are extremely sensitive to EGFR TKI. The high response rates to EGFR TKI have been confirmed in prospective studies of EGFR TKI as first-line treatment in NSCLC harboring the classic mutations. EGFR mutant patients treated with gefitinib show longer survival compared to gefitinib-treated wild-type patients. The longer survival seen in mutant patients are due to the enhanced sensitivity of the mutant tumors to EGFR TKI or the innate indolent biology needs to be answered in randomized studies. Although the biomarker analysis of BR.21 suggested that EGFR mutation does not have role in predicting benefit from erlotinib treatment, the number of EGFR mutation positive patients included in the analysis (34 patients) is too small to draw any definitive conclusion about the role of EGFR mutation in response and survival prediction of EGFR TKI treatment.  Another molecular predictor of EGFR TKI sensitivity is increased EGFR gene copy number determined by FISH which include high polysomy and gene amplification. Single-arm studies from Western populations suggested that EGFR FISH has stronger association with response and survival compared to mutation in gefitinib treated patients. In contrast, Asian studies repeatedly reported that EGFR mutation has stronger association with response and survival in gefitinib-treated NSCLC compared to gene copy number status. Potential explanation for these discrepancies according to ethnicities is the possible ethnic difference in the mechanism of EGFR ‘addiction’ and EGFR TKI sensitivity. EGFR mutation may have major role in Asians compared to high EGFR gene copy number having predominant role in Caucasians. Given the significant association between EGFR mutation and high gene copy number, what leads to the possible difference among the ethnicities warrants further exploration.  The results from the biomarker studies of the randomized phase III trials (BR.21 and ISEL) suggest that EGFR TKI leads to survival prolongation only in the FISH+ patients. The important role of EGFR gene copy number in EGFR TKI treatment among Western population is evident from these studies. However, caution should be taken in directly applying these data to Asian patients. Less than 10% of patients included in the molecular analyses of the phase III trials were Asian origin and the mutational frequencies of EGFR in the studies were lower than those reported in Asian studies. Randomized phase III study having appropriate power for biomarker analysis needs to be conducted in Asian patients who have high mutational frequency to identify the exact roles of EGFR gene copy number and mutation in EGFR TKI treatment among Asians.  In addition to the mutations, polymorphisms of EGFR also show different distribution according to ethnicity. CA dinucleotide repeat polymorphism in intron 1 of EGFR, which can modulate transcription of EGFR, shows higher repeat numbers in Asians compared to other ethnicities. Lower repeat number tends to be associated with better treatment outcome of gefitinib. Two other common polymorphisms (-216G/T and -191C/A) located in the promoter region of EGFR associated with altered promoter activity and gene expression also has ethnic difference in distribution. Asians almost uniformly carry -216G/G and -191C/C, whereas -216G/T or T/T and -191C/A or A/A are also commonly found in other ethnicities.  Collectively, genetic make-up of EGFR in NSCLC seems to be different in Asians and Caucasians. As our understanding of genetic changes in cancer enriches, more ethnic differences are expected to be uncovered. Therefore, different approach in biomarker analysis and customized treatment strategy may be necessary according to ethnicity in the future. Moreover, ethnic background should always be taken into account when performing translational research.  Gastric cancer is one of the leading causes of cancer-related mortality throughout the world, especially in Asian countries. Treatment outcomes are still disappointing although therapeutic improvements have been seen in the past decades. To further improve treatment results of gastric cancer, EGFR or HER2 targeted agents are being evaluated in combination with conventional chemotherapy regimens.  EGFR expression is detected in 30-50% of advanced gastric cancer and is associated with advanced disease. EGFR gene is amplified in 5-10% of gastric cancer. A recent phase II study of cetuximab in combination with FOLFIRI in untreated gastric or gastroesophageal junction adenocarcinoma showed encouraging results. We are conducting a phase II study of cetuximab in combination with modified FOLFOX6 in recurrent or metastatic gastric cancer which have recently completed patient accrual. Comprehensive analyses of biomarkers are also planned.  HER2 is reported to be expressed in 10-90% of gastric cancer and gene amplification is found in 5-25%. HER2 amplification is more frequently found in intestinal type compared to diffuse type cancers. HER2 expression or amplification is associated with advanced stage and poor prognosis. Preclinical studies showed that trastuzumab potentiated antitumor activity of cytotoxic chemotherapies. With these backgrounds, phase III study comparing trastuzumab in combination with fluoropyrimidine and cisplatin versus chemotherapy alone as first-line therapy in HER2 positive advanced gastric cancer is currently underway.