‘stunning’ results when used as adjuvant tx

Early Herceptin use cuts breast Ca recurrence in half: ‘stunning’ results when used as adjuvant tx

Jane Salodof MacNeil

ORLANDO, FLA. — Trastuzumab, a monoclonal antibody that was developed to fight one of the most aggressive forms of breast cancer, cut recurrences by 52% when used as adjuvant therapy in two large phase III trials that were unblinded early by the National Cancer Institute.

A third international trial that included 5,100 women in 39 countries similarly found that the risk of recurrence fell 46% when trastuzumab (Herceptin) was used once every 3 weeks for 12 months after completion of chemotherapy for primary breast cancer.

Oncologists greeted the outcomes with rock-star-style applause at a special session during the annual meeting of the American Society of Clinical Oncology. In a comment echoed by other prominent physicians, discussant George W. Sledge, M.D., described the magnitude of improvement as “the most stunning result I have seen in an adjuvant trial in my entire career.”

Dr. Sledge, codirector of the Indiana University Cancer Center in Indianapolis, added that the results were “true and strong … across the board,” with every subgroup of patients in the three trials showing significant survival benefits.

Trastuzumab inhibits human epidermal growth factor receptor 2 (HER-2). In 20%-30% of breast cancer patients, the HER-2 gene stimulates fast cancer growth by overproducing the HER-2 protein. Patients with tumors positive for HER-2 have poor prognoses and often relapse soon after completing a first round of cancer therapy.

Marketed internationally as Herceptin by Roche and in the United States by Genentech Inc.–both of which provided drugs for the trials–trastuzumab is approved for use in women with HER-2-positive metastatic breast cancer. The three trials tested trastuzumab as an adjuvant agent, either with or following the patient’s first chemotherapy.

Edward Romond, M.D., presented an analysis of the two North American trials, National Surgical Adjuvant Breast and Bowel Project (NSABP)-31 and the North Central Cancer Treatment Group (NC-CTG)-N9831. Patients in those trials were treated with doxorubicin and cyclophosphamide followed by paclitaxel. With a median follow-up of 2 years (2.4 years in NSABP-31 and 1.5 years in NCCTG-N9831), Dr. Romond of the University of Kentucky Markey Cancer Center in Lexington reported that the addition of trastuzumab conferred a 33% reduction in the overall risk of death and a 53% reduction of risk of distant recurrence at 3 years.

In the international Herceptin Adjuvant (HERA) trial, also known as BIG 1, conducted by Roche and the Breast International Group (BIG), patients were randomized to 1 or 2 years of trastuzumab or watchful waiting after completion of initial therapy. Investigator Martine J. Piccart-Gebhart, M.D., of the Jules Bordet Institute, Brussels, reported that only the 1-year arm was unblinded early. In that group, 2-year disease-free survival was 85.8% with trastuzumab and 77.4% without (hazard ratio 0.54).

Distant disease recurrences also were significantly less.

Elaborating on the NCCTG-N9831 trial, investigator Edith A. Perez, M.D., described careful cardiac monitoring of patients in the trial, which excluded women with a history of heart disease because of concerns about trastuzumab-induced cardiac toxicity. Patients given trastuzumab did better than patients who received it sequentially after chemotherapy, but were most likely to have a reduction in left ventricular ejection fraction, reported Dr. Perez, director of the breast cancer program at the Mayo Clinic in Jacksonville, Fla.

Congestive heart failure rates ranged from 0.5% for trastuzumab patients in the HERA trial to 2.2%-3.3% in NCCTG-N9831 and 4.1% in NSABP-31. Dr. Piccart-Gebhart reported that the only cardiac death was in the placebo arm of HERA.

Among outstanding questions, Dr. Sledge listed the appropriate duration of trastuzumab therapy, whether patients can get by with smaller doses to minimize cardiac toxicity, and whether heart damage from trastuzumab is reversible. He also speculated that removing doxorubicin from the chemotherapy cocktail might resolve the cardiotoxicity problem, since trastuzumab appears to become cardiotoxic only “when it keeps company with doxorubicin.”

Observing that trastuzumab therapy could be purchasing early gain with a later problem, Dr. Sledge added that “the benefit clearly outweighs the gain, but the price is real.”

Overall, he concluded, “I sincerely believe we can see the outlines of the breast cancer end campaign.”

Len Lichtenfeld, M.D., deputy chief medical officer of the American Cancer Society, added in an interview that he expected the results to immediately change the standard of care for about 50,000 women diagnosed each year with primary HER-2-positive breast cancer. “My prediction is there are going to be a lot of doctors who are going to very quickly adopt this,” he said.

The early impact on disease-free survival is notable, he continued, because breast cancer is not considered curable once it recurs. “These are the women who are usually going to relapse early, and then treatment does not work very well,” he said of the HER-2-positive population.

Congestive heart failure is a real issue, Dr. Lichtenfeld added. Many women will not be eligible, he said, because close cardiac monitoring is picking up a larger population than anticipated with diminished heart function.

“This is a watershed meeting,” he concluded, pointing to successful trials, not only for trastuzumab, but also for bevacizumab (Avastin) in lung, breast, and colorectal cancers. “This is not only wonderful news for doctors and patients, but also for people who staked their professional reputations on the concept of targeted therapy.


Southwest Bureau

COPYRIGHT 2005 International Medical News Group

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