Trial Information

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.