Investigations into the underlying cellular processes that lead to cancer have revealed a number of interesting findings regarding the biological conditions responsible for tumor development. Individual forms of the disease emerge from mutations and malfunctions of particular genes and the attendant changes in protein complexes and cell structures these mutations give rise to. An understanding of the myriad ways in which certain mutations can affect these agents will hopefully enable scientists to create cancer therapies that precisely target these low-level conditions. These therapies should then result in cancer treatments that are both more effective and less likely to cause serious side effects.

Research into the causes of lung cancer and other epithelial malignancies, such as mesothelioma, has shown that epidermal growth factor receptor (EGFR) is often implicated in the development of some of these cancers. EGFR is the surface receptor for a family of protein ligands known as the epidermal growth factor (EGF) family. When an EGF-member binds to EGFR, the receptor is activated and begins a cascade of downstream signaling activity important for a large number of cellular activities that are necessary for the body to function normally. However, mutations to EGFR can lead to its overexpression and/or its constant activation. When this happens, EGFR is no longer performing within the strict confines of its natural function, but is instead helping to create the conditions of tumor growth by increasing “cell proliferation, motility, and angiogenesis.” EGFR malfunction is also thought to inhibit apoptosis.

Treatments for EGFR have been developed and have shown at least some effectiveness in the treatment of lung cancer, but its effect on the development of mesothelioma, and the disease’s most common forms of pleural mesothelioma and peritoneal mesothelioma, is not really understood. Researchers are also unsure as to the effect that EGFR therapy would have on mesothelioma treatments in general. To answer this question, researchers from Japan enrolled a number of patients with pleural mesothelioma into a study that investigated the relationship between EGFR mutations and overexpression and the development of mesothelioma.

Overview of the Study

The researchers enrolled 25 patients with confirmed pleural mesothelioma into their study. There were 23 male patients and 2 females. The histological sub-types of the tissue samples were as follows: 12 epithelial mesotheliomas, 8 biphasic mesotheliomas, 4 sarcomatous mesotheliomas, and one desmoplastic mesothelioma (this is usually considered to be a sarcomatoid mesothelioma, but the researchers here treat it as a separate entity). A sample of the malignant tissue was taken from each patient and then analyzed for EGFR gene mutation or amplification and then for protein expression levels.

Results

None of the 25 tissue samples evidenced any sign of the 13 mutations of the EGFR kinase domain that have been reported as common in EGFR-implicated lung cancer incidence. Four of the samples demonstrated some form of polysomy, which is a genetic condition where cells possess extra chromosomes, while the other 21 samples demonstrated normal chromosomal structures. When the samples were analyzed for protein expression, 68% (17 of the 25) of them demonstrated some type of membrane immunoreactivity, with eight of the samples (32%) returning scores high enough to be considered positive findings for EGFR overexpression. However, protein overexpression did not correlate with overall survival in any way.

When viewed within the entire data set, none of these findings could be correlated with patient age, gender or tumor pathology. Increased survival was seen in those presenting with epithelial mesothelioma, but this is to be expected as the epithelial subtype always presents with a better prognosis than the other subtypes. Multivariate analysis did not identify any other variable as an independent prognostic factor.

Conclusion

The authors state that although their sample size was small, their results suggest that EGFR mutations only play a role in a small subset of patients with pleural mesothelioma. These findings serve as another identification of the differences between mesothelioma and lung cancer: while specific EGFR mutations have been implicated in the development of lung cancer, this rarely seems the case with mesothelioma development. In terms of gene amplification, four of the cases identified extra chromosomal pairs, indicating anti-EGFR treatment for mesothelioma will only be effective for the subset of patients who present with EGFR polysomy. The authors were unable to correlate EGFR overexpression with any survival data, whether positive or negative, noting that only epithelial mesothelioma demonstrated a survival effect within this dataset.

Labels: mesothelioma