SAN ANTONIO – Adding bevacizumab to neoadjuvant chemotherapy with epirubicin, cyclophosphamide, and docetaxel did not improve pathological complete response in a large, European trial among women with primary HER2-negative breast cancer.

Only patients with triple-negative disease appeared to benefit from the addition of bevacizumab (Avastin) in a planned subgroup analysis of the first phase III trial to report efficacy outcomes for the monoclonal antibody in this setting.

"Hormone receptor–positive patients did have almost identical pCR rates with or without bevacizumab," said Dr. Gunter von Minckwitz, managing director of the German Breast Group in Neu-Isenburg, Germany, at the annual San Antonio Breast Cancer Symposium. "However, the triple-negative patients ... had an increase of around 40% when bevacizumab was added, and this was just statistically significant."

Pathological complete response (pCR) overall – 15% for chemotherapy alone and 17.5% for chemotherapy plus bevacizumab – did not differ significantly between the two arms in the study, which was part of the German Breast Group’s GEPARquinto trial. The primary end point was the pCR rate (defined as no invasive or noninvasive residual viable tumor cells in any resected specimens of the breast and axillary nodes).

This GEPARquinto trial is the first randomized, phase III study to investigate the effect of bevacizumab plus chemotherapy in early or locally advanced breast cancer. An antiangiogenesis agent targeting the vascular endothelial growth factor (VEGF), bevacizumab is approved for first-line treatment of metastatic breast cancer in the United States. The Food and Drug Administration is considering a near-unanimous advisory panel recommendation that this approval be rescinded, however, because follow-up studies failed to confirm the progression-free survival data on which the approval was based.

The GEPARquinto trial randomized women with early or locally advanced HER2-negative breast cancer to receive either standard epirubicin (Ellence)/cyclophosphamide (EC) therapy followed by standard docetaxel (Taxotere) therapy with or without bevacizumab.

Women with untreated primary breast carcinoma were included if they were HER2 negative based on local pathology (immunohistochemical score of 0-1, or negative status by fluorescence in situ hybridization). Participants had to have breast lesions of at least 2 cm as determined by palpation or at least 1 cm as determined by ultrasound. The following tumor stages were included: cT4 or cT3; cT2, if the tumor was hormone receptor negative or clinically node positive; or cT1 if the tumor was hormone receptor negative or non–sentinel lymph node positive. The women also had to have normal organ function, including a left ventricular ejection fraction of at least 55%.

In the first part of the study (four 3-week cycles), epirubicin was administered at a dose of 90 mg/m2, cyclophosphamide at a dose of 600 mg/m2, and bevacizumab at a dose of 15 mg/kg .

"We had an assessment of response after four cycles [EC with or without bevacizumab], and those patients who did not achieve a complete or partial remission were taken out of the initial treatment," said Dr. von Minckwitz.

Patients with a clinical response, as determined by sonographic evaluation, switched to chemotherapy with 100 mg/m2 docetaxel with or without bevacizumab for four 3-week cycles. Surgery was delayed by 1 week for patients in the bevacizumab arm (at least 28 days after the last infusion of bevacizumab).

A total of 968 women started standard treatment and 959 started the same treatment plus bevacizumab. In the standard therapy arm, 36% of patients discontinued treatment (mostly because of lack of response); 30% of patients discontinued all treatment in the bevacizumab arm, and 4% discontinued bevacizumab only.

The median patient age was 48 years in the standard treatment arm and 49 years in the bevacizumab arm. The median palpable tumor size was 4 cm for both groups. In addition, 35% of women in each group were hormone receptor negative.

The researchers also looked at other definitions of pCR. When pCR was defined as no invasive residual tumor cells in the breast and nodes, they still found no significant difference: 18.5% for standard chemotherapy and 20.3% for chemotherapy plus bevacizumab. When pCR was defined as no invasive residual tumor cells in the breast, the difference also was not significant: 21.3% for standard chemotherapy and 23.9% for chemotherapy plus bevacizumab.

The breast conservation rate also did not differ significantly, at two-thirds of women in each arm.

As of Dec. 1, 2010, serious adverse events have occurred in 12% of women on standard EC therapy, 16% for women on EC plus bevacizumab, 13% of those on docetaxel alone, and 23% of those on docetaxel and bevacizumab.

Febrile neutropenia occurred in 13 women on standard EC therapy, 27 women on EC plus bevacizumab, 13 women on docetaxel alone, and 23 women on docetaxel and bevacizumab.

Dr. von Minckwitz reported that he receives grant support from Sanofi-Aventis, Roche, GlaxoSmithKline, and Novartis. Several of his coinvestigators also reported relevant financial relationships with multiple pharmaceutical companies.

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