4 MOLECULAR SUBTYPES OF PANCREATIC CANCER

The new finding that pancreatic cancer can be divided into four unique types, and that one of these types responds particularly well to platinum-based chemotherapy, could be a potential "game-changer" in this cancer, says one of the colead investigators.

The team of international researchers, working with the Australian Pancreatic Cancer Genome Initiative, emphasize the need for new strategies in the treatment of pancreatic cancer, pointing out that it remains one of the most lethal cancers, with a median survival of 6 months and a 5-year survival than remains less than 5%, despite decades of research.

Their study, published online on February 25 in Nature, provides the most comprehensive description to date of the genomic events that characterize pancreatic cancer, they write. It also demonstrates that structural variation is a prominent mechanism of genomic damage in this disease.

The team performed whole-genome sequencing and copy-number variation analysis of 100 pancreatic ductal adenocarcinomas.

One of the main findings was the identification of four distinct patterns of chromosomal rearrangements, which they termed stable (20%), locally rearranged (30%), scattered (36%), and unstable (14%).

Potential for Improving Survival

As the study was an observational cohort study with long-term follow-up, the researchers were also able to track the clinical outcomes of the patients whose tumor tissue they had been studying.

The researchers found that patients who showed the unstable pattern of chromosome rearrangements and defects in the DNA repair pathways appeared to be particularly responsive to treatment with platinum-based chemotherapy.

At the time of the analysis, 53 patients had had a recurrence and 25 patients had received various chemotherapies. Eight patients received platinum-based chemotherapy (seven of whom received either gemcitabine or cisplatin).

Within this subgroup of eight patients who received platinum-based chemotherapy, five were found to have an unstable pattern of chromosomal rearrangements, and four of these five individuals responded well to the treatment.

In fact, two of these patients had exceptional responses (as defined by complete radiological resolution of disease and normalization of CA19.9 levels) and a further two patients had robust partial responses (as defined by RECIST 1.1 criteria), the researchers report.

In contrast, three patients who did not show an unstable pattern but who received platinum-based chemotherapy did not respond to treatment.

Some of the patients with an unstable pattern also had a high BRCA mutational signature burden, and the researchers cite previous studies that have suggested that this characteristic is also associated with better responses for platinum-based chemotherapy.

"The proof of concept data presented here suggest that mutations in the BRCA pathway component genes and surrogate measures of defects in DNA maintenance (genomic instability and the BRCA mutational signature) have potential implications for the therapeutic selection of pancreatic cancer," the researchers conclude. "These data define a putative biomarker hypothesis that needs testing in a clinical trial, as these results are from a small number of patients," they add.

"Being able to identify which patients would benefit from platinum-based treatments would be a game-changing moment for treating pancreatic cancer, potentially improving survival for a group of patients," commented colead investigator Andrew Biankin, MBBS, PhD, director of Translational Research Centre, University of Glasgow, Scotland. He was previously at the Garvan Institute of Medical Research, University of New South Wales, in Sydney, and he led the project jointly with Sean Grimmond, PhD, from the University of Queensland's Institute for Molecular Bioscience in Brisbane, Australia.

"Despite many decades of research into pancreatic cancer we have faced numerous obstacles in finding new and effective treatments. But our crucial study sheds light on how the chaotic chromosomal rearrangements cause a huge range of genetic faults that are behind the disease and provide opportunities for more personalized pancreatic cancer treatment," Dr. Biankin commented in a statement from Cancer Research UK, which funded part of the study.

Peter Johnson, MD, from the University of Southampton in the United Kingdom and chief clinician at Cancer Research UK, commented: "Pancreatic cancer is one of the most difficult cancers to treat, and we have to find better ways to tackle it.... By understanding the different types that might exist and how we may be able to treat them with drugs that are already available in some cases, we can open a new window onto the disease."

The authors have disclosed no relevant financial relationships.

Nature. Published online February 25, 2015. Abstract