Trastuzumab will play a significant role in the evolution of future neoadjuvant therapies for breast cancer, predicted researchers who presented a Phase III trial at the CTRC- AACR San Antonio Breast Cancer Symposium.
Final results of the Austrian Breast and Colorectal Cancer Study Group-24 trial show that the addition of trastuzumab to epirubicin, docetaxel, and capecitabine neoadjuvant chemotherapy significantly increases the pathological complete response (pCR) rate in patients with HER2-positive tumors.
That rate is a predictor of improved patient outcomes, including increased survival in early breast cancer, said Michael Gnant, MD, Professor of Experimental Surgical Oncology at the University of Vienna.
Current standard anthracycline-taxane neoadjuvant regimens achieve a relatively low pCR rate, of 4% to 18%, he noted. In contrast, a trastuzumab-containing regimen was associated with a pCR rate of over 40% in the current study.
Phase II studies have demonstrated that the combination of epirubicin, docetaxel, and capecitabine (EDC) is safe and efficacious in early and advanced breast cancer, Dr. Gnant explained.
The current academic study was undertaken to compare pCR rates with ED and EDC in patients with early breast cancer and to evaluate the impact of adding trastuzumab to these regimens in a subpopulation of patients with HER2-positive breast cancer.
After the initial randomization to six cycles of ED or EDC, the subgroup of patients with HER2-positive disease underwent a second randomization to trastuzumab (8 mg/kg IV on Day 1, followed by 6 mg/kg every 21 days) or placebo.
A total of 536 patients were enrolled, for which 512 were evaluable for treatment with ED or EDC. A total of 89 patients had HER2-positive tumors and were evaluable for treatment with or without trastuzumab.
The baseline demographics, including age, histology, tumor stage, node involvement, and HER2 status were well balanced between the ED and EDC arms in the total population and within the trastuzumab and placebo arms in the HER2-positive subgroup.
pCR Rate Over 40% in Trastuzumab Arm
The primary efficacy analysis demonstrated that EDC was associated with a significantly increased pCR rate, compared with ED (24% vs 16%), he reported. Among HER2-positive patients, the pCR rate was 40.5% in those who received EDC plus trastuzumab, compared with about 28% in those who received EDC plus placebo.
While the difference did not reach statistical significance, this was mainly due to the unexpectedly high rate of pCR achieved in the group not receiving trastuzumab, Dr. Gnant said.
There were 35 serious adverse events in the trastuzumab arm vs 18 in the placebo arm, an increase largely attributable to an increased number of infusion-related serious adverse events in the trastuzumab arm (14 vs 1).
In conclusion, he said, “The addition of capecitabine to ED achieved a significant increase in pCR and was tolerable. In patients with HER2-positive disease, the addition of trastuzumab to EDC neoadjuvant therapy afforded a further benefit, with more than 40% of patients achieving a pCR.
“With a pCR rate of greater than 40%, the EDC-plus-trastuzumab regimen achieves disease eradication, and therefore the potential for long-term survival,” Dr. Gnant said.
The study was funded by F. Hoffmann-La Roche Ltd.
French Study Confirms Trastuzumab Benefit
Also at the meeting, French researchers reported that the addition of trastuzumab to chemotherapy improves the pathological complete response rate in HER2-positive breast cancer patients in the neoadjuvant setting.
“We looked at chemotherapy with or without trastuzumab in the neoadjuvant setting in patients with HER2-positive breast cancer and observed an increase in the pathological complete response rate in those given trastuzumab,” said Jean-Yves Pierga, MD, PhD, of the Department of Medical Oncology at Institut Curie in Paris.
However, the study, which the authors said represents the first report on adding celecoxib to chemotherapy in the neoadjuvant setting in HER2-negative breast cancer, shows that celecoxib is not effective in this setting.
The goal of the study was to assess the antitumor activity of sequential epirubicin/cyclophosphamide followed by docetaxel with the randomized addition of celecoxib in HER2-negative patients or trastuzumab in HER2-positive patients vs no additional treatment, in terms of pCR, defined as absence of residual invasive breast carcinoma and of nodal involvement.
The study involved 340 patients with Stages II and III breast adenocarcinoma whose tumors were ineligible for breast-conserving surgery; 120 had HER2-positive disease.
The median age of the women was 47, and about half had Stage T2 tumors.
The patients received four three-week cycles of epirubicin (75 mg/m2) and cyclophosphamide (750 mg/m2), followed by four cycles of docetaxel (100 mg/m2).
Patients were then randomized according to their HER2-expression status to receive together with docetaxel: celecoxib (800 mg/day) during Cycles 5 to 8 or no additional treatment if they were HER2-negative or to trastuzumab (8 mg/kg loading dose followed by 6 mg/kg) infused together with docetaxel or no additional treatment if they were HER2-positive.
All but eight of the patients with HER2-positive tumors received adjuvant trastuzumab for a cumulative duration of 12 months.
Trastuzumab Benefits HER2-Positive Patients
In the HER2-negative group, the pCR rate was 11.5% and 13% in patients treated without and with neoadjuvant celecoxib, respectively, a difference that was not statistically significant. In the HER2-positive group, the pCR rate reached 26% in those having received neoadjuvant trastuzumab versus 19% in the others.
Patients with triple-negative breast cancers experienced the highest pCR rate—30%, he said.
“Importantly, there was no cardiac toxicity and no deaths related to adverse events,” he added.
Roche, Pfizer inc., and Sanofi-Aventis helped fund the study.
Currently, trastuzumab is approved for use only in the metastatic and adjuvant settings in the US. But many oncologists started using the monoclonal antibody in the preoperative setting after a small trial led by Aman U. Buzdar, MD, of the University of Texas M. D. Anderson Cancer Center showed a clear benefit for trastuzumab plus chemotherapy over chemotherapy alone.
In the study, the pCR rate was 26% among patients receiving FEC (fluorouracil, epirubicin, and cyclophosphamide), compared with 65% with FEC and trastuzumab. The pCR rate was so high in the trastuzumab arm that the study was closed prematurely.
Those findings were bolstered by those of the Neoadjuvant Herceptin (NOAH) trial, which showed that the addition of trastuzumab to neoadjuvant chemotherapy reduced the risk of recurrence by nearly half, pointed out Edith A. Perez, Director of the Breast Cancer Program and Professor of Medicine in the Division of Hematology/Oncology at the Mayo Clinic in Jacksonville, FL.
That study, presented at the 2008 San Antonio Breast Cancer Symposium, showed that the event-free survival rate at a median of three years was 70% in patients given trastuzumab plus chemotherapy, compared with 53% for those who received chemotherapy alone, a significant difference.
The pCR rate, a secondary endpoint, was 43% in the trastuzumab arm vs 23% in the chemotherapy-alone arm, again a significant difference.
Neoadjuvant trastuzumab plus chemotherapy should be a standard of care for patients with locally advanced HER2-positive breast cancer, according to study head Luca Gianni, MD, Director of Medical Oncology at the National Cancer Institute in Milan, Italy.