In the United States, an estimated 222,520 lung and bronchus cancers will be diagnosed in
2010, and 157,300 people will die of this disease. Therefore, there is an urgent need for
safer and more effective therapies for lung cancer.1 Lung cancer falls into two major
classifications, non-small cell lung cancer (NSCLC) which accounts for approximately 87%,
and small cell lung cancer (SCLC), which accounts for the remainder. Thymomas are the
most common tumors of the anterior mediastinum, and typically occur in adults older than
40 years. While surgical resection and radiation often effectively treat these tumors, a
minority continue to progress and eventually lead to death. Thymic carcinomas are a
related subset of tumors that more often metastasize and are more aggressive. Finally,
mesothelioma often behaves as aggressively as lung cancer, and is not frequently amenable
to curative resection.
While the role of molecular alterations has yet to be defined in the treatment of SCLC,
thymoma, and mesothelioma, there is an increasing recognition that molecular alterations
in NSCLC are important predictors of response to novel targeted therapies. Small molecule
tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) signaling
pathway, such as erlotinib and gefitinib, improve survival in the second-line treatment
of unselected patients with NSCLC. However, retrospective subgroup analysis of these
clinical trials has revealed that patients with particular clinical features were more
likely to benefit from therapy, such as those with tumors of adenocarcinoma histology,
women, Asian ethnicity, and light or never smokers. Conventional Deoxyribonucleic acid
(DNA) sequencing of tumors from multiple series of patients that had dramatic responses
to gefitinib, as compared with patients without responses, revealed the presence of
characteristic genetic mutations in the EGFR gene.4-6 The previously identified clinical
markers of response to EGFR TKIs were found to be commonly associated with the presence
of these mutations; thus, these clinical features are actually believed to be surrogates
for the molecular biomarker of EGFR mutation. Over 90% of EGFR tyrosine kinase domain
mutations associated with sensitivity to EGFR Tyrosine kinase inhibitor (TKI) therapy
fall into two categories, in-frame deletions in exon 19, and the L858R point mutation in
exon 21. These mutations appear to specifically activate both cell proliferation, via
activation of the MAP kinase pathway, and survival signals, via activation of the PI3
kinase pathway.7 Therefore, tumors with EGFR mutations are "oncogene addicted" to EGFR
survival signals, relying exclusively upon the EGFR signaling cascade to maintain
viability, which explains their exquisite sensitivity to TKI therapy. A number of recent
large randomized studies have conclusively demonstrated that clinical selection of
patients alone is inadequate, and instead establish EGFR mutation status as the single
most important predictive marker of response to EGFR-TKI therapy.8-10 In another emerging
but similar story, genetic fusion of the anaplastic lymphoma kinase (ALK) tyrosine kinase
to a partner protein, EML4, appears to strongly predict sensitivity to the ALK TKI,
crizotinib. 11 In addition, there is evidence that less common mutations in NSCLC, such
as BRAF mutations and ERBB2 (e.g. HER2) mutations, may also predict response to targeted
therapies.
In summary, identification of genetic alterations in NSCLC is increasingly essential for
individualizing treatments and performing molecular diagnostics. While the investigators
do not anticipate benefits to individual patients, identification of molecular
alterations in small cell lung cancer, thymic malignancies, and mesothelioma may provide
similar keys to the utilization of novel therapies. This project aims to create a
registry of patients and tumors to further the characterization of molecular alterations
in thoracic malignancies and develop markers of early detection.
