Circulating Tumor Cells Predict Drug Response

Gene expression profiling of circulating tumor cells (CTC) may predict whether patients with pancreatic cancer will respond to a particular drug regimen, according to preliminary results of a prospective study presented at the 2013 Gastrointestinal Cancers Symposium of the American Society for Clinical Oncology in San Francisco, CA, in January. The study also identified molecular pathways that warn of emerging drug resistance, suggesting that oncologists could tailor treatment to individual patients, monitor their response, and alter therapy if needed.

People with pancreatic cancer face a grim prognosis: Less than 5% will survive 5 years. Many patients are not candidates for surgery and rely on various chemotherapy regimens to slow disease progression. However, physicians lack a validated biomarker to guide therapy selection, says Kenneth Yu, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York, NY, and the study's senior author. “If we had a model that could give us some guidance in the right direction, I think it would be valuable,” he adds.

The study included 50 patients with pancreatic adenocarcinoma who were not eligible for surgery and who received one of 12 treatment regimens recommended by their oncologist, such as FOLFIRINOX, a combination of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin; gemcitabine (Gemzar; Eli Lilly); and docetaxel (Taxotere; Sanofi).

The researchers performed gene expression profiling on CTCs in participants' blood samples collected prior to chemotherapy and after disease progression. They applied a pharmacogenomic model developed by CellPath Therapeutics (Baltimore, MD) to the gene expression profiles to predict sensitivity to various chemotherapy regimens.

Although the profiling results did not guide treatment, the researchers found that patients who received a chemotherapy regimen that the model indicated would be effective for them did better than those who followed a regimen that the model predicted would be ineffective—with average times to disease progression of 7.3 months and 3.7 months, respectively.

Among the 20 patients whose disease progressed, chemotherapy sensitivity profiles had changed, suggesting that different drugs might be needed.

The researchers also analyzed pathways that might predict treatment response. They found that among patients with stage IV cancers that progressed, disruption of the E2F1 pathway, which regulates cell division, forecast a longer treatment response, whereas disruption of the NF-κB pathway, which has been implicated in cell division and cell survival, predicted a shorter treatment response. Additionally, the researchers discovered disruptions in the Rb1 and phospholipase C pathways at the time of disease progression.

Yu's team will continue to follow these patients and launch additional studies to further validate the approach. “Much work still needs to be done to prove that it will be effective in guiding treatment,” he says.

For more news on cancer research, visit Cancer Discovery online at http://CDnews.aacrjournals.org.