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Mesothelin-related predictive and prognostic factors in malignant mesothelioma: A nested case-control study

Friday, March 14, 2008

Source: Lung Cancer
(Roe OD, et al., Mesothelin-related predictive and prognostic factors in malignant mesothelioma: A nested case-control study, Lung Cancer (2008), doi:10.1016/j.lungcan.2007.12.025)

The search to discover and develop effective markers for mesothelioma is one of the most active areas of mesothelioma research. Doctors and scientists are engaged in a number of programs whose ultimate goal is the creation of simple and reliable tests that can indicate a patient’s disease status at any point in time. There are three major avenues this research is being carried out on: the development of markers for mesothelioma diagnosis, which would allow definitive diagnoses earlier in the disease’s staging, using less-invasive techniques; the development of markers for prognosis tracking and disease progression, which would allow treating physicians to evaluate the efficacy of a patient’s treatment and to make adjustments to it by analyzing the relationship between therapy and marker levels; and, finally, the creation of markers for screening purposes, where likely candidates for mesothelioma development, such as people with a history of asbestos exposure and their families, could under-go a simple test to indicate any underlying change in status possibly indicative of cancer development—much in the same way that people over 50 are recommended colonoscopies for screening of possible colon cancer or the development of precancerous lesions.

In the search for these markers, a number of possible targets have been proposed, but one of the most often studied is mesothelin, a membrane-bound glycoprotein of the mesothelium that previous studies have shown is significantly over-expressed in people with malignant mesothelioma, especially pleural mesothelioma and peritoneal mesothelioma, as well as certain other cancers. Mesothelin is considered to play an important role in cell adhesion, as well as in inter-cell signaling and recognition. Another avenue of marker research in the mesothelin family involves soluble mesothelin-related protein (SMRP), which can be found in serum and in the fluid from pleural effusions, as opposed to mesothelin which is bound to the cell’s surface.

An international team of researchers, including scientists and doctors from Norway, Australia and France, have recently released the results of a study that analyzed the efficacy of these mesothelin-related markers for use in the screening of mesothelioma, as well as their use for mesothelioma diagnosis, prognosis development and progression testing.

Overview of the Study

Previous studies on mesothelin expression and SMRP levels have both shown high sensitivity and specificity regarding mesothelioma diagnosis. One of the studies noted by the present authors suggested that SMRP could also be a screening marker, as that study found elevated SMRP levels one–five years prior to a mesothelioma diagnosis in a subset of asbestos-exposed indviduals.

Along with SMRP, other serum markers that have been proposed as markers for mesothelioma include CYFRA 21-1 (Cytokeratin Fragment 19) and CA125 (Cancer Antigen 125)—both of which have shown elevated levels in previous studies of the disease. The authors specifically noted that some previous studies had implicated CA125 in peritoneal metastasis. They included these markers in their analysis as well, both to compare with SMRP expression and to analyze these levels on their own.

To make their analysis, the authors identified forty-seven archival cases of confirmed mesothelioma where tumor samples and pre-clinical serum were still available for each of the patients. 29 of these cases were identified as pleural mesothelioma, seven as peritoneal mesothelioma and there was a single diagnosis of mesothelioma of the tunica vaginalis, an exceedingly rare form of the disease. Histologically, the cases of pleural mesothelioma were split between 33 cases of epitheloid mesothelioma and 6 cases of bi-phasic mesothelioma. All of the peritoneal cases presented as epitheloid mesothelioma, while the tunica vaginalis case presented as bi-phasic mesothelioma. The levels of SMRP, CYFRA 21-1 and CA125 were then compared to a control group of 121 healthy adults. Mesothelin expression was examined only in the cases of confirmed mesothelioma.

The results of the pre-clinical serum marker tests showed no significant differences between the control group and the mesothelioma group in terms of mean marker levels, which led the authors to conclude that these markers should not be used as part of a screening process. They also noted that much more research needs to be completed in this area before a definitive conclusion can be delivered.

In 36 of the 47 mesothelioma cases (77%), mesothelin was expressed in more than 50% of the identified tumor cells. Three cases did not show any mesothelin expression, five showed expression in less than 25% of malignant cells and three showed expression between 26% and 50%. When mesothelin expression was identified in the bi-phasic cases, it was only in the epitheloid component, as the sarcomatous component in the mixed subtype always returned an expression value of zero. The authors did not find any correlation between mesothelin expression in tumors and SMRP levels in their pre-clinical serum samples.

The authors also divided the mesothelioma cases into two groups: those with mesothelin expression greater than 50% in tumor cells and those with less. Patients in the higher mesothelin expression group had a longer median survival figure at twelve months than did those in the less than 50% subgroup, which showed a median figure of only six months. When they compared mean survival between the pleural mesothelioma group and the peritoneal mesothelioma group, they found that the pleural group’s overall mean survival was eleven months, while the peritoneal group’s mean figure was forty-five months—a substantial difference indicative of the peritoneal disease’s typically enhanced prognosis. Further analysis showed that the peritoneal group highly expressed mesothelin in all its cases, while the pleural group did so in less (75%). Within the epithelial pleural subgroup, they correlated high mesothelin expression with a better prognosis as well.

These findings have led the authors to propose that mesothelin expression is not a marker of disease progression, but is in fact a marker of disease differentiation, so patients presenting with high mesothelin expression may reflect a disease subtype with a better prognosis due to less aggressive malignant behavior.

Conclusion

The authors conclude their paper stating that the serum markers they analyzed—SMRP, CA125 and CYFRA 21-1—were not recommended for use as screening markers. Further investigation into each marker, especially the relationship between mesothelioma, peritoneal metastasis/progression and CA125, is warranted by their expression by the disease, but their use as screening markers should be avoided. They also state that their hypotheses on mesothelin expression call for further research to confirm this behavior, as well as to explain its biological component.

Labels: mesothelioma

posted by Belluck & Fox at 2:31 PM
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