MolecularPredictionofTreatmentOutcomeforLungCancer
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Prof. G. Giaccone
Head, Division of Medical Oncology
Vrije Universiteit Medical Center , 1117 De Boelelaan, Amsterdam , The Netherlands
There are two main types of lung cancer, which differ for the treatment approach. Small cell lung cancer (SCLC), which represents approximately 15-20% of lung cancers, is usually treated with chemotherapy, to which chest radiotherapy is added in case of limited disease, and prophylactic cranial irradiation is added in case of complete remission.
The main treatment modality of non-small cell lung cancer (NSCLC) is surgery, which is radical and feasible in only approximately 20 % -30% of cases. Chemotherapy is becoming standard therapy in the adjuvant setting and is standard in patients with locally advanced disease and in patients with metastatic disease. Locally advanced cases are treated by combined modality approaches, which include surgery and/or chest radiotherapy.
The clinical predictors of treatment outcome are strong and often superior to any biological predictor so far assessed. In particular, a large number of predictors for survival in patients who underwent radical surgery for a NSCLC have been investigated. Among these, are oncogenes and tumor suppressor genes, such as K-ras, and p53 mutations, respectively. Many prognostic factors that are involved in the process of invasion, metastasis and angiogenesis have been retrospectively analyzed in several series. In general, neoangiogenesis, assessed in terms of new formation of vessels, or VEGF expression, have been confirmed as negative prognostic factors and are correlated with more advanced stages of the disease. More recently the expression of ERCC1, an enzyme essential for DNA repair, by nucleotide excision repair, has also been shown to have a strong prognostic factor in patients receiving platinum based adjuvant chemotherapy.
In advanced disease, several studies have addressed the potential predictive value of a number of molecular markers. This has particularly been done more recently with the introduction of targeted therapies, where the evaluation of the putative target may help select patients for the specific treatment (e.g. her2/neu amplification for trastuzumab therapy, EGFR mutations for EGFR tyrosine kinase inhibitor treatment).
Although nowadays the targets of chemotherapy are by and large known, still relatively little success has been obtained in the attempt to develop predictive molecular profiles able to identify the patients who benefit from treatment. In the past years some progress has been made in the identification of ECCR1 as a marker of responsiveness and survival in patients treated with platinum-based chemotherapy in the advanced setting. This result has been now confirmed by different independent series, and may be of some help in the future to select patients for some alternative treatment, if they do not belong to the group that benefits from this type of therapy. Unfortunately, however we do not have any other valid marker that can accurately predict response and/or survival to any other chemotherapeutic agent. Genome based approaches are being investigated in order to identify populations of patients where a specific gene profile may be associated to response. Studies are ongoing, including novel approaches, such as serum proteomics that may help in the future in this endeavor.
Much more information has been collected in the recent years in the selection of patients for targeted agents. The first targeted agent tested in NSCLC was trastuzumab. Unfortunately, due to the very low frequency of amplification of this oncogene in lung cancer (below 5%), it was very difficult to mount studies large enough to be able to demonstrate efficacy of this treatment in selected patients. A randomized phase II study was performed, which allocated patients to receive cisplatin-gemcitabine with or without trastuzumab. Although there was no difference in response and time to progression between the arms, most patients who had FISH positive tumors responded to the treatment, which may suggest that a benefit of the trastuzumab combination in these rare patients may not be excluded.
EGFR inhibitors have been tested in advanced NSCLC. In particular the small molecules, tyrosine kinase inhibitors gefitinib and erlotinib had been extensively investigated. Erlotinib was recently approved for the treatment of patients with advanced NSCLC after failure of chemotherapy, as second or third line therapy. The response rate is lower than 10%, however another 30% of patients have stable disease, and overall there was an improvement in median survival of 2 months in the BR21 study, which compared erlotinib to best supportive care. Although in this study most patient subgroups benefited somewhat from the treatment, some groups of patients benefited to a much larger extent; these include never-smokers, women, adenocarcinoma patients and East Asians. It is now known that these groups of patients are also those whose tumors bear EGFR mutations in the ATP binding site. These are mainly sensitizing mutations, which in vitro confer an increase of sensitivity to these agents of at least 2 log compared to wild type cell lines. In Caucasians, however EGFR mutations are relatively infrequent (approximately 10%), which makes it cumbersome to mount large studies based on the presence of mutations only. However in Asia mutations in EGFR are as frequent as 30-40% of cases, and treatment is also more effective. Studies with these agents have therefore a larger impact in Asia than in the western world. In some studies performed in the western world, the FISH positivity for EGFR (including amplification and polysomy) has also been suggested as a predictive factor for response and survival to EGFR TKIs. Prospective studies utilizing these selection markers have been performed or are ongoing. The use of mutations has been shown in a few prospective studies to be able to predict for a response rate of 75% or higher. Randomized studies are ongoing which compare EGFR TKIs vs chemotherapy in patients selected on the basis of molecular characteristics and/or clinical features.
Prof. G. Giaccone
Head, Division of Medical Oncology
Vrije Universiteit Medical Center , 1117 De Boelelaan, Amsterdam , The Netherlands
There are two main types of lung cancer, which differ for the treatment approach. Small cell lung cancer (SCLC), which represents approximately 15-20% of lung cancers, is usually treated with chemotherapy, to which chest radiotherapy is added in case of limited disease, and prophylactic cranial irradiation is added in case of complete remission.
The main treatment modality of non-small cell lung cancer (NSCLC) is surgery, which is radical and feasible in only approximately 20 % -30% of cases. Chemotherapy is becoming standard therapy in the adjuvant setting and is standard in patients with locally advanced disease and in patients with metastatic disease. Locally advanced cases are treated by combined modality approaches, which include surgery and/or chest radiotherapy.
The clinical predictors of treatment outcome are strong and often superior to any biological predictor so far assessed. In particular, a large number of predictors for survival in patients who underwent radical surgery for a NSCLC have been investigated. Among these, are oncogenes and tumor suppressor genes, such as K-ras, and p53 mutations, respectively. Many prognostic factors that are involved in the process of invasion, metastasis and angiogenesis have been retrospectively analyzed in several series. In general, neoangiogenesis, assessed in terms of new formation of vessels, or VEGF expression, have been confirmed as negative prognostic factors and are correlated with more advanced stages of the disease. More recently the expression of ERCC1, an enzyme essential for DNA repair, by nucleotide excision repair, has also been shown to have a strong prognostic factor in patients receiving platinum based adjuvant chemotherapy.
In advanced disease, several studies have addressed the potential predictive value of a number of molecular markers. This has particularly been done more recently with the introduction of targeted therapies, where the evaluation of the putative target may help select patients for the specific treatment (e.g. her2/neu amplification for trastuzumab therapy, EGFR mutations for EGFR tyrosine kinase inhibitor treatment).
Although nowadays the targets of chemotherapy are by and large known, still relatively little success has been obtained in the attempt to develop predictive molecular profiles able to identify the patients who benefit from treatment. In the past years some progress has been made in the identification of ECCR1 as a marker of responsiveness and survival in patients treated with platinum-based chemotherapy in the advanced setting. This result has been now confirmed by different independent series, and may be of some help in the future to select patients for some alternative treatment, if they do not belong to the group that benefits from this type of therapy. Unfortunately, however we do not have any other valid marker that can accurately predict response and/or survival to any other chemotherapeutic agent. Genome based approaches are being investigated in order to identify populations of patients where a specific gene profile may be associated to response. Studies are ongoing, including novel approaches, such as serum proteomics that may help in the future in this endeavor.
Much more information has been collected in the recent years in the selection of patients for targeted agents. The first targeted agent tested in NSCLC was trastuzumab. Unfortunately, due to the very low frequency of amplification of this oncogene in lung cancer (below 5%), it was very difficult to mount studies large enough to be able to demonstrate efficacy of this treatment in selected patients. A randomized phase II study was performed, which allocated patients to receive cisplatin-gemcitabine with or without trastuzumab. Although there was no difference in response and time to progression between the arms, most patients who had FISH positive tumors responded to the treatment, which may suggest that a benefit of the trastuzumab combination in these rare patients may not be excluded.
EGFR inhibitors have been tested in advanced NSCLC. In particular the small molecules, tyrosine kinase inhibitors gefitinib and erlotinib had been extensively investigated. Erlotinib was recently approved for the treatment of patients with advanced NSCLC after failure of chemotherapy, as second or third line therapy. The response rate is lower than 10%, however another 30% of patients have stable disease, and overall there was an improvement in median survival of 2 months in the BR21 study, which compared erlotinib to best supportive care. Although in this study most patient subgroups benefited somewhat from the treatment, some groups of patients benefited to a much larger extent; these include never-smokers, women, adenocarcinoma patients and East Asians. It is now known that these groups of patients are also those whose tumors bear EGFR mutations in the ATP binding site. These are mainly sensitizing mutations, which in vitro confer an increase of sensitivity to these agents of at least 2 log compared to wild type cell lines. In Caucasians, however EGFR mutations are relatively infrequent (approximately 10%), which makes it cumbersome to mount large studies based on the presence of mutations only. However in Asia mutations in EGFR are as frequent as 30-40% of cases, and treatment is also more effective. Studies with these agents have therefore a larger impact in Asia than in the western world. In some studies performed in the western world, the FISH positivity for EGFR (including amplification and polysomy) has also been suggested as a predictive factor for response and survival to EGFR TKIs. Prospective studies utilizing these selection markers have been performed or are ongoing. The use of mutations has been shown in a few prospective studies to be able to predict for a response rate of 75% or higher. Randomized studies are ongoing which compare EGFR TKIs vs chemotherapy in patients selected on the basis of molecular characteristics and/or clinical features.
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