Taxane-Based Chemotherapy in Triple-Negative Breast Cancers
Taxane-Based Chemotherapy in Triple-Negative Breast Cancers
Our study shows that the addition of bevacizumab to neoadjuvant anthracycline–taxane-containing chemotherapy significantly increased the pCR rate (ypT0 ypN0) from 27.9% to 39.3% in patients with operable or locally advanced TNBC independent of different pCR definitions. The magnitude of the differences in pCR rates were the same when alternative TNBC definitions were considered. In TNBC, the pCR rate is an important surrogate marker concerning prognosis.
When this randomized trial started in 2007, patients with <10% of tumor cells stained positive for HRs were classified as HR-negative. The new classification, considering tumors with ≤1% positively stained tumor cells, was recommended after the end of the GeparQuinto recruitment.
In contrast to our results, the NSABP B-40 study did not show a benefit in the TNBC subgroup of 490 patients by adding bevacizumab to anthracycline–taxane-based neoadjuvant chemotherapy. The reasons for these divergent results have been discussed in detail previously. To summarize, these results might be attributed to the smaller sample size of TNBC in the NSABP B-40 compared with our study, the exclusion of patients with T4a-d carcinomas in NSABP B-40, which corresponded to 12% of our TNBC cohort; the inclusion of patients with HR-positive, HER2-negative and node-negative tumors in NSABP B-40, who were excluded in GeparQuinto. Patients with lack of response after four EC ± B were considered nonresponders and excluded from the following taxane-based therapy; however, only 18 of these nonresponders had a pCR and did not relevantly change the pCR rate in the total population. Also, the sequence anthracycline-containing regimen followed by docetaxel in our study was reversed in the NSABP study. Moreover, the NSABP B-40 study tested the additive effect of two antimetabolites using a 2-by-3 factorial design and therefore applied a decreased dose of docetaxel (75 mg/m) in the experimental arms. Bevacizumab was administered during the first six chemotherapy cycles only.
In vitro and in vivo data, suggesting that cessation of bevacizumab will stimulate tumor growth, have yet to be confirmed in metastatic breast cancer. Based on preclinical models, the concern is that anti-angiogenic agents might stimulate cancer stem cells by generating intratumoral hypoxia, and might increase invasive and metastatic properties of breast cancer cells, impairing patient outcome. A proposed phase III trial to test the suitability of VEGF-A as a biomarker for effectiveness of bevacizumab in breast cancer seems to be a step in the right direction.
In conclusion, the addition of bevacizumab to anthracycline–taxane-based chemotherapy in TNBC increased the pCR rate significantly. It has to be awaited if the observed increase in pCR rate is large enough to translate into a survival benefit, especially in the light of the negative results of the BEATRICE study.
Discussion
Our study shows that the addition of bevacizumab to neoadjuvant anthracycline–taxane-containing chemotherapy significantly increased the pCR rate (ypT0 ypN0) from 27.9% to 39.3% in patients with operable or locally advanced TNBC independent of different pCR definitions. The magnitude of the differences in pCR rates were the same when alternative TNBC definitions were considered. In TNBC, the pCR rate is an important surrogate marker concerning prognosis.
When this randomized trial started in 2007, patients with <10% of tumor cells stained positive for HRs were classified as HR-negative. The new classification, considering tumors with ≤1% positively stained tumor cells, was recommended after the end of the GeparQuinto recruitment.
In contrast to our results, the NSABP B-40 study did not show a benefit in the TNBC subgroup of 490 patients by adding bevacizumab to anthracycline–taxane-based neoadjuvant chemotherapy. The reasons for these divergent results have been discussed in detail previously. To summarize, these results might be attributed to the smaller sample size of TNBC in the NSABP B-40 compared with our study, the exclusion of patients with T4a-d carcinomas in NSABP B-40, which corresponded to 12% of our TNBC cohort; the inclusion of patients with HR-positive, HER2-negative and node-negative tumors in NSABP B-40, who were excluded in GeparQuinto. Patients with lack of response after four EC ± B were considered nonresponders and excluded from the following taxane-based therapy; however, only 18 of these nonresponders had a pCR and did not relevantly change the pCR rate in the total population. Also, the sequence anthracycline-containing regimen followed by docetaxel in our study was reversed in the NSABP study. Moreover, the NSABP B-40 study tested the additive effect of two antimetabolites using a 2-by-3 factorial design and therefore applied a decreased dose of docetaxel (75 mg/m) in the experimental arms. Bevacizumab was administered during the first six chemotherapy cycles only.
In vitro and in vivo data, suggesting that cessation of bevacizumab will stimulate tumor growth, have yet to be confirmed in metastatic breast cancer. Based on preclinical models, the concern is that anti-angiogenic agents might stimulate cancer stem cells by generating intratumoral hypoxia, and might increase invasive and metastatic properties of breast cancer cells, impairing patient outcome. A proposed phase III trial to test the suitability of VEGF-A as a biomarker for effectiveness of bevacizumab in breast cancer seems to be a step in the right direction.
In conclusion, the addition of bevacizumab to anthracycline–taxane-based chemotherapy in TNBC increased the pCR rate significantly. It has to be awaited if the observed increase in pCR rate is large enough to translate into a survival benefit, especially in the light of the negative results of the BEATRICE study.