Preliminary results from an ongoing prospective study suggest that gene expression profiling of circulating tumour cells in the bloodstream may help personalise chemotherapy choice for patients with pancreatic cancer.

Researchers found that specific sets of genetic changes – or gene expression profiles – detectable in circulating tumour cells may predict whether or not patients will respond to standard chemotherapy regimens.

They also identified key molecular pathways in cancer cells that signal the development of treatment resistance and cancer worsening.

The use of circulating tumour cells – cells that are shed by the tumour and can be collected through a simple blood draw – offers a less invasive way to analyze the molecular makeup of tumour cells than the traditional approach of biopsy tissue analysis.

The new strategy can be easily repeated throughout the course of treatment to monitor patients’ response to treatment – and, potentially, to shift course when needed.

This approach would be particularly beneficial in pancreatic cancer care because a tumour biopsy sample is often not obtainable.

“This research lays important groundwork for customizing treatments according to a patient’s genetic
composition,” said lead author Kenneth Yu, MD, Assistant Attending Physician in the Gastrointestinal Oncology Service at Memorial Sloan-Kettering Cancer Center in New York and senior author on the study.

“We’re seeing encouraging signs that this strategy can help us determine which patients will benefit most from chemotherapy and more quickly identify the development of treatment resistance, even before physical changes in the patient’s tumour appear.”

In the study, 46 patients with stage II-IV pancreatic adenocarcinoma, received one of 12 different drug combinations as recommended by their physician, including FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan and oxaliplatin), which is one of the most effective treatment regimens for pancreatic cancer, as well as other active treatments such as gemicitabine and docetaxel.

Chemotherapy sensitivity and gene expression profiling were carried out on circulating tumour cells collected both prior to starting chemotherapy and at the time of disease progression.

Researchers applied a new model, created by CellPath Therapeutics and originally developed through preclinical (in vitro) research, to the gene expression profiles to predict sensitivity to chemotherapy regimens the patients received.

While such profiling results were not used to guide treatment selection for patients in this study, researchers observed that patients who received chemotherapy regimens that the model predicted to be effective appeared to do better (average time to disease progression 4.2 months) than those for which the model predicted chemotherapy would be ineffective (average time to disease progression 2.7 months), confirming the utility of this strategy in predicting drug response.

Importantly, when circulating tumour cells were analysed again among the 11 patients who experienced tumour progression, researchers noted that chemotherapy sensitivity profiles had changed, suggesting that a different drug treatment may be required.

Specifically, disease progression and treatment resistance were accompanied by increased dysregulation in the Rb1 and PLC biological pathways and changes in the ErbB3, ARE/Nrf2, and insulin pathways. Among patients with stage IV cancers who experienced progression, major differences were seen in the E2F1 and NFκB pathways.

“Ultimately, we hope this strategy can be used to determine which drug cocktail would be most suitable for the patient and monitor patients during the course of therapy, so treatments can be modified at the earliest molecularsign of disease worsening,” said Dr. Yu. “With the new technologies for isolating circulating tumour cells, there is great potential for this approach in clinical care.”

Different people have different genomic compositions and they respond to the same drug and same amount of drug differently.

Pharmacogenomics is a branch of pharmacology that explores the effect of the genome on the drug response. While there have been prior studies of pharmacogenomic modeling in other cancers, this is the first study to examine the response to a cocktail of drugs.

Pancreatic cancer is the fourth leading cause of cancer-related death in the United States. Pancreatic
adenocarcinoma is the most common form of pancreatic cancer, accounting for 95 percent of pancreatic cancer cases.

This cancer usually begins in the ducts of the pancreas, which make enzymes that help the body digest food, particularly starches and fats.

Source: ASCO