Purpose

EGFR mutations underlie the sensitivity of lung cancers to erlotinib and gefitinib and can occur in any patient with this illness. Here we examine the frequency of EGFR mutations in smokers and men.

Methods

We determined the frequency of EGFR mutations and characterized their association with cigarette smoking status and male sex.

Results

We tested 2,142 lung adenocarcinoma specimens for the presence of EGFR exon 19 deletions and L858R. EGFR mutations were found in 15% of tumors from former smokers (181 of 1,218; 95% CI, 13% to 17%), 6% from current smokers (20 of 344; 95% CI, 4% to 9%), and 52% from never smokers (302 of 580; 95% CI, 48% to 56%; P < .001 for ever v never smokers). EGFR mutations in former or current smokers represented 40% of all those detected (201 of 503; 95% CI, 36% to 44%). EGFR mutations were found in 19% (157 of 827; 95% CI, 16% to 22%) of tumors from men and 26% (346 of 1,315; 95% CI, 24% to 29%) of tumors from women (P < .001). EGFR mutations in men represented 31% (157 of 503; 95% CI, 27% to 35%) of all those detected.

Conclusion

A large number of EGFR mutations are found in adenocarcinoma tumor specimens from men and people who smoked cigarettes. If only women who were never smokers were tested, 57% of all EGFR mutations would be missed. Testing for EGFR mutations should be considered for all patients with adenocarcinoma of the lung at diagnosis, regardless of clinical characteristics. This strategy can extend the use of EGFR tyrosine kinase inhibitors to the greatest number individuals with the potential for substantial benefit.

Structured Abstract

Introduction

The detection of mutations in the epidermal growth factor receptor (EGFR) gene, which predict sensitivity to treatment with EGFR tyrosine kinase inhibitors (TKIs), represents a major advance in the treatment of lung adenocarcinoma. KRAS mutations confer resistance to EGFR -TKIs. The prevalence of these mutations in African-American patients has not been thoroughly investigated.

Methods

We collected formalin-fixed, paraffin-embedded material from resected lung adenocarcinomas from African-American patients at three institutions for DNA extraction. The frequencies of EGFR exon 19 deletions, exon 21 L858R substitutions and KRAS mutations in tumor specimens from African-American patients were compared to data in Caucasian patients (n=476).

Results

EGFR mutations were detected in 23 of the 121 specimens from African-American patients (19%, 95% CI 13–27%), while KRAS mutations were found in 21 (17%, 95% CI 12−25%). There was no significant difference between frequencies of EGFR mutations comparing African-American and Caucasian patients, 19% vs. 13% (61/476, 95% CI 10–16%) (p=0.11). KRAS mutations were more likely among Caucasians, 26% (125/476, 95% CI 23−30%) (p=0.04).

Conclusions

This is the largest study to date examining the frequency of mutations in lung adenocarcinomas in African-Americans. Although KRAS mutations were somewhat less likely, there was no difference between the frequencies of EGFR mutations in African-American patients as compared to Caucasians. These results suggest that all patients with advanced lung adenocarcinomas should undergo mutational analysis prior to initiation of therapy.

Aims

EGFR mutations now guide the clinical use of EGFR-targeted therapy in lung cancer. However, standard EGFR mutation analysis requires a minimum amount of tumor tissue, which may not be available in certain situations. In this study, we combined a mass spectrometry genotyping assay (Sequenom) with a mutant-enriched PCR (ME-PCR) to detect EGFR mutations in free plasma DNA from patients with lung cancer.

Method

DNAs were extracted from 31 plasma samples from 31 patients and analyzed by both methods for EGFR exon 19 deletion and EGFR L858R mutation. Results in plasma DNA samples were compared with EGFR mutation status obtained in tumor DNA (18/31 EGFR mutant). The relationship of EGFR mutation status in tumor and/or plasma samples to overall survival was assessed.

Results

The EGFR mutation status in plasma DNA was identical to the primary tumor in 61% of patients (19/31). By mass spectrometry genotyping, the plasma samples contained mutant DNA corresponding to 5/14 EGFR exon 19 deletions and 3/4 EGFR L858R mutations previously diagnosed in the matched tumors. Two samples were positive in plasma DNA but negative in primary tumor tissue. Results were similar for ME-PCR. For patients treated with erlotinib, overall survival was correlated with the presence of EGFR mutation in plasma and/or tumor tissue (p=0.002), with the two patients positive only in plasma DNA showing responses and favorable outcomes.

Conclusion

The detection of EGFR mutations in plasma DNA samples by mass spectrometry genotyping and ME-PCR is feasible. A positive EGFR result in plasma DNA has a high predictive value for tumor EGFR status and for favorable clinical course on EGFR-targeted therapy and could therefore be useful in guiding clinical decisions in patients with insufficient or unavailable tumor specimens.

Introduction

Dual inhibition of SRC and EGFR -dependent pathways may overcome acquired resistance to EGFR-TKIs for patients with lung adenocarcinoma with EGFR mutations. The SRC-inhibitor dasatinib demonstrates anti-tumor activity in gefitinib-resistant cells lines and xenografts. Dasatinib is tolerable for patients with advanced non-small cell lung cancer, and in combination with erlotinib.

Methods

We conducted this phase II study of dasatinib 70 mg twice daily in patients with EGFR-mutant lung adenocarcinoma and acquired resistance to EGFR-TKIs. After a protocol amendment based upon evolving data about both drugs, patients received dasatinib at a dose of 100 mg daily with continued erlotinib after developing acquired resistance. Enrolled patients either harbored an activating mutation in EGFR or experienced clinical benefit with single-agent erlotinib or gefitinib, followed by RECIST documented progression while being treated with an EGFR-TKI.

Results

Twenty-one patients were enrolled, nine under the original trial design and 12 after the protocol amendments. We observed no complete or partial responses (0% observed rate, 95% CI 0–18%). The median time to progression was 0.5 months (range 0.2–1.8 months) in patients treated with dasatinib, and 0.9 months (range 0.4–5 months) for patients treated with dasatinib and erlotinib in combination. Pleural effusions and dyspnea were frequent toxicities.

Conclusions

Dasatinib has no activity in patients with EGFR-mutant lung adenocarcinoma with acquired resistance to erlotinib and gefitinib.