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Background Some but not all patients with non-small-cell lung cancer (NSCLC) respond to treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). We developed and tested the ability of a predictive algorithm based on matrix-assisted laser desorption ionization (MALDI) mass spectrometry (MS) analysis of pretreatment serum to identify patients who are likely to benefit from treatment with EGFR TKIs. Methods Serum collected from NSCLC patients before treatment with gefitinib or erlotinib were analyzed by MALDI MS. Spectra were acquired independently at two institutions. An algorithm to predict outcomes after treatment with EGFR TKIs was developed from a training set of 139 patients from three cohorts. The algorithm was then tested in two independent validation cohorts of 67 and 96 patients who were treated with gefitinib and erlotinib, respectively, and in three control cohorts of patients who were not treated with EGFR TKIs. The clinical outcomes of survival and time to progression were analyzed. Results An algorithm based on eight distinct m/z features was developed based on outcomes after EGFR TKI therapy in training set patients. Classifications based on spectra acquired at the two institutions had a concordance of 97.1%. For both validation cohorts, the classifier identified patients who showed improved outcomes after EGFR TKI treatment. In one cohort, median survival of patients in the predicted 'good' and 'poor' groups was 207 and 92 days, respectively (hazard ratio [HR] of death in the good versus poor groups = 0.50, 95% confidence interval [CI] = 0.24 to 0.78). In the other cohort, median survivals were 306 versus 107 days (HR = 0.41, 95% CI = 0.17 to 0.63). The classifier did not predict outcomes in patients who did not receive EGFR TKI treatment. Conclusion This MALDI MS algorithm was not merely prognostic but could classify NSCLC patients for good or poor outcomes after treatment with EGFR TKIs. This algorithm may thus assist in the pretreatment selection of appropriate subgroups of NSCLC patients for treatment with EGFR TKIs.

Background: Gefitinib is a selective inhibitor of the epidermal growth factor (EGFR) tyrosine kinase, which is overexpressed in many cancers, including non-small-cell lung cancer (NSCLC). We carried out a clinical study to compare the relationship between EGFR gene copy number, EGFR protein expression, EGFR mutations, and Akt activation status as predictive markers for gefitinib therapy in advanced NSCLC. Methods: Tumors from 102 NSCLC patients treated daily with 250 mg of gefitinib were evaluated for EGFR status by fluorescence in situ hybridization (FISH), DNA sequencing, and immunohistochemistry and for Akt activation status (phospho-Akt [P-Akt]) by immunohistochemistry. Time to progression, overall survival, and 95% confidence intervals (CIs) were calculated and evaluated by the Kaplan-Meier method; groups were compared using the log-rank test. Risk factors associated with survival were evaluated using Cox proportional hazards regression modeling and multivariable analysis. All statistical tests were two-sided. Results: Amplification or high polysomy of the EGFR gene (seen in 33 of 102 patients) and high protein expression (seen in 58 of 98 patients) were statistically significantly associated with better response (36% versus 3%, mean difference = 34%, 95% CI = 16.6 to 50.3; P

Background: There are no currently approved methods for the screening and early detection of lung cancer. We compared the ability of conventional white-light bronchoscopy (WLB) and laser-induced fluorescence endoscopy (LIFE) to detect preneoplastic lung lesions in a randomized trial in which both the order of the procedures and the bronchoscopists were randomly assigned. Methods: The study included high-risk subjects enrolled because of a cigarette smoking history of at least 30 pack-years, an air-flow obstruction, and either an abnormal sputum cytology (n = 48) or a previous or suspected lung cancer (n = 7). LIFE and WLB were performed on all patients. Biopsy specimens were assessed for histologic abnormalities, including the presence of angiogenic squamous dysplasia. All statistical tests were two-sided. Results: A total of 391 biopsy specimens were taken from the 55 patients. Thirty-two patients (58%; 95% confidence interval [CI] = 44% to 71%) had at least one biopsy with moderate or severe dysplasia, and 19 (59%; 95 % CI = 41% to 76%) of these patients could be diagnosed based solely on the results of LIFE. LIFE was statistically significantly more sensitive than WLB for detecting moderate dysplasia or worse (68.8% versus 21.9%, respectively) (difference = 46.9%; 95% CI = 25% to 68%; P [is less than] .001). The relative sensitivities (WLB = 1.0) were 3.1 (95% CI = 1.6 to 6.3) for LIFE and 3.7 (95% CI = 1.9 to 7.3) for LIFE and WLB combined. LIFE was less specific than WLB (69.6% versus 78.3%, respectively; P = .45), but the difference was not statistically significant. The relative specificities (WLB = 1.0) were 0.9 for LIFE (95% CI = 0.6 to 1.3) and 0.6 (95% CI = 0.4 to 1.0) for LIFE and WLB combined. The results were similar regardless of the order of the procedures or the order of the bronchoscopists. Also, LIFE was better at identifying angiogenic squamous dysplasia lesions than WLB (detection ratio [DR], which indicates the relative likelihood of getting a positive result in a sample with dysplasia compared with one without, for LIFE = 1.39 [95% CI = 1.17 to 1.65] versus DR for WLB = 0.67 [95% CI = 0.38 to 1.21]). Conclusion: LIFE was more sensitive than WLB in detecting preneoplastic bronchial changes in high-risk subjects. The prognostic implication of this finding is not yet clear. [J Natl Cancer Inst 2001;93:1385-91]