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Genetic Makeup of Tumors More Complex Than Thought

New Research Shows ‘Personalized’ Treatment for Cancer Not So ‘Simple’

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.

Evolutionary Changes

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.

Evolutionary Trees

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.

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