Biomarkers may predict rectal cancer response to cetuximab

NEW YORK (Reuters Health) - The effect of cetuximab on genes involved in tumor proliferation and inflammation might help predict the response of rectal cancer to cetuximab-based chemoradiotherapy.

In the March 30th Journal of Clinical Oncology, Annelies Debucquoy from University Hospital Gasthuisberg, Leuven, Belgium, and colleagues describe efforts to characterize the molecular pathways modified by cetuximab-based chemoradiation in patients with rectal cancer. The researchers also sought to identify molecular profiles and biomarkers that might improve patient selection for such treatments.

Using biopsy and plasma samples from 41 participants in a phase I/II clinical study, the researchers were able to identify 16 genes significantly influenced by cetuximab, including 3 involved in proliferation and 3 involved in tumor invasion.

Cetuximab monotherapy also brought significant increases in epidermal growth factor receptor (EGFR) and plasma transforming growth factor (TGF)-alpha, as well as other proteins involved in inflammation and lipid metabolism, the authors report.

"Proteomic and microarray analysis did not identify simple predictive signatures for pathologic response" to cetuximab, the authors report. They did find, however, that disease-free survival was better in patients who responded to the initial dose of cetuximab with upregulated EGFR in the tumor or whose resected tumors showed fibro-inflammatory changes.

In patients without recurrence, 38% of the pathways upregulated were related to inflammation, the researchers note.

In patients who did have recurrence, the researchers observed upregulation of growth hormone, IgM, thrombopoietin, and tumor necrosis factor-beta, downregulation of interleukin-4, and less of a decrease in adiponectin.

"The biomarkers and profiles identified in our study clarified some of the molecular mechanisms behind cetuximab treatment in rectal cancer and might be useful indicators for response," Debucquoy told Reuters Health.

"We believe that TGF-alpha is the most valuable marker to date for the prediction of response to cetuximab," she continued. "If the use of this marker, which can be easily measured in blood samples, could be validated, this might be very useful to assess the response to cetuximab in patients after only one loading dose."

"We believe that more molecular/translational research is needed before starting new combination treatments to obtain a better understanding of these complex interactions in order to be able to avoid negative clinical trials," Debucquoy said.

"Non-invasive functional imaging using MRI or PET-CT with different tracers should also be investigated...as they may offer a more simple and straightforward early response assessment," Debucquoy added.

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