Giving a gold standard back its luster

Illustration of women's chest

Ruth O'Regan is leading an effort to give those with HER2-positive breast cancer another option when they develop resistance to Herceptin

Oncologist Ruth O'Regan saw promising results from clinical trials of Taxol and Afinitor in Herceptin-resistant patients.

Oncologist Ruth O'Regan saw promising results from clinical trials of Taxol and Afinitor in Herceptin-resistant patients.

By Martha Nolan McKenzie

When Carolyn Akin discovered a lump in her breast, the prognosis was grim. Her initial diagnostic visit confirmed that she had HER2-positive breast cancer, which had already spread to her lungs, liver, and bones.

That was nearly 3½ years ago. Today the soft-spoken 68-year-old retired psychologist is still enjoying gardening, bird watching, and playing with grandchildren. "I can still go everywhere and do everything I want to do, I just can't do it for as long as I used to," says Akin.

Akin credits her continual good health to the care she has received at Emory's Winship Cancer Institute, which for the past two years has included participation in a clinical trial. As part of the trial, Akin has been receiving a drug called Afinitor (everolimus) along with chemotherapy and Herceptin (trastuzumab). Led by Emory oncologist Ruth O'Regan, the trial is testing whether Afinitor can reverse resistance to Herceptin in metastatic HER2-positive breast cancer patients.

In Akin's case, the answer seems to be yes. She reports that all the tumors save the original one in her breast are gone.

"Carolyn has had an unbelievable response to these study drugs and has been on this therapy longer than any other patient in the trial," O'Regan says. "It is remarkable, particularly because she has had almost no toxicity."

Why Herceptin works

About 25% to 30% of breast cancers are HER2 -positive, which means they test positive for a protein called human epidermal growth factor receptor-2 (HER2). This protein promotes the growth of cancer cells, making HER2 -positive breast cancers more aggressive than other types. They also tend to be less responsive to hormone treatment. That's the bad news. The good news is that this type of cancer responds extremely well to Herceptin.

Herceptin specifically targets HER2 cells, killing them while sparing healthy cells, so side effects are minimal. Its effectiveness has made Herceptin the gold standard of treatment for HER2 -positive breast cancer.

"Most patients with HER2-positive breast cancer are cured at their initial diagnosis because they get Herceptin and chemotherapy," says O'Regan. "Five years ago, these patients had a very high recurrence rate over the first five years after diagnosis and were very likely to develop metastatic disease. But now with Herceptin, the rate of developing metastatic disease is pretty low—10% or maybe even 5%."

The problem is, some cancers are resistant to Herceptin. "We know that about 10% of patients who present with HER2-positive breast cancer have cancers that are resistant to Herceptin at the time of diagnosis," says O'Regan. "Once HER2-positive breast cancers become metastatic, almost all of them will become resistant to Herceptin at some point."

That's what happened to Akin. "As soon as I was diagnosed, Dr. O'Regan started me on Herceptin and Taxol," says Akin. "That worked really well for about a year and a half, but then the disease started to grow again. So Dr. O'Regan enrolled me in a clinical trial taking Herceptin, Taxol, and RAD001 (Afinitor). The RAD001 apparently makes the cancer cells receptive to Herceptin again."

Finding a helper for Herceptin

Afinitor, an oral m TOR inhibitor, is an investigational drug that acts on the pathway that is believed to mediate Herceptin resistance. "We don't really know exactly how it works, but m TOR inhibitors basically block cell signaling quite far downstream from the HER2 receptor," says O'Regan. "Researchers here at Emory have demonstrated that m TOR inhibitors also activate what's known as the Akt pathway. One theory is that the activation of the Akt pathway actually resensitizes the cells to Herceptin, but that's just a theory."

Whatever the exact mechanism, the results from the Phase I clinical trial were very promising. Twenty-five heavily pre-treated Herceptin-resistant women received a combination of Herceptin, Taxol and Afinitor. About 45% had their cancer shrink, and almost 80% had disease control, which means their cancer either got smaller or it didn't get any worse.

"Overall, in this kind of setting, you'd expect to see a disease control rate of something like 40% to 50%," says O'Regan. "So we were very encouraged by the results we got."

O'Regan's team also studied a subset of patients with cancers that were not only Hercepin resistant but also were resistant to taxanes—a group of chemotherapy drugs that includes paclitaxel (Taxol) and docetaxel (Taxotere). "So these were very resistant cancers," says O'Regan. "In that group, the disease control rate was about 85%—even higher than the Herceptin-resistant group. These results suggest that Afinitor is reversing resistance to these drugs."

O'Regan's team is participating in a multi-site Phase II clinical trial that they hope will confirm the promising results of the Phase I trial. She hopes to have data from the Phase II trial early this year. A Phase III trial began in January.

"We know this combination isn't going to cure these cancers, but the aim of treating metastatic breast cancer is to extend meaningful life," says O'Regan. "If you can control the disease for a long time with an agent that is nontoxic, that is definitely a good outcome. We don't just want to extend their survival, we want their quality of life to be as normal as possible." EM

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winter cover 2010