Promising Therapy, Powerful Response

November, 2007

Vinnie Pullom tried not to panic when a mass was detected in her breast last year. “I didn’t have any hard lumps or anything like that; I just had a mass,” she remembers. But she had lived long enough to see several of her friends get breast cancer. Some of them even had to undergo full mastectomies.

Though Ms. Pullom was eventually diagnosed with cancer, she was spared a lengthy ordeal of treatment thanks to an important clinical trial currently under way at the UAB Comprehensive Cancer Center. Using a Food and Drug Administration-approved monoclonal antibody, UAB doctors have been able to bolster the effectiveness of traditional hormonal cancer therapy to the point where – in Ms. Pullom’s case – her breast mass disappeared entirely.

“We’ve observed good things with this therapy,” says Cancer Center Scientist Andres Forero-Torres, M.D., principal investigator of the trial. “But it’s just an observation at the moment. Now the challenge is to take that observation and move forward.”

Clues to a Combination
The new therapy has its roots in findings made years ago by doctors that breast cancer patients often develop resistance to hormonal treatments. Upon further investigation, doctors discovered that the resistant tumor cells were overexpressing a protein called vascular endothelial growth factor (VEGF), which contributes to the formation of new blood vessels (a process called angiogenesis), which allows cancer cells to spread. “That’s a required step for the progression of cancer,” Dr. Forero explains. “If the tumor is growing, those tumor cells require more and more nutrients, and the only way to supply that is with new vessels.”

Fortunately, the discovery of VEGF overexpression came right on the heels of the creation of a monoclonal antibody called Avastin® (Bevacizumab), which genetically alters the VEGF-expressing cells and effectively “switches off” the production of the protein. A UAB investigator created an animal model in which some mice with breast cancer tumors were given hormonal agents alone, some mice were given Avastin®, and a third group was given both. When the third group showed markedly better results than the other two, Dr. Forero’s research group decided to try that same combination of drugs in human patients.

He conducted a pilot study of patients who were postmenopausal, older than 60, and had never received therapy. Those patients received the hormonal agent combined with Avastin® over a period of six months before they went for surgery. “It was difficult at first because some thought that method would not work, but over time we are proving that it might be the right approach after all,” Dr. Forero says.

The trial is still open, but of the 12 patients who have completed the six-month therapy regimen and for whom data has been collected, two have experienced a total disappearance of their tumors. “That’s what we call a pathologically complete response,” Dr. Forero says. “That means that when a piece of the tissue is evaluated in surgery, the pathologist cannot find any evidence of a tumor.” In contrast, he says, the use of hormonal agents alone results in pathologically complete responses less than 10% of patients. With chemotherapy alone, it’s less than 5%.

Ms. Pullom counts herself fortunate to be one of the study’s two cancer-free patients. “After I had all my tests, they said it had disappeared,” she says. “I was so glad – I knew that if the mass had stayed there long enough, it would’ve gotten much worse.”

Next Steps
Dr. Forero is quick to caution that the trial is far from over. “Out of a total of 27 patients, only 12 have completed the therapy,” he says. “Two patients are not enough to declare a success just yet, but it tells us that there is something interesting here that has to be evaluated.”

Dr. Forero hopes to have the evaluation wrapped up by the end of the year, with data on all 27 patients. At that point he and his colleagues will begin a national trial as part of the Breast Cancer Research Consortium (BCRC), an alliance of U.S. cancer centers that includes UAB, Harvard, Johns Hopkins, M.D. Anderson and nine others.

The national trial will involve 75 patients, 50 of whom receive the combination treatment while the rest receive the hormonal agent alone. That trial will lead to an international trial even larger in scope. The BCRC also will collect blood and tissue samples from patients and evaluate the samples in an effort to find biological markers pertaining to receptiveness to treatment.

“Markers will allow us to predict which patients will respond to which treatment,” Dr. Forero explains. “In the future, if we can find markers that tell us ‘These patients who have this marker will respond well to a certain treatment, while these patients without the marker will not respond,’ then we can continue trying to tailor custom therapies to individual patients, which is a big trend in cancer treatment right now.”

Ms. Pullom has nothing but praise for her doctors and her experience at the Cancer Center, and she treasures the “Purple Heart Award” she was given on August 16, 2006, the day she completed her therapy. Dr. Forero says this is the kind of experience his group is trying to repeat.

“Not everybody responds to hormonal therapy,” he explains, “and chemotherapy, as good as it is for some people, has a lot of problems – there’s a lot of toxicity due to the fact that the therapy attacks normal tissues. So anytime you have an approach that is nonchemotherapeutic but still gives you better outcomes, that’s very exciting. This trial is just a start – but it’s exciting.”