HER2 Driven Non-Small Cell Lung Cancer (NSCLC)
HER2 Driven Non-Small Cell Lung Cancer (NSCLC)
Oncogenic driver mutations identified in non-small cell lung cancer (NSCLC) have triggered the development of drugs capable of interfering in intracellular signaling pathways involved in tumorigenesis. Tyrosine kinase inhibitors, such as erlotinib or gefitinib, have demonstrated promising results in patients with advanced NSCLC that harbor EGFR mutations. Human epidermal growth factor 2 (HER2/ERBB2/neu) is a member of the ERBB family of tyrosine kinase receptors, and is activated by homodimerization or heterodimerization with other ERBB receptors. Deregulation of HER2 gene, by overexpression and/or gene amplification has been proved important in breast and gastric cancer, in which overexpression of HER2 confers greater response to specific anti-HER2 treatment, including trastuzumab. In lung carcinogenesis, HER2 mutations are thought to be more clinically relevant than overexpression or gene amplification. HER2 mutations in NSCLC, described exclusively in adenocarcinoma histology, are present in approximately 4% of this subset of lung cancer patients, suggesting that thousands of patients per year may possibly benefit from targeted therapy. Therefore, we conclude that systematic genotypic testing in this subgroup of NSCLC patients should include detection of HER2 mutations. In addition, clinical trials with standard antiHER2 agents and new investigational therapies are ongoing, with promising preliminary results, as illustrated in this review, although further research is warranted in this field.
Lung cancer continues to be the leading cause of cancer-related death, as estimated by the American Cancer Society, responsible for 26% of all female cancer deaths and 29% of all male cancer deaths in the U.S. in 2012. Considering that non-small cell lung cancer (NSCLC) accounts for 80–85% of cases of lung cancer and that significant improvement in survival rates, approximately 17% at 5 years for recently diagnosed NSCLC and less than 4% if presenting with distant metastasis, has not been achieved in the last decade with conventional chemotherapy, novel therapeutic approaches are warranted in this field. As a result of these advances, systematic genomic testing for patients with NSCLC is becoming the new standard of care in clinical decision-making, due to the identification of driver mutations that have triggered the development of new molecules targeting these specific alterations in cancer cells. For example, somatic mutations in epidermal growth factor receptor (EGFR) confer greater response rates to tyrosine kinase inhibitors (TKIs) that target the catalytic domain of EGFR, such as erlotinib and gefitinib, compared to standard therapy in advanced NSCLC, 70% vs. 33.2% in first-line trials. In a similar manner, crizotinib, the anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor, has demonstrated response rates of approximately 60% with progression-free survival greater than 10 months in those NSCLC characterized by ALK rearrangements. These studies have enabled to conclude that both EGFR-mutant and ALK-positive NSCLC constitute two defined subgroups of oncogene-driven tumors with potentially effective targeted therapy. Furthermore, approximately 15–20% of NSCLC diagnosed in Europe and North America bear EGFR mutations or ALK rearrangements, enhancing the significance of the development of drugs capable of interfering with their intracellular effects.
Based on these results, the identification of other activating mutations has been pursued in hopes of improving survival in NSCLC by specifically treating these genomic alterations. These potential therapeutic targets include KRAS, BRAF, HER2 and PIK3CA, in addition to ROS1 fusions. KRAS mutations, in codons 12, 13 and 61, reported in approximately 20% of cases of lung adenocarcinomas, predict negative outcome in terms of response to EGFR TKIs. No targeted therapies have demonstrated an increase in overall survival in KRAS-mutant NSCLC, although selumetinib, an inhibitor of MAPK extracellular signal-regulated kinase (MEK) 1/2 (downstream of KRAS), in combination with docetaxel in previously treated advanced NSCLC has shown promising results in a recent phase 2 trial.
Regarding activating mutations in BRAF, HER2 and PIK3CA, incidence reported for each group ranges from 1–4%, a lower although significant frequency that is encouraging further investigation of these genetic alterations and consequent therapeutic implications. HER2 mutations in NSCLC constitute a clear molecular target, particularly in a subset of patients with distinct clinical features, including female non-smokers with adenocarcinomas, similar to those patients with EGFR-mutant lung cancer. Here, we seek to review the characteristics of HER2 mutations that enable interaction with molecules that specifically target these receptors in lung adenocarcinomas, as well as the results of preliminary studies that assess the efficacy of anti-HER2 therapy applied to NSCLC.
Abstract and Introduction
Abstract
Oncogenic driver mutations identified in non-small cell lung cancer (NSCLC) have triggered the development of drugs capable of interfering in intracellular signaling pathways involved in tumorigenesis. Tyrosine kinase inhibitors, such as erlotinib or gefitinib, have demonstrated promising results in patients with advanced NSCLC that harbor EGFR mutations. Human epidermal growth factor 2 (HER2/ERBB2/neu) is a member of the ERBB family of tyrosine kinase receptors, and is activated by homodimerization or heterodimerization with other ERBB receptors. Deregulation of HER2 gene, by overexpression and/or gene amplification has been proved important in breast and gastric cancer, in which overexpression of HER2 confers greater response to specific anti-HER2 treatment, including trastuzumab. In lung carcinogenesis, HER2 mutations are thought to be more clinically relevant than overexpression or gene amplification. HER2 mutations in NSCLC, described exclusively in adenocarcinoma histology, are present in approximately 4% of this subset of lung cancer patients, suggesting that thousands of patients per year may possibly benefit from targeted therapy. Therefore, we conclude that systematic genotypic testing in this subgroup of NSCLC patients should include detection of HER2 mutations. In addition, clinical trials with standard antiHER2 agents and new investigational therapies are ongoing, with promising preliminary results, as illustrated in this review, although further research is warranted in this field.
Introduction
Lung cancer continues to be the leading cause of cancer-related death, as estimated by the American Cancer Society, responsible for 26% of all female cancer deaths and 29% of all male cancer deaths in the U.S. in 2012. Considering that non-small cell lung cancer (NSCLC) accounts for 80–85% of cases of lung cancer and that significant improvement in survival rates, approximately 17% at 5 years for recently diagnosed NSCLC and less than 4% if presenting with distant metastasis, has not been achieved in the last decade with conventional chemotherapy, novel therapeutic approaches are warranted in this field. As a result of these advances, systematic genomic testing for patients with NSCLC is becoming the new standard of care in clinical decision-making, due to the identification of driver mutations that have triggered the development of new molecules targeting these specific alterations in cancer cells. For example, somatic mutations in epidermal growth factor receptor (EGFR) confer greater response rates to tyrosine kinase inhibitors (TKIs) that target the catalytic domain of EGFR, such as erlotinib and gefitinib, compared to standard therapy in advanced NSCLC, 70% vs. 33.2% in first-line trials. In a similar manner, crizotinib, the anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor, has demonstrated response rates of approximately 60% with progression-free survival greater than 10 months in those NSCLC characterized by ALK rearrangements. These studies have enabled to conclude that both EGFR-mutant and ALK-positive NSCLC constitute two defined subgroups of oncogene-driven tumors with potentially effective targeted therapy. Furthermore, approximately 15–20% of NSCLC diagnosed in Europe and North America bear EGFR mutations or ALK rearrangements, enhancing the significance of the development of drugs capable of interfering with their intracellular effects.
Based on these results, the identification of other activating mutations has been pursued in hopes of improving survival in NSCLC by specifically treating these genomic alterations. These potential therapeutic targets include KRAS, BRAF, HER2 and PIK3CA, in addition to ROS1 fusions. KRAS mutations, in codons 12, 13 and 61, reported in approximately 20% of cases of lung adenocarcinomas, predict negative outcome in terms of response to EGFR TKIs. No targeted therapies have demonstrated an increase in overall survival in KRAS-mutant NSCLC, although selumetinib, an inhibitor of MAPK extracellular signal-regulated kinase (MEK) 1/2 (downstream of KRAS), in combination with docetaxel in previously treated advanced NSCLC has shown promising results in a recent phase 2 trial.
Regarding activating mutations in BRAF, HER2 and PIK3CA, incidence reported for each group ranges from 1–4%, a lower although significant frequency that is encouraging further investigation of these genetic alterations and consequent therapeutic implications. HER2 mutations in NSCLC constitute a clear molecular target, particularly in a subset of patients with distinct clinical features, including female non-smokers with adenocarcinomas, similar to those patients with EGFR-mutant lung cancer. Here, we seek to review the characteristics of HER2 mutations that enable interaction with molecules that specifically target these receptors in lung adenocarcinomas, as well as the results of preliminary studies that assess the efficacy of anti-HER2 therapy applied to NSCLC.
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