Addition of Bevacizumab to Neoadjuvant Chemotherapy Increases Pathologic Complete Response Rate in HER2-negative Disease

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Two studies reported in The New England Journal of Medicine showed that the addition of bevacizumab (Avastin) to neoadjuvant chemotherapy significantly increased the pathologic complete response rate in women with HER2-negative breast cancer. In one study, from the German Breast Group, the benefit was restricted primarily to patients with triple-negative tumors (estrogen receptor–negative, progesterone receptor–negative, and HER2-negative). The other study, from the National Surgical Adjuvant Breast and Bowel Project (NSABP), however, found that the greatest benefit was in patients with hormone receptor–positive disease.

German Breast Group Study

The German Breast Group reported the results from 1,948 patients with previously untreated primary invasive breast cancer enrolled in the HER2-negative components of the larger GeparQuinto phase III study. The patients were randomly assigned to receive neoadjuvant epirubicin and cyclophosphamide followed by docetaxel, with or without concomitant bevacizumab. “All patients who received at least one cycle of epirubicin and cyclophosphamide were included in the efficacy and safety analyses,” the authors noted.

Overall, the rates of pathologic complete response were 14.9% without and 18.4% with bevacizumab (P = .04), but among the 663 patients women with triple-negative disease, the corresponding rates of pathologic complete response were 27.9% without and 39.3% with bevacizumab (P = .003). For the 1,262 patients with hormone receptor–positive tumors, the rates of pathologic complete response were 7.8% without and 7.7% with bevacizumab (P = 1.0).

“Breast-conserving surgery was possible in 66.6% of the patients in both groups. The addition of bevacizumab, as compared with neoadjuvant therapy alone, was associated with a higher incidence of grade 3 or 4 toxic effects (febrile neutropenia, mucositis, the hand–foot syndrome, infection, and hypertension) but with a similar incidence of surgical complications,” the investigators reported.

“Because of the short follow-up period, we cannot confirm that the observed increases in the rate of pathological complete response translate into a survival advantage. However, given that pathological complete response has been shown to be highly correlated with outcome, particularly in patients with triple-negative disease, we speculate that the beneficial effect will be sustained,” the investigators said.

NSABP B-40 Study

NSABP B-40 found that among women with operable HER2-negative breast cancer receiving neoadjuvant chemotherapy, the addition of bevacizumab to treatment significantly increased the rate of pathologic complete response (28.2% without bevacizumab vs 34.5% with bevacizumab, P = .02). The patients, totaling 1,206, had been randomly assigned to receive neoadjuvant therapy with either docetaxel, docetaxel plus capecitabine (Xeloda), or docetaxel plus gemcitabine, with all regimens followed by treatment with doxorubicin/cyclophosphamide. One-half of patients were also randomly assigned to receive bevacizumab at a dose of 15 mg/kg for the first six cycles of chemotherapy.

“The addition of capecitabine or gemcitabine to docetaxel therapy, as compared with docetaxel therapy alone, did not significantly increase the rate of pathological complete response (29.7% and 31.8%, respectively, vs 32.7%; P = .69),” the authors reported. Both capecitabine and gemcitabine were associated with hand–foot syndrome, mucositis, and neutropenia, while “bevacizumab increased the rates of hypertension, left ventricular systolic dysfunction, the hand–foot syndrome, and mucositis,” the authors wrote.

When the pathologic complete response rate was examined according to hormone-receptor status, “the effect of bevacizumab was more pronounced in the hormone-receptor–positive subset (15.1% without bevacizumab vs 23.2% with bevacizumab, P = .007), with a weaker effect in the hormone receptor–negative subset (47.1% without bevacizumab vs 51.5% with bevacizumab, P = .34),” the researchers reported.

Disparity between Trials

“It is unclear why the greatest benefit from adding an antiangiogenic agent was seen in patients with hormone receptor–positive tumors, in contrast to the findings” from the German Breast Group trial, where “the benefit was confined to patients with hormone receptor–negative tumors,” the NSABP investigators stated. “The disparity in the results of the two trials may be related to differences in the inclusion criteria and the study design, particularly the inclusion in the GeparQuinto trial of patients with more advanced disease, a different sequencing of drug regimens in the GeparQuinto trial than that in our trial, and the withdrawal from the GeparQuinto study of patients who did not have a response to the initial four cycles of treatment.”

The German investigators generally concurred that these differences could have contributed to the divergent results despite many similarities in the NSABP B-40 and GeparQuinto trials, “including the fact that the median tumor size at baseline was similar in the two trials.” ■

von Minckwitz G, et al: N Engl J Med 366:299-309, 2012.

Bear HD, et al: N Engl J Med 366:310-320, 2012.