Lung cancer mutation targets nonsmokers

<body leftmargin="0" bgcolor="#000060" text="#FFFFFF" link="#FFFF00" vlink="#FF9900"> <b> <p class="MsoNormal"><font face="Arial" size="4">Lung cancer mutation targets nonsmokers</font></p> </b> <p class="MsoNormal"><font face="Arial" size="1">Posted March 2, 2005<br> Courtesy the University of Texas Southwestern Medical Center<br> and World Science staff<br> </font><font face="Arial" size="2"><b><br> </b></font><b><font face="Arial" size="2">Lung cancer patients who have never smoked are more likely than smokers to harbor one of two genetic mutations that researchers have now linked to the disease. <br> <br> “This study describes the first known mutation to occur in lung cancer patients who have never smoked,” said Adi Gazdar of University of Texas Southwestern Medical Center and senior author of the study, published in the March 1 issue of the <i>Journal of the National Cancer Institute</i>. <br> <br> “These findings may help explain why certain lung cancer patients respond dramatically to a specific form of targeted therapy while others have little or no response.” <br> <br> Mutations in the gene, called epidermal growth factor receptor (EFGR), are present mainly in adenocarcinomas, the most common form of lung cancer found in smokers and non-smokers, as well in women and people under 45. These mutations have shown increased sensitivity to two drugs targeting the gene, gefitinib (also known as Iressa) and erlotinib (also known as Tarceva).<br> <br> To understand better the role of the mutation in the development of lung cancer, Gazdar and his colleagues analyzed tissue samples from tumors of 519 patients in the United States, Japan, Taiwan and Australia. Mutations in the DNA of nonmalignant lung tissue from many of these patients and from other separate cancer tissues also were examined.<br> <br> The researchers found mutations in the gene were much more common <br> <br> - in people with lung cancer who never smoked compared to smokers (51 percent vs. 10 percent); <br> - in adenocarcinomas compared to other lung cancers (40 percent vs. 3 percent); <br> - in women compared to men (42 percent vs. 14 percent); <br> - in Asians compared to other ethnicities (30 percent vs. 8 percent). <br> <br> Another mutation studied was in a gene called KRAS. This gene is also known to participate in the chain of molecular chain events influenced by the epidermal growth factor receptor gene.<br> <br> Mutations in the KRAS gene were found in 8 percent of lung cancers but in none with the EGFR mutation, the researchers said. This mutation was more common in males, Caucasians, and current or former smokers.<br> <br> As a result, it appears that two distinct molecular chains of events, or pathways, are involved in formation of lung cancer, Gazdar said. The pathway in smokers involves KRAS gene mutations, while the pathway in people who never smoked involves EGFR gene mutations.<br> <br> The next step is to move these findings toward development of better treatments for lung cancer, said Gazdar.<br> <br> A related study in the current issue of Cancer Research with Gazdar and his colleagues found that mutations in EGFR and HER2, another gene in the EGFR pathway that is associated with certain cancers, targeted the same patient subpopulations. The discovery that HER2 also is a mutation occurring mainly in tumors of people who never smoked suggests different pathways may be involved in lung cancer formation in smokers and nonsmokers.<br> <br> “Our work is very important because if you have a mutation in the EGFR gene in the tumor, a patient likely will have a dramatic response to a relatively nontoxic once-daily oral therapy,” Minna said. <br> <br> “The research has found these tumors can vary by several thousandfold on how sensitive they are to a drug,” said Minna. “We also have been able to identify in advance a pattern of gene expression [activity] that tells whether a tumor is going to be resistant or sensitive to a particular drug. We want to be capable of examining a patient’s tumor, profile each human gene and then select the best current therapy.” <br> <br> Minna and another colleague, Jonathan Dowell, contributed to an editorial in the Feb. 24 issue of <i>The New England Journal of Medicine</i> that found a lung cancer that initially was very sensitive to gefitinib because of a mutation in the EGFR gene developed resistance to the drug because of a second EGFR mutation.<br> <br> The enhanced understanding of EGFR and these mutations reported in the <i>New England Journal of Medicine</i> study will allow new drugs to be designed to combat these drug-resistant forms, enabling effective second-line therapy to be devised, Minna wrote.</font></p> </b> </body>