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December 16, 2008 • Volume 5 / Number 25 E-Mail This Document  |  Download PDF  |  Bulletin Archive/Search  |  Subscribe

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Featured Article

Trials Suggest Potential Expanded Use for HER2-Targeted Agents

Results from two phase III clinical trials presented last week at the San Antonio Breast Cancer Symposium (SABCS) suggest that there may be an expanded role for HER2-targeted therapies in breast cancer treatment, according to the trials' leaders.

The smaller of the two trials, dubbed NOAH, tested the combination of trastuzumab (Herceptin) and chemotherapy given prior to surgery, called neoadjuvant therapy, compared with neoadjuvant chemotherapy alone in 327 patients with HER2-positive breast cancer.

Data on "event-free survival" (time between randomization and disease recurrence, disease progression, or death from any cause) and response rate were available. According to the trial's principal investigator, Dr. Luca Gianni from the Istituto Nazionale Tumori Milano in Italy, the 3-year event-free survival rate for patients receiving the combination therapy was significantly better than that of patients receiving chemotherapy alone, 70.1 percent vs. 53.3 percent.

Rates of overall response and pathologic complete response (disappearance of all signs of the tumor) were also superior in the combination therapy arm, Dr. Gianni stressed, and cardiac side effects were limited, with serious cardiac events in less than 2 percent of patients.

"We think that this establishes preoperative trastuzumab with chemotherapy as a standard treatment option in women with locally advanced HER2-positive breast cancer," Dr. Gianni said. The results, he added, "most likely will translate advantage in terms of survival."

Preoperative systemic therapy is commonly used in women with locally advanced breast cancer (see sidebar), notes Dr. Jo Anne Zujewski, a senior investigator in NCI's Cancer Therapy Evaluation Program who specializes in breast cancer. Trastuzumab in combination with chemotherapy is standard therapy for women with HER2-positive breast cancer, and the NOAH trial is the first large study to demonstrate that a high pathological complete response rate can be obtained in women with HER2-positive locally advanced breast cancer when the combination is used prior to surgery.

NCI sponsored a state-of-the-science conference on preoperative therapy for locally advanced breast cancer in 2007. A series of papers based on the conference, and updated results from two breast cancer neoadjuvant therapy clinical trials, were published in the February 10, 2008 Journal of Clinical Oncology.

But before this regimen, which used anthracycline epirubicin, can be considered for standard use in the clinic, there needs to be more data, said Dr. Zujewski. "Given the relatively small number of patients in the trial, oncologists may still be apprehensive about the potential for cardiac effects from the concurrent use of trastuzumab and anthracycline-based chemotherapy," she said.

Additional data will be available from ACOSOG Z1041, an ongoing, U.S.-based clinical trial of epirubicin-based chemotherapy with concurrent trastuzumab in women with operable HER2-positive breast cancer.

The second trial presented at SABCS, known as EGF30008, compared the combination of the HER2-targeted agent lapatinib (Tykerb) and the aromatase inhibitor letrozole with letrozole alone in women with advanced, metastatic breast cancer.

Although the trial enrolled 1,300 patients, the results presented focused on a subset of 219 patients who were HER2-positive and hormone receptor (HR)-positive, for whom endocrine therapy with letrozole or other aromatase inhibitors is a standard first-line treatment.

Progression-free survival was markedly improved in the lapatinib/letrozole arm, 8.2 months versus 3.0 months, explained the study's lead investigator, Dr. Stephen Johnston from the Institute of Cancer Research in London. Patients in the combination arm also had superior rates of overall response and stable disease.

"These patients would previously be treated with endocrine therapy alone," Dr. Johnston said. "Now the suggestion is that combined therapy may certainly be a better approach."

The trial, he explained, builds on the fact that lapatinib is a dual-targeted tyrosine kinase inhibitor, targeting both HER2 and EGFR, another cell-surface receptor in the same family. Trastuzumab, by comparison, is a monoclonal antibody that targets only HER2. Women with advanced metastatic breast cancer often have, or eventually develop, resistance to endocrine therapy with tamoxifen or aromatase inhibitors, Dr. Johnston explained, and studies indicate that this resistance is associated with the expression of both HER2 and EGFR.

"So there exists this complex crosstalk between these pathways," he said, "and it therefore makes sense to think about targeting both pathways together with drugs available to do that, to try and improve on just using hormonal treatments alone."

Based on these results, Dr. Zujewski noted, breast oncologists may opt to use this combination approach in some patients with HR-positive, HER2-positive metastatic breast cancer.

—Carmen Phillips

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