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Trastuzumab-based regimen improved survival without cardiotoxicity

The best treatment for early stage HER2-positive breast cancer was obtained with docetaxel, carboplatin and trastuzumab.

Issue: January 1, 2007

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SAN ANTONIO — Combining the molecularly targeted therapy trastuzumab with chemotherapy in women with early stage breast cancer significantly improved disease-free survival for patients with a specific genetic mutation that results in very aggressive disease, researchers reported.

Dennis Slamon, MD, whose laboratory and clinical research lead to the development of trastuzumab (Herceptin, Genentech), presented results of the phase-3 study of more than 3,200 women here at the 29th Annual San Antonio Breast Cancer Symposium.

The three-arm study compared the standard therapy of doxorubicin (Adriamycin, Pfizer) and carboplatin followed by docetaxel (Taxotere, Sanofi-Aventis), an experimental regimen of doxorubicin and carboplatin followed by docetaxel and one year of trastuzumab, and an experimental regimen of docetaxel and carboplatin with one year of trastuzumab.

Preferred treatment option

Slamon and colleagues assessed trastuzumab with and without doxorubicin, an anthracycline commonly used to treat breast cancer but one that, when paired with trastuzumab, can cause permanent heart damage. Researchers examined whether they could provide a therapy as effective as standard chemotherapy plus trastuzumab without the associated cardiac toxicity. The study, Slamon said, showed that the women who did not receive doxorubicin did just as well as those who did; they experienced a fivefold decrease in significant heart toxicities, compared with those who received the anthracycline. Also, some women in the standard therapy plus trastuzumab arm developed leukemias. None of the women on the non-doxorubicin arm did.

“This study demonstrates unequivocally that the best treatment for early stage HER2-positive breast cancer is obtained with a non-anthracycline regimen [docetaxel, carboplatin and trastuzumab] that avoids the significant cardiac damage found when doxorubicin is used with Herceptin,” said Slamon, director of clinical/translational research at UCLA’s Jonsson Cancer Center. “This trial should affect the way early stage breast cancer is treated, with TCH being considered the preferred option,” he said during his presentation.

Improved survival

Trastuzumab is effective in women with HER2-positive breast cancer, which accounts for about one in four breast cancer diagnoses every year, or about 250,000 women annually worldwide. HER2-positive breast cancer is more aggressive, and results in a poorer prognosis and shorter survival times, said Slamon.

The study enrolled 3,222 women with early stage breast cancer between April 2001 and March 2004. Researchers randomized patients to one of the three arms. Slamon’s report is the second interim analysis at a three-year median follow-up of the study data.

The study showed a survival advantage for patients in both of the trastuzumab-containing arms, with 92% of patients on standard chemotherapy plus trastuzumab and 91% of patients on docetaxel, carboplatin and trastuzumab still alive at four years, compared with 86% in the standard arm. The risk of death was reduced by 40% among patients in the standard chemotherapy plus trastuzumab arm and 33% in the docetaxel, carboplatin and trastuzumab arm, Slamon said.

“Now we know we can provide a very effective therapy for women with early stage breast cancer that reduces by five times the risk of heart damage,” Slamon said. “And we’ve shown that women with HER2-positive early stage breast cancer benefit from Herceptin therapy in that it significantly improves their disease-free survival times.”

Eliminating chemotherapy?

Also presented here were results of a promising phase-2 study that combined two molecularly targeted therapies to treat advanced breast cancer without using conventional chemotherapy.

The study tested trastuzumab with the angiogenesis inhibitor bevacizumab (Avastin, Genentech).

The researchers enrolled 37 women with breast cancer that had metastasized to other organs. Results indicated that 83.8% of patients achieved a clinical response, Slamon said.

“This represents the next generation of studies that take chemotherapy completely out of the picture,” Slamon said.

For more information:

• Slamon D, Eiermann W, Pienkowski T, et al. BCIRG 006: 2nd interim analysis phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (ACET) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (ACETH), with docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive early breast cancer patients. Abstract 52. Presented at: 29th Annual San Antonio Breast Cancer Symposium; Dec. 14-17, 2006; San Antonio.
• Pegram M, Chan D, Dichmann RA, et al. Phase II combined biological therapy targeting the HER2 proto-oncogene and the vascular endothelial growth factor using trastuzumab (T) and bevacizumab (B) as first line treatment of HER2-amplified breast cancer. Abstract 301. Presented at: 29th Annual San Antonio Breast Cancer Symposium; Dec. 14-17, 2006; San Antonio.
• Slamon D. Update on HER-2 directed therapy. Abstract 1. Presented at: 28th Annual San Antonio Breast Cancer Symposium; Dec. 8-11, 2005; San Antonio.