ORLANDO-A lung cancer patient's smoking history may help predict his or her response to gefitinib(Drug information on gefitinib) (Iressa) and erlotinib (Tarceva), according to two studies. If follow-up studies turn out as hoped, smoking history could become a useful tool forselecting treatments for patients with non-small-cell lung cancer (NSCLC), investigators reported. In one study (abstract 7069), the investigators sequenced the epidermalgrowth factor receptor (EGFR) gene in 265 tumor samples from patients with lung adenocarcinomas, looking for mutations that have been associated with response to gefitinib and erlotinib. They then correlated the presence of the mutations with each patient's smoking history. The rate of mutations in never smokers was 50.7%, in former smokers, 19.2%, and in current smokers, 4.3%, reported lead investigator Duy Khanh Pham, MD, a researcher in the Department of thoracic surgery, Memorial Sloan-Kettering Cancer Center in New York. EGFR mutations were present in tumors from patients with a smoking history of 15 or fewer pack years; in fact the incidence of mutations in these former smokers did not differ from the incidence of mutations in never smokers, Dr. Pham told ONI. Patients who had beensmoke-free for more than 25 years also were likely to have mutations. The investigators concluded that a thorough smoking history can assist clinicians in assessing the probability of the presence of EGFR mutations and, consequently, in estimating the likelihood of response to treatment with gefitinib or erlotinib. 15 Pack-Year Cutoff In discussing the trial, Roman Perez-Soler, MD, chief of the oncology division at Montefiore Medical Center, New York, agreed that the findings had potential clinical implications. Particularly interesting, he said, were the data indicating that 15 pack years could be a cutoff point for the presence of EGFR mutations. "I think that's an important and potentially useful finding..." he said. "It might be that [the 15 pack-year cutoff] would be a better way to select patients." Dr. Perez-Soler suggested that data from the National Cancer Institute of Canada's landmark BR.21 trial with erlotinib could be used to confirm these findings. "Can we validate this? I think so," he said, recommending that the BR.21 results be analyzed using that particular cutoff. Smoking and BR.21 Data Although the BR.21 data may not have been analyzed yet according to the smokers' number of pack years, one group of investigators has examined the smoking history of BR.21 patients in relation to EGFR expression (abstract 7033). Gary Clark, PhD, and colleagues at OSI Pharmaceuticalsin Boulder, Colorado, found that smoking history was more predictive of a survival benefit from erlotinib than whether a patient overexpressed EGFR. These investigators looked at 311 BR.21 patients whose EGFR status and smoking history was known. Those who had never smoked were more likely to respond to erlotinib than those who were former or current smokers, although there were responses in all three categories. By contrast, there was no significant correlation between EGFR expression and response, said Dr. Clark, who is vice president for biostatistics and data management at OSI. Dose-Escalation Study Planned One reason for the lower response rate in current smokers may be that not enough erlotinib reaches their tumors, Dr. Clark said. He added that "according to this hypothesis, erlotinib is cleared from the body more quickly in smokers, as smoking is known to upregulate enzymes CYP1A1 and CYP1A2, which speed the clearance of erlotinib. If true, higher doses of erlotinib might compensate for the increased clearance, and physicians could prescribe higher doses of the drugs for smokers in order to achieve the desired exposure." OSI is planning a dose-escalation study that will test this idea, he said. Commenting on this study, Manuel Hidalgo, MD, of the Johns Hopkins School of Medicine, Baltimore, said it was notable for the large number of patients. This makes it a welcome confirmation of smaller studies that have shown a higher response rate to tyrosine kinase inhibitors in nonsmokers, he added.