Molecular Analysis of Thoracic Malignancies

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.

Inclusion Criteria:

1.Histologically proven diagnosis of non-small cell lung cancer, small cell lung cancer,
thymoma, thymic carcinoma, mesothelioma, or carcinoma of unknown primary consistent with
the presentation of a primary thoracic malignancy.

2.18 years of age or older.

3.Ability to understand and the willingness to sign a written informed consent document.