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Studies Analyze EGFR and K-ras Mutations in Bronchioalveolar Carcinoma

Studies Analyze EGFR and K-ras Mutations in Bronchioalveolar Carcinoma

ORLANDO-In patients with bronchioalveolar carcinoma (BAC), are epidermal growth factor receptor (EGFR) and K-ras mutations associated with response to treatment with tyrosine kinase inhibitors (TKIs) like gefitinib (Iressa) and erlotinib (Tarceva)? The answer to this question varied in three different studies. Bronchioalveolar carcinoma is a type of lung cancer with unique features that is increasing in incidence, said Fred R. Hirsch, MD, PhD, professor of medicine and pathology at the University of Colorado Cancer Center in Aurora, and the principal investigator of one of the three studies. It is more frequent among women and nonsmokers. While pure BAC is not common, occurring in just 2% to 3% of patients, many lung cancers have BAC characteristics. Previous studies have suggested that patients with BAC features are more likely to respond to TKIs. Other studies have found that patients with nonsmall- cell lung cancer who have EGFR mutations are more likely to respond to gefitinib and erlotinib, whereas those with K-ras mutations are less likely to respond. The new studies are among the first to investigate EGFR and KRas mutations exclusively in BAC. MSKCC Erlotinib Trial EGFR mutations were more common in adenocarcinoma with BAC features than in "pure" BAC in the findings in one study reported by Mark Kris, MD, chief of the Thoracic Oncology Service at Memorial Sloan-Kettering Cancer Center, New York, and colleagues (abstract 7029). In their molecular analysis of specimens from about 50 patients with stage IIIb or IV BAC, they found a 9% mutation rate among those with pure BAC vs 31%for those who had adenocarcinoma with BAC characteristics. The normal mutation rate in North America is estimated at about 10%. In these patients, who are being treated with erlotinib in an ongoing phase II trial, the investigators reported a 77% partial response rate among those with EGFR mutations vs 8% among those without mutations, a statistically significant difference. Two SWOG Gefitinib Studies A second study, led by Paul Gumerlock, PhD, of the University of California, Davis, Cancer Center in Sacramento (abstract 7008) analyzed tumor tissue from 67 BAC patients enrolled in a Southwestern Oncology Group phase II trial of gefitinib (SWOG-0126). It found EGFR mutations in 18% of the patients. This study did not find a statistically significant link between EGFR mutation and response overall, but a subgroup of patients with EGFR mutations and without K-ras mutations were significantly more likely to respond. The third study, led by Dr. Hirsch, analyzed tissue samples from patients with BAC from the same SWOG trial and also found no statistically significant association between EGFR mutations and response (abstract 7030). This study, however, did find that ahigh number of EGFR gene copies were significantly correlated with response (see article on amplification, page 16). Two of these studies also looked at the association between response to TK inhibitors and mutations in the Kras gene, which plays a key role in one of the EGFR signaling pathways. Similar to the findings by Dr. Kris and colleagues that no patients with K-ras mutations responded to erlotinib, in the SWOG cohort, Dr. Gumerlock reported that only 1 of 19 patients with K-ras mutations had responded to the drug. K-ras mutation rates in the two studies did differ, however, at 30% in the SWOG group vs 13% in the other group. In discussing the differences in the EGFR findings, Manuel Hidalgo, MD, PhD, co-director of the Drug Development Program at Johns Hopkins University School of Medicine, noted that recent reports in the literature have also had conflicting evidence regarding the association between EGFR mutations and response. "I don't have an obvious explanation other than the differences in the studies themselves that limit their comparability," he said. All studies so far are relatively small and retrospective, he noted, and patient populations and analytical methods have differed.

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