The efficacy of neoadjuvant chemotherapy, as measured by the rate of pathological complete response varies according to breast-cancer subtype. When anthracyclines, taxanes, and agents directed against HER2 (if indicated) are used, approximately 30 to 40% of all breast cancers that are HER2-positive or triple-negative are completely eradicated locally at the time of surgery. Long-term follow-up studies have shown a consistent correlation between pathological complete response and low rates of relapse and death among patients with these two subtypes of breast cancer.
Two RCTs of neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer have been published in the New England Journal of Medicine (NEJM).
The GeparQuinto phase III study was initiated to investigate subtype-specific treatment approaches for patients with HER2-negative primary breast cancer (group 1), HER2-negative primary breast cancer that did not have a response to four cycles of neoadjuvant chemotherapy (group 2), or HER2-positive primary breast cancer (group 3). The first report in the NEJM focuses on patients in group 1 (n=1948), who were randomised to receive neoadjuvant epirubicin and cyclophosphamide followed by docetaxel, with or without concomitant bevacizumab. Patients were eligible if they had no increased cardiovascular or bleeding risk. The primary objective of this part of the study was to compare the rates of pathological complete response.
The following findings were reported:
• The rates of pathological complete response were 14.9% with epirubicin and cyclophosphamide followed by docetaxel and 18.4% with epirubicin and cyclophosphamide followed by docetaxel plus bevacizumab (odds ratio with addition of bevacizumab= 1.29; 95% CI, 1.02 to 1.65; p = 0.04).
• The corresponding rates of pathological complete response were 27.9% and 39.3% among 663 patients with triple-negative tumours (p = 0.003) and 7.8% and 7.7% among 1262 patients with hormone-receptor–positive tumours (p= 1.00).
• 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, hand–foot syndrome, infection, and hypertension) but with a similar incidence of surgical complications.
The researchers conclude that “adding bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response among patients with early-stage HER2-negative breast cancer, with the most notable and pronounced improvement seen in the subgroup of patients with triple-negative disease. Long-term follow-up data are needed before this treatment option can be fully understood.”
The second report is from the National Surgical Adjuvant Breast and Bowel Project (NSABP), which aimed to determine whether adding capecitabine or gemcitabine to docetaxel, followed by doxorubicin plus cyclophosphamide, would improve outcomes in patients with operable, HER2–negative breast cancer. The effect of the addition of bevacizumab to these neoadjuvant chemotherapy regimens was also evaluated.
The study included 1206 patients who were randomised to receive the following neoadjuvant therapy, all of which were followed by treatment with doxorubicin–cyclophosphamide for 4 cycles.
• Docetaxel (100mg/m2 per on day 1)
• Docetaxel (75mg/m2 on day 1) plus capecitabine (825mg/m2 twice a day on days 1 to 14)
• Docetaxel (75mg/m2 on day 1) plus gemcitabine (1000mg/m2 on days 1 and 8) for 4 cycles,
Patients were also randomly assigned to receive or not to receive bevacizumab (15mg/kg) for the first 6 cycles of chemotherapy. The primary end point was the rate of pathological complete response in the breast.
The following findings were reported:
• 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 = 0.69).
• Both capecitabine and gemcitabine were associated with increased toxic effects - specifically, hand–foot syndrome, mucositis, and neutropenia.
• The addition of bevacizumab statistically significantly increased the rate of pathological complete response (28.2% without bevacizumab vs. 34.5% with bevacizumab, p = 0.02).
• The effect of bevacizumab on the rate of pathological complete response was not the same in the hormone-receptor–positive and hormone-receptor–negative subgroups.
• The addition of bevacizumab increased the rates of hypertension, left ventricular systolic dysfunction, hand–foot syndrome, and mucositis.
The researchers conclude from these findings that neither capecitabine nor gemcitabine added to an anthracycline–taxane based chemotherapy regimen improved the rates of clinical or pathological response, despite the suggestive results that have been seen in patients with metastatic breast cancer. This they suggest makes it unlikely that these drugs would add much benefit in the adjuvant setting. The addition of bevacizumab resulted in a modest but statistically significant increase in the rate of pathological complete response in the breast, but the rate of pathological complete response in the breast and nodes was not significantly increased, which they note may indicate that this drug will have a lesser effect on patient outcomes. Furthermore, the addition of bevacizumab was linked to an increase in the number of toxic effects.