This study used cutting-edge technology to identify the gene mutations in both metastatic breast cancer cells and cells from the original cancer that was diagnosed 9 years earlier. The researchers found that most of the cells from the original cancer had five gene mutations that caused the cells to become cancerous. Nine years later, the metastatic cancer had 21 more gene mutations.
The researchers found that some gene mutations were shared by only some of the cancer cells. This means that the cells that make up a cancer are not all the same. Instead, the cancer is made up of related "families" of abnormal cells and each family has its own set of gene mutations. This is probably why many cancers respond to a treatment for a time -- a long time in some cases -- but then stop responding. It's likely that some cancer cell families in the tumor were destroyed by the treatment while other cell families with different genes were able to survive, thrive, and ultimately take over.
The advanced genetic testing done in this study isn't routinely available right now. Still, understanding the gene mutations that cause normal cells to become cancer cells can help doctors understand how cancer happens and how it might be prevented or treated in a more targeted way. Advanced genetic analysis also may some day help doctors choose treatments that are most effective against the gene mutations in a specific cancer.
Stay tuned to Breastcancer.org for more news on research that may offer better ways to prevent, diagnose, and treat breast cancer.
In what they called a "watershed event," Canadian researchers reported that the genetic code of breast cancer evolves over time, a finding they said might lead to more targeted treatments.
The researchers, using cutting edge gene sequencing technology, identified all three billion nucleotides from a metastatic breast tumor and then used the same process on the original cancer, diagnosed and treated nine years earlier.
In the metastatic cancer, they found 32 protein-altering mutations that were not found in healthy tissue from the same woman, according to Samuel Aparicio, BM BCh, PhD, MRCPath, of the British Columbia Cancer Agency, and colleagues.
But in the original tumor, they found only 11 of the 32 and of those, six were seen only in 13% or fewer of the tumor cells, they reported in the Oct. 8 issue of Nature.
The findings show that:
The key finding was "not only that the primary cancer evolved a lot, but the primary tumor was a mosaic of different mutations which then increased over time," Aparicio said.
He called the study "a watershed event in our ability to understand the causes of breast cancer and to develop personalized medicines for our patients."
While the sequencing technology used for the study remains expensive, the researcher said, costs are coming down and it may soon be possible to monitor genetic changes in individual patients in order to adjust therapy on the fly.
"Within a few years, we might be able to get the cost down to a few thousand dollars per patient," he told reporters.
For this study, the researchers analyzed tissue from an estrogen-receptor positive metastatic lobular breast cancer, sequencing it 43 times to find all of the single nucleotide variations.
They used a device that can read out three billion base pairs of DNA every day, according to co-author Marco Marra, PhD, of the BC Cancer Research Centre.
Then, using the same approach, they looked back at cancer tissue taken from the same woman during treatment nine years earlier, to see which variants were present then.
Five variants -- in the genes ABCB11, HAUS3, SLC24A4, SNX4, and PALB2 -- were common in the DNA of the primary tumor. They had previously been unknown to researchers.
Another six -- in the genes KIF1C, USP28, MYH8, MORC1, KIAA1468, and RNASEH2A -- were found in between 1% and 13% of the primary tumor cells.
There were 19 that weren't detected and two were undetermined, the researchers said.
The new mutations might have arisen as part of the natural evolution of the tumor, Aparicio said, or as a result of radiation therapy after the first diagnosis.
Aparicio told reporters that the study took 18 months and cost "tens of thousands" of dollars. But he added that he and his colleagues have smoothed out the process and are now sequencing several cancers a week to hunt for mutations.
The pattern the Canadians found is "quite interesting and quite reflective of the pathway the metastatic cancer must have taken in its lifetime," commented Tyler Jacks, PhD, of the Massachusetts Institute of Technology and president of the American Association for Cancer Research.
But he commented that it seems to contrast with earlier research, showing -- in colon cancer -- that there was little change between the genetics of primary and metastatic tumors.
On the other hand, it may be that not all of the new mutations found in the metastatic tissue play a role in driving the spread of the cancer, said Robert Weinberg, PhD, also of MIT.
Some of them, he said, may be "passengers" accumulated as the tumor developed, but not playing a role in its growth.
The study was funded by the BC Cancer Foundation and the CBCF BC/Yukon chapter, with platform support from the Canadian Institutes of Health Research, Genome Canada, Genome BC, the Canada Foundation for Innovation, and the Michael Smith Foundation for Health Research.
The researchers reported no conflicts.
Primary source: Nature Source reference: Shah SP, et al "Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution" Nature 2009; 461: 809-13.
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