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1.  Novel Therapeutic Approaches for Small Cell Lung Cancer: The Future has Arrived 
Current Problems in Cancer  2012;36(3):156-173.
doi:10.1016/j.currproblcancer.2012.03.005
PMCID: PMC3392558  PMID: 22495056
SCLC; tyrosine receptor kinases; developmental pathways; immunology; oncolytic replication-selective viruses
2.  Local therapy with continued EGFR tyrosine kinase inhibitor therapy as a treatment strategy in EGFR mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors 
Background
Development of acquired resistance limits the utility of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) for the treatment of EGFR mutant lung cancers. There are no accepted, targeted therapies for use after acquired resistance develops. Metastasectomy is used in other cancers to manage oligometastatic disease. We hypothesized that local therapy is associated with improved outcomes in patients EGFR mutant lung cancers with acquired resistance to EGFR TKI.
Methods
Patients who received non-CNS local therapy were identified by a review of data from a prospective biopsy protocol for patients with EGFR-mutant lung cancers with acquired resistance to EGFR TKI therapy and other institutional biospecimen registry protocols.
Results
Eighteen patients were identified that received elective local therapy (surgical resection, radiofrequency ablation or radiation). Local therapy was well-tolerated, with 85% of patients restarting TKI therapy within one month of local therapy. The median time to progression after local therapy was 10 months (95% Confidence interval [CI]: 2 to 27 months). The median time until a subsequent change in systemic therapy was 22 months (95% CI: 6 to 30 months). The median overall survival from local therapy was 41 months (95% CI: 26 to not reached).
Conclusions
EGFR- mutant lung cancers with acquired resistance to EGFR TKI therapy are amenable to local therapy to treat oligometastatic disease when used in conjunction with continued EGFR inhibition. Local therapy followed by continued treatment with an EGFR TKI is well tolerated, and associated with long PFS and OS. Further study in selected individuals in the context of other systemic options is required.
doi:10.1097/JTO.0b013e31827e1f83
PMCID: PMC3673295  PMID: 23407558
3.  Coexistence of PIK3CA and other oncogene mutations in lung adenocarcinoma – rationale for comprehensive mutation profiling 
Molecular cancer therapeutics  2011;11(2):485-491.
PIK3CA encodes the p110α subunit of the mitogenic signaling protein phosphatidylinositol 3-kinase (PI3K). PIK3CA mutations in the helical binding domain and the catalytic subunit of the protein have been associated with tumorigenesis and treatment resistance in various malignancies. Characteristics of patients with PIK3CA-mutant lung adenocarcinomas have not been reported.
We examined EGFR, KRAS, BRAF, HER2, PIK3CA, AKT1, NRAS, MEK1, and ALK in patients with adenocarcinoma of the lung to identify driver mutations. Clinical data were obtained from the medical records of individuals with mutations in PIK3CA.
Twenty-three of 1125 (2%, 95% confidence interval (CI) 1–3%) patients had a mutation in PIK3CA, 12 in Exon 9 (10 E545K, 2 E542K) and 11 in Exon 20 (3 H1047L, 8 H1047R). The patients (57% women) had a median age of 66 at diagnosis (range 34–78). Eight patients (35%) were never smokers. Sixteen of 23 (70%, 95% CI 49 – 86%) had coexisting mutations in other oncogenes - 10 KRAS, 1 MEK1, 1 BRAF, 1 ALK rearrangement, and 3 EGFR exon 19 deletions.
We conclude that PIK3CA mutations occur in lung adenocarcinomas, usually concurrently with EGFR, KRAS, and ALK. The impact of PIK3CA mutations on the efficacy of targeted therapies such as erlotinib and crizotinib is unknown. Given the high frequency of overlapping mutations, comprehensive genotyping should be performed on tumor specimens from patients enrolling on clinical trials of PI3K and other targeted therapies.
doi:10.1158/1535-7163.MCT-11-0692
PMCID: PMC3593239  PMID: 22135231
lung adenocarcinoma; oncogene; PIK3CA
4.  EGFR mutant lung adenocarcinomas treated first-line with the novel EGFR inhibitor, XL647, can subsequently retain moderate sensitivity to erlotinib 
Journal of Thoracic Oncology  2012;7(2):434-442.
Introduction
EGFR mutant lung cancers are sensitive to EGFR tyrosine kinase inhibitors (TKIs). Unfortunately, they develop resistance, often due to acquisition of a second-site mutation (T790M). Current EGFR TKIs select for T790M in preclinical models of acquired resistance. We explored whether all EGFR TKIs similarly select for the T790M mutation using data from early clinical trials and established in vitro models of acquired resistance.
Methods
We analyzed the clinical characteristics of 8 patients with metastatic EGFR mutant lung adenocarcinoma who were treated first-line with XL647 and then progressed. XL647 is an ATP-competitive inhibitor of EGFR, HER2, KDR, and EPHB4. Additional molecular preclinical studies were performed to characterize resistance.
Results
Four patients displayed confirmed partial responses (PRs), three patients had unconfirmed PRs, and one patient displayed stable disease. Only one of five patients’ tumor samples available for analysis after disease progression harbored the T790M mutation. Eight patients subsequently received erlotinib, with (n=3) or without (n=5) chemotherapy. Three of five patients treated with single agent erlotinib derived additional benefit, staying on drug up to 9 months. EGFR mutant PC-9 cells with acquired resistance to XL647 did not harbor the T790M mutation, displayed a distinct mRNA profile from PC-9 cells with T790M-mediated resistance, and were moderately sensitive to erlotinib in growth inhibition assays. Crystal structure analyses of XL647/EGFR T790M did not reveal a different binding mode from that of erlotinib.
Conclusions
The findings of this exploratory study suggest different EGFR TKIs may select for distinct mechanisms of resistance. These results raise the possibility that different EGFR TKIs could be sequentially used to improve outcomes in patients with EGFR mutant lung cancer. Further work investigating this hypothesis is warranted.
doi:10.1097/JTO.0b013e31823c5aee
PMCID: PMC3261336  PMID: 22173702
non-small cell lung cancer; EGFR mutations; XL647; EGFR tyrosine kinase inhibitors; acquired resistance; gefitinib; erlotinib; afatinib
5.  Incidence of EGFR Exon 19 Deletions and L858R in Tumor Specimens From Men and Cigarette Smokers With Lung Adenocarcinomas 
Journal of Clinical Oncology  2011;29(15):2066-2070.
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.
doi:10.1200/JCO.2010.32.6181
PMCID: PMC3296671  PMID: 21482987

Results 1-5 (5)