Doctors try to make sense of cancer’s genetic jumble

• Cancer • Jun 05, 12

Not too long ago, knowing the organ where a cancer first takes hold was generally all a doctor needed to determine what treatments to use. Not anymore.

Advances in understanding cancer at the molecular level mean doctors can better select the drugs that will most help individual patients. To do so, they must identify which genetic mutations are driving the growth of a patient’s tumor, and that shift is making their work much harder.

“We’ve had this biological revolution that has sliced the pie for these cancers finer and finer as we’ve learned more about the genomics of cancer,” said Dr. George Sledge, co-director of the breast cancer program at Indiana University and a past president of the American Society of Clinical Oncology (ASCO).

For example, during a scientific presentation at the ASCO annual meeting this week in Chicago, Sledge said he learned of at least 17 different subtypes of acute lymphoblastic leukemia, or ALL, the most common type of leukemia in children. “Even trying to wrap your head around that is hard,” Sledge said.

New clinical trial findings released at the meeting show how quickly personalized medicine is taking root, offering further evidence in favor of targeting treatment to specific tumor mutations rather than their location in the body. The studies point to new treatments for breast and prostate cancers and the deadly skin cancer melanoma. As a result, doctors face a growing demand for sophisticated genetic sleuthing. That raises the bar for oncologists at well-funded academic medical centers armed with the latest technology, and also makes it tougher for tens of thousands of U.S. oncologists in smaller, community practices to compete.

Companies like Pfizer Inc often partner with other firms or work in-house to develop companion diagnostic tests to help predict if a patient would respond to their drugs. Researchers increasingly are finding more than one mutation influencing a cancer’s growth, requiring a more complex analysis that may lead to a combination of treatments for patients.

“Cancers that may look identical under the microscope may actually have very different genetic abnormalities, and therefore, are likely to respond to very different kinds of therapies,” said Dr. Mace Rothenberg, senior vice president for oncology at Pfizer. “What is happening is a very rapid evolution in thinking - from one test on one tumor to actually doing multiple tests on one tumor sample.”

NEW TESTING INDUSTRY EVOLVES

U.S. university-affiliated medical centers are developing their own genetic tests to serve patients and researchers, while new diagnostic companies are emerging to help community-based doctors select the best medicines or find clinical trials where drugs that target specific genetic mutations are being tested.

“The technology is evolving so quickly that there is now the availability to screen for literally 250 different cancer- associated genes in a single tumor sample,” Rothenberg said.

Foundation Medicine, based in Cambridge, Massachusetts, was founded by a group of cancer geneticists from the Broad Institute, Dana-Farber Cancer Institute, Harvard Medical School and Massachusetts Institute of Technology.

The company’s lab opened in October and has been doing genomic profiling for drugmakers including Sanofi, Celgene, Novartis and Johnson & Johnson. Foundation Medicine unveiled its genetic profiling test at the ASCO meeting.

“Somehow we expect that the community oncologist is magically going to get his or her arms around the vast number of molecular diagnostic tests that are available for any given mutation,” said Dr. Michael Pellini, Foundation Medicine’s president and chief executive officer.

The company’s FoundationOne test costs $5,800. It scans a single tumor sample for more than 200 genetic alterations known to be at work in cancers and gives doctors a report suggesting both approved drugs and ones being tested in clinical trials. Pellini said the company plans to expand the number of gene mutations its test analyzes as the science advances.

“Clearly, the diagnostic companies are going in this direction and we must go in this direction,” said Dr. Paolo Paoletti, president of oncology for GlaxoSmithKline.

Other countries are trying different approaches to adopting more sophisticated methods of cancer diagnostics. France’s government-run healthcare system has selected several regional labs to which tumor tissue can be sent from across the country, Paoletti said.

“Whenever a cancer patient in France has melanoma, they send the tissue there to see if there is a BRAF mutation or not. It’s fantastic,” Paoletti said. Glaxo is testing a drug that works by blocking BRAF, a genetic mutation linked to some melanoma cases.

In Germany, Dr. Thomas Zander of the University Hospital Cologne and colleagues sought to meet the needs of community hospitals by setting up a network to send lung tumor samples to a central lab.

Forty percent of the samples sent to the lab had genetic mutations that could be targeted with available drugs, Zander said. They included Roche Holding’s Tarceva and Pfizer’s Xalkori, which target different specific genetic alterations in lung cancer.

Among patients with lung adenocarcinomas, the most common type of lung cancer, the lab spotted mutations in five other gene mutations for which there are now drugs in clinical trials.

RAISING MORE QUESTIONS

In addition to the Foundation Medicine genetic profiling test, other U.S.-based initiatives include two other methods: sequencing the whole genome of tumors, or sequencing the exome - only the genes that code for proteins.

A team from the Johns Hopkins Kimmel Cancer Center in Baltimore, including Dr. Victor Velculescu and Luis Diaz, has started a company called Personal Genome Diagnostics Inc that does this type of testing.

“Right now, you can use any of the three methods to identify most of the alterations that are targetable for drugs,” said Dr. Bert Vogelstein, who directs the Ludwig Center for Cancer Genetics & Therapeutics at Johns Hopkins. “As more drugs become available, which approach will be most effective? The market will work that out.”

Foundation Medicine has helped guide treatment in some puzzling cancer cases. It cited one patient with inflammatory breast cancer who had already been treated extensively with little success when a sample of her tumor was sent for testing.

The team found an amplification of the protein HER-2, which is routinely tested for in clinics and treated with the Roche drug Herceptin, or trastuzumab, and also found a mutation in a gene called EGFR more typically linked to lung cancer.

“This mutation was provocative because it is similar to those for which the drug erlotinib or Tarceva is highly successful in lung cancer,” said Dr. Vincent Miller, senior vice president of clinical development at Foundation Medicine. The results raised the question of whether the patient’s doctor should use Tarceva even though it is not approved for breast cancer, or seek a clinical trial where it is being tested.

“It changes the way people have to think, and it raises questions people might not want to wrestle with,” Miller said.

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(Reuters)