Neoadjuvant Bevacizumab for Breast Cancer

Results of a randomized study [N Engl J Med. 2012;366(4):310-320] show that the addition of capecitabine or gemcitabine to anthracycline-taxane–based neoadjuvant chemotherapy did not improve pathologic complete response in women with breast cancer, whereas the addition of neoadjuvant bevacizumab had a modest but significant increase in the rate of pathologic complete response in the breast. However, the rate of pathologic complete response in the breast and nodes was not significantly increased with the addition of bevacizumab which, according to the authors of the study, “may indicate that this drug will have a lesser effect on patient outcomes.”

The study also found that the addition of bevacizumab increased a number of toxic side effects including left ventricular dysfunction. The study, conducted by investigators from the National Surgical Adjuvant Breast and Bowel Project, was undertaken to determine whether the addition of capecitabine or gemcitabine to anthracycline-taxane–based (docetaxel followed by the anthracycline doxorubicin plus cyclophosphamide) neoadjuvant chemotherapy regimens would increase rates of pathologic complete response in the breast in women with operable breast cancer, and whether the addition of bevacizumab to these neoadjuvant chemotherapy regimens would increase the rates of pathologic complete response. Between January 2007 and June 2010, 1206 patients were enrolled in the study and randomized to 1 of 3 neoadjuvant chemotherapy regimens: (1) docetaxel group (100 mg/m2 of body surface area on day 2; n=201); (2) docetaxel-capecitabine group (75 mg/m2 on day 1 of docetaxel and 825 mg/m2 on days 1-14 of capecitabine; n=204); or (3) docetaxel-gemcitabine (75 mg/m2 on day 1 of docetaxel and 1000 mg/m2 on days 1 and 8 of gemcitabine; n=197). All regimens were followed by doxorubicin-cyclophosphamide for 4 cycles. Half of the patients were also randomized to receive neoadjuvant bevacizumab (15 mg per kilogram of body weight) for the first 6 cycles of chemotherapy.

Overall, 199 patients received docetaxel plus bevacizumab, 201 received docetaxel-capecitabine plus bevacizumab, and 204 received docetaxel-gemcitabine plus bevacizumab. Women included in the study had primary operable HER2-negative breast cancer, palpable primary tumor ≥2.0 cm in diameter of the breast, tumor stage T1c to T3, nodal stage N0 to N2a, metastasis stage M0, an Eastern Cooperative Oncology Group performance status of 0 or 1, and normal left ventricular ejection fraction. The primary end point of the study was the rate of pathologic complete response in the breast, defined as the absence of histologic evidence of invasive tumor cells in the surgical breast specimen. Pathologic complete response in the breast and nodes was among the secondary end points examined. Of the 1206 randomized patients, 1186 were available for the primary analyses. The study found the rate of pathologic complete response did not significantly increase with the addition of either capecitabine or gemcitabine to docetaxel therapy compared with docetaxel therapy alone (29.7% and 31.8%, respectively, vs 32.7%; P=.69). For the patients also treated with bevacizumab, the rate of pathologic complete response was significantly increased compared with those who did not receive bevacizumab (34.5% vs 28.2%; P=.02).

Patients with hormone-receptor–positive breast cancer had an even greater increased rate of pathologic complete response (23.2% with bevacizumab vs 15.1% without; P=.007), whereas the rate of pathologic complete response was not significantly different between the 2 treatment groups in women with hormone-receptor–negative breast cancer (51.5% with bevacizumab vs 47.1% without; P=.34). When looking at the rate of pathologic complete response in the breast and nodes, the study found no significant difference between patients who received bevacizumab and those who did not (27.6% vs 23.0%, respectively; P=.08).

The study also found that the addition of bevacizumab was associated with increased rates of left ventricular systolic dysfunction, hypertension, mucositis, and hand-foot syndrome. The addition of capecitabine and gemcitabine was associated with increased hand-foot disease, mucositis, and neutropenia. According to the authors, a major advantage to the neoadjuvant approach of using bevacizumab is the “opportunity to discover molecular markers that might predict a benefit from bevacizumab. Such markers would allow the selective use of this agent in the subsets of patients most likely to have improved outcomes with the use of the drug,” they concluded.