Fall 2009

VITALResearch

Medicine Gets Personal

After Marcia Popp of Bloomington, Ind., had breast cancer surgery in March 2009 she was told that she likely would "lose the next year of my life" undergoing chemotherapy and radiation treatments. It was not news she wanted to hear.

As a self-employed businesswoman and single mom, Popp, 45, was worried about the problems such a grueling regimen could cause.

"What if I couldn't get up some morning?" she wondered. It seemed like a lot of risk and misery for a relatively small reduction in the chances of her cancer returning. And so, after peppering her local oncologist with questions, she was referred to oncologist George Sledge, M.D., at the Indiana University Melvin and Bren Simon Cancer Center, where it turned out genetics would have as much to say about her treatment plan as would her cancer history.

THE GENETICS OF CANCER

Less than a decade ago, the completion of the Human Genome Project—and the emergence of new technologies to detect many genetic differences at once—offered the promise that doctors would be able to customize medical treatments based on those differences.

Now that promise is coming true, and there's no better example than the diagnosis and treatment of breast cancer.

Once seen as a single disease, genetic testing now identifies four distinct types.

It's like "a group of criminals living in the same boarding house," is the way Dr. Sledge describes it to his patients. And just as the criminal justice system treats petty thieves different from murderers, physicians need to treat different types of breast cancer differently, said Dr. Sledge, co-director of research for the Breast Care and Research Center and Ballve Lantero Professor of Oncology at the IU School of Medicine.

Popp already knew that her cancer was "estrogen-receptor positive," meaning that it is stimulated to grow by the presence of the hormone estrogen. However, there are two important sub-types of estrogen sensitive cancers: one treatable with hormone therapy, the other susceptible to chemotherapy. Popp was pleased to learn, from a test called Oncotype DX, that she would not receive chemotherapy – that in fact chemotherapy would do her no good.

"I was incredibly relieved – and grateful that we did the test," she said. Popp began hormone therapy, instead of chemotherapy, in June.

Change in the field has come quickly, said Dr. Sledge: "Five years ago, before this test was available, those women would have been routinely offered chemotherapy as part of their treatment, because we didn't have any way of separating them out. [Now] We don't have to expose women to the toxic side effects of drugs that won't help them." And for women whose cancer type does call for chemotherapy, "we can promise them a much higher likelihood of benefit."

NEW DRUGS AND TAILORED TREATMENTS

Genomic testing is also directing research into new drugs—clinical trials now target specific cancer types, providing better answers to questions about effectiveness. But new tools also let researchers investigate how patients will respond to particular drugs, not just cancers.

"As oncologists we think specifically about targeting tumors and trying to capitalize on the genetic differences within tumors. That's how we're all fundamentally trained," said Bryan P. Schneider, M.D. '99, Res '01, Fel '05, an assistant professor of medicine and of medical and molecular genetics and a cancer center physician. "I think one area of variability that we really have overlooked for a long time is that innate genetic variability we all possess, the code that makes us different, that allows us to respond differently to medications."

Among the compounds Dr. Schneider and his cancer center colleagues have been studying is a drug called Avastin, which works to prevent the development of blood vessels that allow tumors to grow. But, as Dr. Schneider noted, the genetic controls that oversee blood vessel production can vary from person to person.

So Dr. Schneider looked back at advanced breast cancer patients who'd taken Avastin in a research trial to see if particular patient genetic profiles were associated with whether they benefitted from Avastin. In the study, overseen by IU Simon Cancer Center oncologist Kathy Miller, M.D., and reported in December 2007, some patients received Taxol and some received both Taxol and Avastin. The combined drug treatment resulted in a delay in the progression of metastatic cancer, but overall survival times for patients receiving the combined regimen did not improve significantly.

Dr. Schneider, however, found that there was a group of patients receiving Avastin whose survival time did increase, by about two years. Those patients tended to have a particular genetic marker – a difference in a gene related to blood vessel production.

Dr. Schneider and his colleagues also looked for connections between forms of the gene and high blood pressure—a side effect of Avastin for some patients—and found them: two forms of the gene were linked to significantly increased blood pressure.

"What we had hoped to find was a group with a huge two-year survival benefit and no high blood pressure. But that's not the way it works," said Dr. Schneider.

Instead, it turned out that the patients who benefitted the most in terms of longer survival also tended to be patients who encountered significant blood pressure problems.

David Flockhart, M.D., Ph.D., chief of the division of clinical pharmacology and an Avastin study co-author, cautions that these are early results that need validation, and aren't 100 percent predictive. In other words, not everyone who could benefit from Avastin would necessarily get high blood pressure—and patients who don't get high blood pressure should not assume the drug is not helping.

"It's important for people to understand, we're not that good yet. But our goals are to get that good, to tell people with a lot higher degree of accuracy: 'You're probably going to respond, and you're probably going to get a side effect,'" said Dr. Flockhart, who is Harry and Edith Gladstein Professor of Cancer Epidemiology and Genetics and a cancer center researcher.

With such powers, physicians should be able to prevent the effects—and avoid the costs of drugs that can be very expensive—when patients are not likely to respond.

But if they are likely to respond, and likely to get the side effects, "it helps in medical practice to be able to look somebody in the eye and say, we think it's quite likely you're going to get this, so we're going to prepare you for it," said Dr. Flockhart. "It makes medical care better."

Marcia Popp of Bloomington, Ind., seen here riding bikes with her daughter, benefited from a genetic test that informed her and her physician that hormone rather than chemotherapy would be the best treatment for her type of breast cancer.

This graphic represents how a genetic analysis found that although a group of women with breast cancer didn’t appear to benefit from a new drug there were “hidden subgroups” who did.