Pancreatic cancer might be fatal. The patient generally dies within two years of diagnosis. Now it turns out that the disease takes a pretty long time to develop. Hence early intervention could help.
Tissue from seven newly deceased patients showed that cells in the pancreas took at least 10 years to mutate enough to produce the first cancer cells, and seven more years before a tumor could develop and become capable of spreading to other organs.
The pace of pancreatic cancer means that earlier detection could bring survival rates more in line with patients who have prostate, breast or colon tumors, says a study released today in Nature.
Two-thirds of patients diagnosed with pancreatic cancer have shown evidence that their malignancy has metastasized. The study found that metastasis, which often is the cause of death, occurs late in the development of pancreatic cancer, leaving time for detection of the disease earlier.
Actually in the main research work published in Nature, scientists have uncovered the complexity of the evolution in cancer cells. Not only is cancer genetically different between different patients, but each new focus of cancer spread within a patient has acquired distinct mutations, they have shown. The work helps to explain the difficulty of treating the disease but also strengthens the need for improved methods for early diagnosis.
"We have always known that pancreatic cancer is a particularly aggressive disease," says Dr Peter Campbell, from the Wellcome Trust Sanger Institute and first author on the paper. "This study illustrates why it is so challenging. Each metastasis is its own tumour, each evolving, each striving for dominance, each adapting to life outside the pancreas. When we treat cancer that has spread through the body, we're not just treating one tumour, we might be treating tens of genetically distinct tumours."
The researchers, from the Wellcome Trust Sanger Institute, near Cambridge, UK and the Sol Goldman Pancreatic Cancer Research Center at Johns Hopkins Medical Institutions, Baltimore, USA, looked at cancers in 13 patients who died from pancreatic cancer. They mapped rearrangements in the genomes of cancer samples: in some cases, they looked at several metastases from a patient.
They discovered that pancreatic cancer genomes often contain a distinctive pattern of genome rearrangement that possibly reflects changes to repair mechanisms in the cancer cells. The pattern of mutation events is dramatically different to that found in breast cancer, for example.
"With each study, cancer genomes are being revealed in their intricate complex detail," says Dr Andy Futreal, Head of Cancer Genetics and Genomics at the Wellcome Trust Sanger Institute and a senior author on the paper. "Genome instability is common in cancer, but this study has further revealed the dynamic nature of that instability and its role in spread of disease in the patient -- with instability being an engine of selection that allows the tumour to adapt to new sites in the body.
"We can see a root of common lesions -- about half of the mutations are shared across metastases. Metastatic cancer is therefore like a family: the different deposits of tumour are genetically related to one another, as brothers, sisters and cousins are, but also have distinguishing genetic features that make them individual. Identifying and targeting the shared mutations with drugs is likely to be a route to more effective treatment."
In a companion study Dr Iacobuzio-Donahue and her colleagues show that single-letter mutations show a similarly complex pattern. The team on that paper suggest that there might be a long time lag from the first cancer-causing mutations in the primary tumour to the violent and rapid metastasis of late-stage disease.
Both papers suggest that the galloping mutation rate that develops produces cells that, because of specific mutations they acquire, can colonize other organs. Different combinations of active genes are needed to survive in different tissues. This is a return to the 120-year-old seed and soil hypothesis that some organs provide particularly fertile ground for particular cancer cells to grow. This work shows that even in one person's cancer, clones of cells can evolve genomes specialised for life in defined organs.
The researchers emphasize that the shared mutations common to many early-stage pancreatic cancers could provide a route to discovery of new drug targets. In addition, the long time between the initial genetic changes in the developing primary cancer and spread to other organs might offer a window in which early diagnosis could detect disease while it is still curable by surgery, said Dr. Bert Vogelstein of Johns Hopkins University in Baltimore, who helped lead the study.
Pancreatic cancer is one of the deadliest cancers, killing 95 percent or more of its victims within five years of diagnosis. The American Cancer Society says 42,000 Americans were diagnosed with pancreatic cancer in 2009 and more than 35,000 died of it.
Hardly 6 percent of patients survive at least five years after being diagnosed with pancreatic cancer, while the rates are 65 percent for colon and rectal cancer, 89 percent for breast cancer, and 100 percent for prostate cancer, according to the American Cancer Society, based in Atlanta.
But screening for pancreatic cancer would be more complex than a mammogram, a prostate-related blood test or a colonoscopy. Dr Iacobuzio-Donahue said it would require getting an endoscopy -- which gives doctors a look inside the body through a tiny camera at the end of a long, thin tube -- coupled with ultrasound, an imaging technique using sound waves.
Patients currently get tested after they experience pain or show jaundice, Iacobuzio-Donahue said. Because there are few nerves in the pancreas, the pain is caused when the tumor grows beyond the gland into areas with nerves. The tumor causes jaundice by enlarging to the point that it compresses a bile duct, she said.
Iacobuzio-Donahue employed a rapid-autopsy program, used in the study of Alzheimer's disease and Parkinson's, to garner the consent of dying patients to allow an immediate autopsy to retrieve live tumor cells.
The genome sequencing was funded partly by the U.S. National Institutes of Health, based in Bethesda; the Bill & Melinda Gates Foundation, based in Seattle; and the Sol Goldman Pancreatic Cancer Research Center, at Johns Hopkins.