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Is Cancer Outwitting 'Personalized Medicine'?
Date:3/7/2012

By Jenifer Goodwin
HealthDay Reporter

WEDNESDAY, March 7 (HealthDay News) -- The genetic makeup of cancer cells differs significantly from region to region within a single tumor, according to new research that raises questions about the true potential of personalized cancer medicine.

With this treatment approach, doctors study a tumor's genetic makeup to determine which drugs would work best in a particular patient. But if the genetic mutations driving the cancer cells vary widely, a single tissue sample won't necessarily give the full picture.

This "targeted therapy" involves "sticking a needle into the primary tumor site and taking a small sliver of a tumor, doing a gene analysis, and creating a genetic profile of the tumor to predict how the tumor will behave," explained Dr. Dan Longo, an oncologist and deputy editor at the New England Journal of Medicine.

"What this paper tells us is that is an oversimplification of the complexity of tumors and their heterogeneity," he said. "If you look at different sites of the very same tumor and the very same person, one site might tell you a gene profile associated with a good prognosis and the other site will tell you a gene profile associated with a bad prognosis."

Longo wrote an editorial accompanying the new study, published in the March 8 issue of the New England Journal of Medicine.

In the study, scientists from Cancer Research UK London Research Institute took 13 biopsies, or tissue samples, from a patient whose kidney cancer had spread. The biopsies were from eight regions of the kidney tumor and four tumors in the chest and lungs.

Researchers also took normal tissue, sequenced the patient's genome and compared that to what they found in the biopsies.

Genetic analysis turned up 128 mutations in the tumors. But only about one-third, or about 40 of those mutations, were present in all of the biopsies.

"The majority of mutations are not shared in every biopsy," said senior study author Charles Swanton, a professor of cancer medicine at the research institute.

Swanton and his colleagues also analyzed tumor tissue samples from another three patients with kidney cancer. From a total of 30 biopsies from all four patients, 26 tissue samples had mutations that were highly heterogenous, or varied, from one another.

Some advances have been made using targeted treatments. Tarceva (erlotinib) treats non-small-cell lung cancer by inhibiting epidermal growth factor receptor (EGFR) gene, and Herceptin (trastuzumab) is used to target breast cancers that are human epidermal growth factor receptor 2 (HER-2)-positive.

But once cancer has metastasized, it remains notoriously difficult to treat, Swanton said. "We have not made huge progress in curing advanced metastatic solid tumors over the last decade, despite the new array of targeted therapies," he noted.

The heterogeneity of tumors is likely one reason why, he added.

The targeted drugs that work probably target some ubiquitous, or common, mutations, such as HER-2 or EGFR. "Different parts of the tumor can evolve independently," he said. "What we think is that the drugs that are working are hitting the mutations that are present at every site of the disease."

Moving forward, the key may be figuring out what those common mutations are and targeting drugs there, he added. But finding those targets will be challenging, he added. One patient, he said, had three mutations in the same gene occurring in three regions of the primary tumor. And tumor cells also develop resistance to medications.

"The level of complexity is sobering in the extreme," he said.

Dr. Len Lichtenfeld, deputy chief medical officer for the American Cancer Society, called the research "elegant, important work."

"Cancer is not just a single mass of tissue that has the same genetic signature throughout it. There are changes that occur within cancer as it develops, not only at the primary tumor but elsewhere in the body. This particular research goes to great lengths to demonstrate how that is in fact the case," Lichtenfeld said.

Cancer is incredibly complex, and this study adds another layer to that complexity, he said. "As we have learned more about cancer cells, we have learned that as many questions as we answer, as many questions come from those answers," he said.

More information

The U.S. National Cancer Institute has more on personalized cancer care.

SOURCES: Charles Swanton, Ph.D., professor, cancer medicine, Cancer Research UK-London Research Institute, London; Dan Longo, M.D, oncologist, and deputy editor, New England Journal of Medicine; Len Lichtenfeld, M.D., deputy chief medical officer, American Cancer Society, Atlanta; March 8, 2012, New England Journal of Medicine


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