The therapy Herceptin with chemotherapy in patients with early stage breast cancer significantly increases disease-free survival time in women who test positive for a genetic mutation.

The study also tested Herceptin with a chemotherapy combination that eliminated Adriamycin, an anthracycline commonly used to treat breast cancer but a drug that, when used with Herceptin, can result in heart damage.

Conducted by the Breast Cancer International Research Group ( BCIRG ), this study is the fourth large clinical trial to show that Herceptin plus chemotherapy significantly reduces risk of disease recurrence in early breast cancer.

" The chemotherapy combinations we tested with Herceptin proved to be superior to the best available standard therapy for early breast cancer," said Dennis Slamon, principal investigator for the BCIRG study. "This further illustrates the promise of targeted therapies and moves us closer to our goal of minimizing the toxicity of therapy while maximizing efficacy."

Herceptin ( Trastuzumab ) is effective in women with HER-2 positive breast cancer, about one in four diagnosed with the disease every year.
HER-2 positive breast cancer patients have a particularly aggressive form of the disease, a poorer prognosis and shorter survival times, said Slamon, who discovered the link between HER-2 positivity and aggressive breast cancer in 1987.

The study enrolled 3,222 women from all over the world with early stage HER-2 positive breast cancer between March 2001 and February 2004.

Patients received one of three regimens:

- the standard therapy of Adriamycin and Carboplatin followed by Taxotere ( ACT );

- an experimental regimen of Adriamycin and Carboplatin followed by Taxotere and one year of Herceptin ( ACTH );

- an experimental regimen of Taxotere and Carboplatin with one year of Herceptin ( TCH ).

Reduction in risk of disease recurrence, the study's primary endpoint, was 51 percent in the ACTH study arm and 39 percent in the TCH arm.

The BCIRG study also resulted in two other important findings.
Researchers knew that giving Herceptin with Adriamycin resulted in heart damage in some patients, the most severe of which was congestive heart failure. It was theorized, however, that this damage was not long lasting. But the BCIRG study showed the cardiac toxicity was significant and still persisted for more than 18 months at the date of the last follow up.

Of the 3,222 patients in the study, 353 experienced a greater than 10 percent loss of heart function. Of those, 91 patients ( 9 percent ) were enrolled in the ACT study arm; 82 patients ( 8 percent ) were in the TCH arm; and 180 patients ( 17.3 percent ) were in the ACTH arm, which paired Adriamycin with Herceptin.

" We've always known that the major safety problem with Herceptin has been cardiac toxicity when it is used with Adriamycin," Slamon said. " When breast cancer patients lose their hair, it grows back. When we suppress their bone marrow, that comes back, too. Heart failure, however, is a much larger problem, especially if it does not improve over time."

The good news, Slamon said, is that Herceptin given with the chemotherapy combination that eliminates Adriamycin is still significantly superior to the best available chemotherapy alone, reducing risk of relapse by 39 percent. That gives physicians and patients worried about heart damage an additional option.

The study's other important finding is that a subset of HER-2 positive patients - about 35 percent - also have amplification of a gene called topo II, which makes them more likely to respond to Adriamycin.
As Herceptin targets HER-2, Adriamycin targets topo II. Patients who test positive for amplification of both HER-2 and topo II might opt for the drug regimen with Adriamycin, risking heart damage in exchange for a better response to therapy.

Slamon said a test that indicates both HER-2 and topo II amplification is being developed.

" Women will have the information they need to decide if the risk is worth the benefit," Slamon said.

At UCLA's Jonsson Cancer Center, doctors are testing Herceptin in combination with other targeted therapies such as the angiogenesis inhibitor Avastin ( Bevacizumab ).

Source: University of California - Los Angeles, 2005


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