From Our 2012 Archives
Genetic Makeup of Tumors More Complex Than Thought
New Research Shows 'Personalized' Treatment for Cancer Not So 'Simple'
Reviewed by Laura J. Martin, MD
March 8, 2012 -- A small study that shows a surprising complexity of genetic changes within a single tumor has far-reaching implications for the march toward personalized cancer therapy, according to researchers.
A single biopsy from a tumor might not be sufficient to give a full picture of its genetic landscape, a team from the United Kingdom reports.
When the researchers examined 10 biopsies taken from a single kidney cancer tumor, they found "an extraordinary amount of diversity" in the genetic changes that had taken place in different parts of the tumor.
"There were more differences between biopsies from the same tumor at the genetic level than there were similarities," said researcher Charles Swanton, MD, PhD, from the Cancer Research UK, London Institute, and the University College London, United Kingdom.
The findings, published in the New England Journal of Medicine, were highlighted at a London news conference organized by Cancer Research UK, which funded the study.
The team also found differences in genetic changes between the primary tumor and places in the body where the cancer spread. Similar findings have been documented by other research groups.
But it is the extent of the genetic changes that is surprising, the researchers note.
The findings have far-reaching implications for the efforts currently being directed toward personalized cancer therapy, in which therapy is targeted at genetic changes identified in tumor tissue. Swanton cautioned that "if you take only one biopsy, you could be misled clinically."
"I don't want to rain on anyone's parade, but the whole situation is far more complex than we could have imagined," he said.
"The simple view of directing therapy on the basis of genetic tumor markers is probably too simple," agrees Dan Longo, MD, deputy editor of the New England Journal of Medicine, in an accompanying editorial.
"A whole new world has been anticipated in which patients will undergo a needle biopsy of a tumor in an outpatient clinic, and a little while later, an active treatment will be devised for each patient on the basis of the distinctive genetic characteristics of the tumor," Longo writes.
However, a serious flaw in this imagined future of cancer treatment is the underestimation of genetic diversity within a tumor, he notes.
Differences Within a Single Tumor
The study evolved out of research into kidney cancer that was aiming to find a biomarker that would predict response to the drug Afinitor, explained co-author James Larkin, MD, PhD, consultant medical oncologist at the Royal Marsden Hospital in Surrey, U.K.
In that trial, patients underwent a six-week course of treatment with Afinitor; then after stopping the drug for one week they had the diseased kidney removed. Several biopsies were taken from the primary tumor and from where it spread both before and after treatment with Afinitor.
The team analyzed the cancer genes in biopsy samples taken from four patients. In total, 30 biopsies were taken from four primary tumors, and the genome analysis revealed that 26 of these 30 biopsies were different, Larkin said.
One hundred eighteen different genetic mutations were identified. The researchers also noted that genetic signals associated with a good prognosis and those associated with a bad prognosis were detected in different regions of the same tumor.
When the researchers modeled the genetic changes, they found an evolution pattern that resembles the trunk and branches of a tree. The tumor began with a number of genetic changes that developed early on in the "trunk"; over time, different groups of cells evolved different genetic changes and formed different "branches" of the cancer's evolutionary tree.
This theory is in stark contrast to current cancer theories being taught in medical schools, Swanton said. A mainstay of the medical school curriculum is that cancer is a disease that evolves in a linear fashion, with mutations arising in a sequential fashion. "This is what ... is guiding our research, but this theory is driven by a single biopsy from a tumor," he said.
However, this revolutionary way of thinking about cancer is based on a very small study. "We only analyzed four patients," Swanton acknowledged. More work is needed and is already under way as part of Cancer Research UK's Genomics Initiative.
Nevertheless, the theory could explain a number of clinical observations, Swanton said. Targeted drugs that have already succeeded in the treatment of cancer could be acting on genetic mutations that occur early in the evolution -- in the trunk of the tree, he explained. Examples of such agents are Herceptin for HER2-positive breast cancer, and Tarceva and Iressa, which block the action of a substance involved in tumor growth in non-small-cell lung cancer.
Other cancers would have a very short trunk and many branches, perhaps like pancreatic cancer, which is notoriously difficult to treat and has not responded well to any targeted therapies.
Swanton is concerned that some of the newer drugs targeting new mutations will be acting only on the branches, so will not have a big impact on the cancer. "Just because a mutation is there doesn't mean that you are going to see a robust response when you target it," he said.
"This research is going to change the way that we analyze cancers," predicted Peter Johnson, MD, chief clinician at Cancer Research UK, who also spoke at the press conference. "We are clearly only at the beginning of this process."
The findings highlight the extreme complexity of cancer genetics, but they also point to a way forward despite this complexity, he said. "They suggest a way to improve the success rate of personalized medicine."
Swanton and several of his co-authors report receiving research grants from Novartis.
SOURCES: Swanton, C. New England Journal of Medicine, March 8, 2012.Charles Swanton, MD, PhD, Cancer Research UK, London Institute, and the University College London, United Kingdom.Dan Longo, MD, deputy editor of the New England Journal of Medicine.James Larkin, MD, PhD, consultant medical oncologist at the Royal Marsden Hospital in Surrey, United Kingdom.Peter Johnson, MD, chief clinician at Cancer Research UK.
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