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All women in the BEATRICE trial with triple negative early breast cancer received chemotherapy. One half were also given Avastin (bevacizumab). There was no difference in outcome with or without Avastin.

According to Dr. Silvana Martino, though there was much excitement with this drug when it was first available and initial preliminary results were positive, two studies further confirm that in breast cancer Avastin adds little benefit yet adds toxicity.

Avastin (bevacizumab) has failed to show substantial efficacy in yet another breast cancer setting, according to a Spanish–German study presented here at the 35th Annual San Antonio Breast Cancer Symposium (SABCS).

This time, bevacizumab was added to either letrozole (Femara, Novartis) or fulvestrant (Faslodex, AstraZeneca) as first-line treatment for advanced hormone receptor (HR)-positive breast cancer. But the combination therapy failed to demonstrate a statistically significant increase in progression-free survival compared with endocrine monotherapy, according to Miguel Martin, MD, who presented the results on behalf of investigators from the Letrozole/Fulvestrant and Avastin (LEA) trial.

Dr. Martin is from the Instituto de Investigacion Gregorio Marañón in Madrid, Spain, and is a member of the Spanish Group for Breast Cancer Research (GEICAM). The study was cosponsored by the German Breast Group.

The first efficacy results from the study show that progression-free survival was better with the combination of bevacizumab plus endocrine therapy than with endocrine monotherapy (18.4 vs 13.8 months; P = .14). This translated into a nonsignificant hazard ratio of 0.83 (95% confidence interval, 0.65 - 1.06). There were 131 progression-free survival events in the combination group and 117 in the monotherapy group over the 4-year study period.

The difference in progression-free survival of 4.6 months resulted in a 17% reduction in time to progression, which fell short of the goal of a 31% reduction, said Dr. Martin.

Adding bevacizumab to endocrine therapy did not improve median overall survival, which was 41 months for the 191 women receiving combination therapy and 42 months for the 189 women receiving monotherapy (P = .469).

However, the addition of bevacizumab to endocrine therapy resulted in significantly more hematologic and nonhematologic adverse events.

The trial was designed to test the hypothesis that antivascular endothelial growth-factor (VEGF) treatment can delay resistance to endocrine therapy in patients with HR-positive advanced breast cancer, Dr. Martin said.

He explained the origin of the hypothesis. Preclinical and retrospective clinical data have suggested that high VEGF levels in tumor tissue from breast cancer are associated with a decreased response to endocrine therapy. Furthermore, early clinical data suggest that the downregulation of VEGF can overcome resistance to hormonal therapy and improve efficacy.

Neither trial of bevacizumab presented here at SABCS showed statistically significant benefits in new settings. The absence of a robust positive effect in the LEA trial and the BEATRICE trial (of women with triple-negative disease) had one expert doubting the efficacy of angiogenesis inhibition in breast cancer.

"It makes me wonder if there is a role for angiogenesis inhibitors like bevacizumab in breast cancer," Kent Osborne, MD, from the Baylor College of Medicine in Houston, Texas, told Medscape Medical News. He is one of the codirectors of the symposium.

The collective data on bevacizumab suggest that the drug will have a "very limited role, if any" in breast cancer, he told reporters at a meeting press conference.

More Toxicity With Bevacizumab

Participants in the LEA trial were postmenopausal and had histologically confirmed inoperable locally advanced or metastatic breast cancer. The women had estrogen- and/or progesterone-positive cancers that were also HER2-negative.

About half of both groups had received previous adjuvant endocrine therapy, and about half had received previous chemotherapy. A small minority of women had locally advanced disease (about 3%); most had metastatic disease (about 80%). About 15% had advanced disease that was not precisely determined. About two thirds of the women had multiple metastatic sites.

In the LEA trial, about 90% of the women received letrozole 2.5 mg/day and about 10% received intramuscular fulvestrant 250 mg every 28 days. The dose of bevacizumab was 15 mg/kg every 3 weeks.

In terms of hematologic toxicities (all grades), there was more neutropenia (11.2% vs 5.7%; P = .061) in the combination group than in the monotherapy group, more leukopenia (24.6% vs 11.4%; P = .001), and more thrombocytopenia (19.3% vs 9.1%; P = .006).

In terms of nonhematologic toxicities (all grades), there was more fatigue (50.5% vs 29%; P < .001) in the combination group than in the monotherapy group, more hypertension (59% vs 15.9%; P < .001), more hemorrhage (18.6% vs 1.7%; P < .001), more elevated liver enzymes (46.5% vs 28%; P < .001), and more proteinuria (30.3% vs 2.8%; P < .001).

Financial and drug support were provided by Roche Spain and Germany. Dr. Martin reports being a consultant for Amgen, Roche, Bayer, Novartis, GSK, and Sanofi. Dr. Osborne reports being a consultant/advisor for Genentech, Novartis, and AstraZeneca.

35th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S1-7. Presented December 5, 2012.

Citation: Bevacizumab Fails in Advanced, HR-Positive Breast Cancer. Medscape. Dec 11, 2012