Affiliations of authors: Program in Cancer Biology and Genetics (WP); Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine (WP, VAM, MGK), and Department of Epidemiology and Biostatistics (EV), Memorial Sloan-Kettering Cancer Center, New York, NY; Weill Medical College of Cornell University, New York, NY
Correspondence to: Mark G. Kris, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021 (e-mail: krism{at}mskcc.org)
The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor of the ErbB family that is abnormally activated in epithelial tumors (1). Receptor activation leads to recruitment and phosphorylation of downstream intracellular substrates. Multiple pathways are activated, including the phosphatidylinositol 3kinase/Akt (PI3K/Akt) cascade implicated in cell survival and the RAS/RAF/mitogen-activated protein kinase (MAPK) cascade associated with cell proliferation (2,3). Aberrant signaling through EGFR can lead to tumor-promoting cellular activities.
EGFR is the target for cancer therapies such as gefitinib (4-quinazolinamine, N-[3-chloro-4-fluorophenylamino]-7-methoxy- 6-[3-(4-morpholinyl) propoxy]) (4,5), which inhibits the tyrosine kinase activity of EGFR by reversibly competing with adenosine triphosphate (ATP) at the ATP-binding site within the EGFR protein. Gefitinib selectively inhibits EGFR when tested against several other kinases in vitro (6). In phase I trials, gefitinib induced responses in 10 of 100 unselected patients with nonsmall-cell lung cancer (NSCLC). Subsequently, in two phase II trials, radiographic regression of NSCLC was observed in 28% of patients enrolled in a study from Japan (7) and in 10% of patients enrolled in a study from Europe and the United States (8). On the basis of these two studies, regulatory authorities approved gefitinib for the treatment of patients with NSCLC after other chemotherapies had failed.
At the time the drug received approval, the specific target(s) of gefitinib in human tumors were unknown. Many groups, including ours, have sought clinical and/or molecular predictors of response. Analyses of clinical trial data suggested that gefitinib was more efficacious in patients who smoked fewer than 100 cigarettes during their lifetime (i.e., never smokers); among individuals with adenocarcinomas, particularly bronchioloalveolar carcinoma (9); and in Japanese patients (7). In analyses of both preclinical xenograft models (10) and specimens from gefitinib-sensitive and -refractory tumors (11), no relationship between EGFR expression levels and tumor sensitivity was detected. No single clinical or molecular factor predictive of drug response was identified in these studies.
Recently, two groups have shown that mutations in the tyrosine kinase domain of EGFR are strongly associated with gefitinib sensitivity in persons with NSCLC (12,13). In total, deletions or amino acid substitutions in exons 18, 19, and 21 of EGFR were found in 13 of 14 tumors sensitive to the drug but in none of 11 insensitive tumors. Lynch et al. (12) found mutations in another two of 25 collected NSCLCs, and Paez et al. (13) found EGFR mutations in 16 of 119 unselected tumors, with the majority (15 of 58) of mutations found in a Japanese cohort rather than in a U.S. cohort (one of 61). The high incidence of mutations in tumor specimens from Japan likely explains the higher response rates seen in a Japanese study (7).
In this issue of the Journal, Cappuzzo and colleagues (14) used another approach, immunohistochemistry, to predict sensitivity or resistance to gefitinib. Because EGFR activates the PI3K/Akt and MAPK cascades, and because activation of such pathways depends upon the phosphorylation status of the signaling components, Cappuzzo et al. (14) evaluated the association between phosphorylation status of Akt (P-Akt) and MAPK (p-MAPK) and gefitinib activity. They immunohistochemically stained lung tumor specimens with phospho-specific, commercially available antibodies. Patients whose tumors were positive for P-Akt had a better response rate, "disease control rate," and time to progression than patients whose tumors were negative for P-Akt, as determined in a univariate analysis. The only multivariable analysis reported was for time to progression, which is seldom a primary endpoint in NSCLC trials. Staining for P-Akt was associated with known clinical predictors of response, i.e., being a never smoker, female sex, and adenocarcinoma histology. Cappuzzo et al. (14) found no correlation between p-MAPK status and any outcome. They concluded that gefitinib may be most effective in patients with activated Akt.
The significance of the findings by Cappuzzo et al. (14) can be evaluated on three levels: scientific, clinical, and statistical. Scientifically, given the new information about EGFR tyrosine kinase domain mutations and sensitivity to gefitinib, the data from Cappuzzo et al. (14) are hard to interpret without knowing the mutation status of the tumors they examined. Does P-Akt positivity matter if EGFR mutations accurately predict gefitinib response? Can P-Akt positivity act as a "surrogate" for detecting EGFR mutations? At present, it is not clear whether mutated EGFRs lead to preferential signaling through any pathway including PI3K/Akt and/or MAPK. It will be interesting to see future data from this group analyzing associations between mutation status and immunohistochemical findings.
How applicable are the findings from Cappuzzo et al. (14) to the clinic? Phosphorylated Akt is reported to have been detected in 33%75% of unselected NSCLC specimens (1517). As response rates for gefitinib in NSCLC are 10%28%, tests based on P-Akt positivity alone would overestimate the number of patients having gefitinib-sensitive tumors. Others have also studied P-Akt and p-MAPK staining in gefitinib-sensitive and -refractory tumors, and results have varied. Using the same antibody and definition of positivity as used by Cappuzzo et al. (14), our group has shown that seven of 15 tumors from patients with partial responses following gefitinib were positive for P-Akt versus 10 of 28 tumors from patients with gefitinib-refractory disease (P = .53) (18). Similarly, Franklin et al. (19) reported that P-Akt levels were not associated with survival in an analysis of patients with bronchioloalveolar carcinoma who were receiving gefitinib.
Cappuzzo et al. (14) achieved their primary statistical endpoint, i.e., associating improvements in response rate and time to progression with P-Akt status. However, they present no analysis to show that P-Akt status is superior to clinical variables, such as smoking status, sex, and histologic subtype, or that it provides valuable additional information in predicting response or survival. Moreover, Cappuzzo et al. (14) do not account for the impact of response or disease stabilization rate on the difference in time to progression distribution seen in the curves shown in their figure 1. Thus, the clinical relevance of their observation here is uncertain.
Although the report of Cappuzzo et al. (14) is interesting, the findings do not supersede better predictors of response to gefitinib. When patients with NSCLC enter the clinic today, treatment decisions must be guided by both clinical characteristics and EGFR mutation status.
NOTES
V. Miller has received research funding from Genentech and AstraZeneca and commercial support for continuing medical educationapproved speaking program and consultancy. M. Kris has received research funding from AstraZeneca, maker of gefitinib, and has represented AstraZeneca before the U.S. Food and Drug Administration. He has also received research funding from Genentech, maker of erlotinib, and received consulting fees from Bristol-Myers Squibb, Imclone, Inc., and Genentech.
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