Adding Bevacizumab to Neoadjuvant Chemotherapy Improves Complete Response Rates in Patients with Breast Cancer

JHOP - March 2012, VOL 2 NO 1 - From the Literature, From the Literature
Robert J. Ignoffo, PharmD, FASHP, FCSHP, FHOPA
Clinical Professor Emeritus
University of California, San Francisco
Professor of Pharmacy
College of Pharmacy, Touro University–California
Mare Island, Vallejo, CA

Background: In previous studies, the addition of bevacizumab to first-line chemotherapy regimens in the treatment of metastatic cancer led to modest improvements in ORR and PFS. Now 2 separate studies have investigated the efficacy of adding the VEGF inhibitor bevacizumab to adjuvant chemotherapy regimens in patients with early-stage breast cancer.

Design: In the first study, 1206 women with primary operable HER2-negative breast cancer were randomized to receive docetaxel, alone or combined with capecitabine or gemcitabine, every 3 weeks, followed by doxorubicin plus cyclophosphamide every 3 weeks, for 4 cycles. In addition, 604 of these patients also received bevacizumab (15 mg/kg) with each of the first 6 chemotherapy cycles. The primary end point was the pathologic complete response (pCR). In the second study, the German Breast Group study, 1948 women with untreated HER2-negative breast cancer (median tumor size, 40 mm) were randomized to receive neoadjuvant epirubicin and cyclophosphamide every 3 weeks, followed by docetaxel every 3 weeks, for 4 cycles. Half of this group (974 patients) also received bevacizumab (15 mg/kg) for 8 cycles, beginning with the first cycle of epirubicin and cyclophosphamide.

Summary: In the first study, 59% of the tumors were hormone receptor (HR)-positive. Among 1186 evaluable patients, the addition of capecitabine or gem­citabine to docetaxel therapy did not increase the pCR rate over docetaxel alone (P = .69), but both were associated with increased toxicities, particularly hand-foot syndrome, mucositis, and neutropenia. Compared with the 595 patients who did not receive bevacizumab, however, the 591 patients who received bevacizumab showed a significant improvement in pCR in the breast (28.2% vs 34.5%, respectively; P = .02) but not in the breast and nodes (23.0% vs 27.6%; P = .08). The pCR with bevacizumab was more pronounced in women with HR-positive tumors (23.2% with bevacizumab vs 15.1% without; P = .007). In the second study, a similar overall benefit of bevacizumab was demonstrated. As in the first study, the pCR was greater in patients who received bevacizumab than in those who did not (18.4% vs 14.9%, respectively; odds ratio, 1.29; 95% CI, 1.02-1.65; P = .04). Unlike the other study, however, the benefit of bevacizumab was significantly greater among 663 patients with triple-negative tumors (39.3% vs 27.9%, respectively; P = .003), not among the 1262 women with HR-positive tumors (7.7% vs 7.8%; P > .05). In both studies, bevacizumab was associated with increased rates of grade 3 or 4 toxicities, including mucositis, hand-foot syndrome, and hypertension. An increased incidence of left-ventricular systolic dysfunction was also noted in the first study, and increased febrile neutropenia cases and infections were noted in the German study.

Takeaway: These 2 studies evaluated the addition of bevacizumab to neoadjuvant chemotherapy for early-stage breast cancer. The study by Bear and colleagues (docetaxel chemotherapy) reported an improvement in the pCR rate of HR-positive patients. This implies that more women would be spared primary surgery for their breast cancer.

In the von Minckwitz study (epirubicin plus cyclophosphamide chemotherapy), the greatest benefit was observed in women with triple-negative disease. Complete pathologic remission was 29% higher in the bevacizumab group. The authors caution that it is unclear whether this increase in pCR will translate into prolonged survival. By contrast, women with hormone-responsive tumors did not show a benefit over chemotherapy alone. This study also implies the need for fewer primary surgeries for patients with triple-negative disease.
 
Bear HD, et al. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012;366:310-320; von Minckwitz G, et al. Neoadjuvant chemotherapy and bevacizumab for HER-2 negative breast cancer. N Engl J Med. 2012;366:299-309.

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