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Gene predicts response to esophagogastric cancer therapy.


SAN FRANCISCO--A new 86-gene signature may add to metabolic imaging in guiding early treatment decisions for esophagogastric junction cancer, researchers reported.

The leptin gene, among others, stood out as having the potential to become a clinically useful biomarker in analyses that were presented at the meeting.

Dr. Russell Petty of the University of Aberdeen (Scotland) and colleagues studied 182 patients with locally advanced or metastatic disease. The investigators performed FDG-PET (18fluorodeoxyglucose positron emission tomography) imaging and CT imaging, as well as gene expression profiling, and immunohisto-chemistry of pretreatment tumor tissue.

Results showed that among a subgroup of 14 patients who had a PET metabolic response to the first cycle of neoadjuvant chemotherapy, a set of 86 genes in pretreatment tumor tissue distinguished those who had a radiologic response on CT after completing all cycles of that chemotherapy, compared with those who did not respond. In a variety of predictive models, this gene signature correctly predicted radiologic response in all cases.

"We have shown that gene expression profiling can subclassify FDG-PET metabolic responders into those patients that will and will not subsequently go on to have a [radiologic] response. We have also shown that combining molecular biomarkers and FDG-PET allows an optimization of response prediction," Dr. Petty said.

This is key, as PET alone has a poor positive predictive value in this setting, with only half of PET responders to neoadjuvant chemotherapy eventually showing a histopathologic response.

"While I suppose there is little doubt that if we used PET in this way to make treatment decisions, we would have a system that would be better than unstratified empirical treatment, what it still means is that quite significant proportions of our patients will go on to receive ineffective and intensely toxic therapy," he commented.

A subsequent gene enrichment and pathway analysis identified a half-dozen pathways that provided potential mechanistic explanations for the different tumor behavior. "Within the pathways identified, the adipocytokine-signaling pathway immediately caught our attention because of the strong known [epidemiologic] link between obesity and body weight, and esophagogastric adenocarcinoma," Dr. Petty noted.

Additional analyses specifically fingered the leptin gene (among others) and showed that among PET responders, leptin expression was higher in radiologic nonresponders than in responders (P = .026).

Yet, immunohistochemistry in an independent group of 154 patients showed that strong leptin staining was also associated with better survival (P = .021), an association that held up in multivariate analysis (hazard ratio, 0.85; P = .04).

In stratified analyses, patients with leptin-positive tumors derived little survival benefit from neoadjuvant chemotherapy, whereas those with leptin-negative tumors fared considerably better if they received this therapy (indeed, about as well as the positive group).

"Leptin in particular may be a molecular biomarker that is useful to combine with PET," Dr. Petty commented. "Leptin expression is associated with chemoresistance, but at the same time is also a favorable therapy-independent biomarker, so this combination of predictive and therapy-independent prognostic impacts mean that leptin has the potential to be a clinically useful biomarker."

"I really think that this is groundbreaking. ... The real future is here" when it comes to predicting treatment response in this cancer, as suggested by this study and others," session cochair Dr. Mark Krasna of the St. Joseph Medical Center in Towson, Md., commented in an interview.

"The question now is, are we ready for prime time to adopt that throughout?"

At present, more research is needed, according to Dr. Krasna, such as the ongoing validation of the 86-gene signature and trials like CALGB (Cancer and Leukemia Group B) 80803 exploring response-adaptive treatment in this cancer.

"I think those are the important things we can do today. We are ready for that," he concluded.


Major Finding: An 86-gene signature in pretreatment tumor tissue discriminated between early PET responders who had a radiologic response at the end of neoadjuvant chemotherapy vs.those who did not.

Data Source: An observational study of esophagogastric junction adenocarcinoma involving gene expression profile analysis in 28 patients and immunohistochemical and outcome analysis in 154 patients.

Disclosures: Dr. Petty and Dr. Krasna reported they had no relevant conflicts of interest.
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Author:London, Susan
Publication:Internal Medicine News
Date:Apr 1, 2012
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