New predictors of metastasis found in patients with early-stage pancreatic cancer

MADRID, (EUROPA PRESS) – Researchers from Weill Cornell Medicine (USA) and an international team have used liver biopsies to identify cellular and molecular markers that could be used to predict whether pancreatic cancer will spread to the liver or other organs, such as the lung, and when.

The study, published in Nature Medicine, suggests that information from a liver biopsy – a small sample of tissue collected for analysis in a laboratory – when pancreatic cancer is diagnosed can help guide doctors in personalising treatment, such as liver-targeted immunotherapies, before cancer cells have a chance to metastasize.

In this regard, only 10 percent of people with pancreatic cancer survive more than two years after their initial diagnosis. “If we can predict the timing and location of metastasis, this could be a game-changer in the treatment of pancreatic cancer, especially in patients at high risk of metastasis,” said study co-author David Lyden, the Stavros S. Niarchos Chair of Pediatric Cardiology and professor of Pediatrics and Cell and Developmental Biology at Weill Cornell Medicine.

In 2015, Lyden and colleagues discovered that pancreatic cancer cells secrete factors that reach distant organs, most often the liver, to establish a premetastatic niche where new tumors form.

To find out how these alterations prime their new location for cancer colonization, Lyden collaborated with senior author Linda Bojmar, Ph.D., a research assistant professor of molecular biology in pediatrics at Weill Cornell Medicine and an assistant professor of clinical and experimental medicine at Linköping University in Sweden.

Together with other researchers from Memorial Sloan Kettering Cancer Center (USA) and the hepatopancreatobiliary team, they obtained liver biopsies from 49 individuals who underwent surgery for early-stage pancreatic cancer. They also collected liver biopsies from 19 people who underwent similar surgery for conditions unrelated to cancer, for example, removal of benign pancreatic cysts.

LIVER BIOPSIES REVEAL EARLY SIGNS OF RAPID METASTASIS

The researchers then conducted a series of molecular, cellular and metabolic analyses of these samples to determine whether they could identify hallmarks that preceded – or potentially prevented – subsequent metastasis in the patients.

They found that the livers of the recurrence-free survivors, who showed no signs of the cancer spreading after a follow-up period of at least three years, closely resembled the livers of people who had never had cancer.

At the other end of the spectrum were those who developed liver metastases within six months of diagnosis, a group of patients with a poor prognosis and limited therapeutic options. Their livers were riddled with so-called neutrophil extracellular traps (NETs), dense tangles of DNA and enzymes released by dying neutrophils, immune cells that form the first line of defense against infection. Because these NETs are closely linked to future metastases and develop so early in the course of the disease, it is possible that in the near future radiological imaging will be able to detect them and identify patients at risk of this aggressive spread.

“These individuals could then receive a full course of chemotherapy or, if metastases are detected when only a few have appeared, the secondary tumors could perhaps be surgically removed,” Lyden said.

IMMUNE RESPONSES IN SUBSEQUENT METASTASES

The researchers identified two other categories of patients in the study: those who would later develop metastases in the liver and those whose cancer had spread to other sites, such as the lung. Patients whose cancers spread to organs other than the liver showed a strong immune response against the cancer: protective T cells and natural killer cells had infiltrated their livers and many immune system regulatory genes had been activated. For the authors, these people prone to developing metastases outside the liver could benefit from immunotherapy to strengthen their anti-tumor immune response.

On the other hand, those whose livers succumbed to subsequent metastases also accumulated immune cells, but these showed signs of metabolic exhaustion. “It’s as if the liver tried to protect itself, but in the end it lost the battle,” Bojmar said.

The researchers plan to validate their findings in a larger cohort of pancreatic cancer patients and examine whether this approach might be useful with other newly diagnosed cancers. “We hope to develop a tool to predict which patients with colorectal cancer will develop liver metastases based on the cellular, molecular and metabolic profiles of their liver biopsies,” said Robert Schwartz, co-senior author and associate professor of medicine at Weill Cornell Medicine.