Neoadjuvant chemotherapy with sequential anthracycline-docetaxel with gemcitabine for large operable or locally advanced breast cancer: ANZ 0502 (NeoGem)

McCarthy, N., Boyle, F., Zdenkowski, N., Bull, J., Leong, E., Simpson, A., Kannourakis, G., Francis, P. A., Chirgwin, J., Abdi, E., Gebski, V., Veillard, A. S., Zannino, D., Wilcken, N., Reaby, L., Lindsay, D. F., Badger, H. D. and Forbes, J. F. (2014) Neoadjuvant chemotherapy with sequential anthracycline-docetaxel with gemcitabine for large operable or locally advanced breast cancer: ANZ 0502 (NeoGem). The Breast, 23 2: 142-151. doi:10.1016/j.breast.2013.12.001


Author McCarthy, N.
Boyle, F.
Zdenkowski, N.
Bull, J.
Leong, E.
Simpson, A.
Kannourakis, G.
Francis, P. A.
Chirgwin, J.
Abdi, E.
Gebski, V.
Veillard, A. S.
Zannino, D.
Wilcken, N.
Reaby, L.
Lindsay, D. F.
Badger, H. D.
Forbes, J. F.
Title Neoadjuvant chemotherapy with sequential anthracycline-docetaxel with gemcitabine for large operable or locally advanced breast cancer: ANZ 0502 (NeoGem)
Journal name The Breast   Check publisher's open access policy
ISSN 0960-9776
1532-3080
Publication date 2014-04-01
Year available 2014
Sub-type Article (original research)
DOI 10.1016/j.breast.2013.12.001
Open Access Status
Volume 23
Issue 2
Start page 142
End page 151
Total pages 10
Place of publication London, United Kingdom
Publisher Churchill Livingstone
Language eng
Subject 2746 Surgery
Abstract Background: Neoadjuvant chemotherapy has a sound rationale for use in women with large operable breast cancer, and achievement of pathological complete response (pCR) is prognostic. Epirubicin and cyclophosphamide followed by docetaxel is a standard chemotherapy regimen for early breast cancer. Inmetastatic breast cancer the combination of gemcitabine and a taxane has shown promising results. This phase II study investigated the efficacy and safety of incorporating gemcitabine into neoadjuvant therapy. Methods: Female patients with operable breast cancer that was clinically T2 (≥3cm) or T3-4, N0-1, M0 were enrolled to receive 24 weeks of neoadjuvant chemotherapy using epirubicin and cyclophosphamide followed by docetaxel and gemcitabine, plus trastuzumab if HER2-positive. The primary endpoint was the pathological complete response (pCR) rate in the breast in separate HER2-negative and HER2-positive cohorts. Secondary endpoints included pCR in both the breast and axillary lymph nodes, clinical and radiological response rates, disease free survival and safety. Results: 81 patients were enrolled: 63 HER2-negative and 18 HER2-positive. 67 (84%) completed all cycles of chemotherapy, and 78 (96%) proceeded to surgery. pCR was achieved by 12 (20%) patients with HER2-negative, and 9 (53%) with HER2-positive disease. At the first interim analysis, addition of prophylactic G-CSF was recommended due to excess neutropenia. The HER2-negative cohort was closed to accrual because it did not meet the pre-specified target for pCR, and the HER2-positive cohort was closed due to slow accrual. At a median follow-up of 24 months, 12 of 81 (15%) patients had experienced a relapse of their breast cancer. Conclusion: Neoadjuvant gemcitabine, when added to docetaxel, after epirubicin and cyclophosphamide, did not reach the pre-specified expectations for pCR rate in HER2-negative tumours. Excess neutropenia was observed, requiring growth factor support. Addition of gemcitabine to docetaxel in this schedule cannot be recommended.Australia and New Zealand Clinical Trials Registry (www.anzctr.org.au) registration number ACTRN12606000191594. Summary: NeoGem is a Phase II study of neoadjuvant epirubicin and cyclophosphamide, followed by docetaxel and gemcitabine in women with large operable or locally advanced primary breast cancer. Trastuzumab was added if the tumour overexpressed HER2. The primary endpoint was pathologic complete response (pCR). Secondary endpoints included pCR in both the breast and axillary lymph nodes, clinical and radiological response rates, disease free survival and safety. Eighty-one patients were enrolled, and 12(20%) with HER2-negative and 9(53%) with HER2-positive breast cancer achieved a pCR. A high rate of grade 3/4 neutropenia resulted in a protocol amendment to include growth factor support. The study was closed: (1) after an interim analysis showed that patients with HER2-negative disease had a pCR rate that was below the futility boundary, and (2) due to slower than expected accrual in the HER2-positive cohort. Addition of gemcitabine to this anthracycline and taxane schedule cannot be recommended.
Formatted abstract
Background
Neoadjuvant chemotherapy has a sound rationale for use in women with large operable breast cancer, and achievement of pathological complete response (pCR) is prognostic. Epirubicin and cyclophosphamide followed by docetaxel is a standard chemotherapy regimen for early breast cancer. In metastatic breast cancer the combination of gemcitabine and a taxane has shown promising results. This phase II study investigated the efficacy and safety of incorporating gemcitabine into neoadjuvant therapy.

Methods
Female patients with operable breast cancer that was clinically T2 (≥3 cm) or T3-4, N0-1, M0 were enrolled to receive 24 weeks of neoadjuvant chemotherapy using epirubicin and cyclophosphamide followed by docetaxel and gemcitabine, plus trastuzumab if HER2-positive. The primary endpoint was the pathological complete response (pCR) rate in the breast in separate HER2-negative and HER2-positive cohorts. Secondary endpoints included pCR in both the breast and axillary lymph nodes, clinical and radiological response rates, disease free survival and safety.

Results
81 patients were enrolled: 63 HER2-negative and 18 HER2-positive. 67 (84%) completed all cycles of chemotherapy, and 78 (96%) proceeded to surgery. pCR was achieved by 12 (20%) patients with HER2-negative, and 9 (53%) with HER2-positive disease. At the first interim analysis, addition of prophylactic G-CSF was recommended due to excess neutropenia. The HER2-negative cohort was closed to accrual because it did not meet the pre-specified target for pCR, and the HER2-positive cohort was closed due to slow accrual. At a median follow-up of 24 months, 12 of 81 (15%) patients had experienced a relapse of their breast cancer.

Conclusion
Neoadjuvant gemcitabine, when added to docetaxel, after epirubicin and cyclophosphamide, did not reach the pre-specified expectations for pCR rate in HER2-negative tumours. Excess neutropenia was observed, requiring growth factor support. Addition of gemcitabine to docetaxel in this schedule cannot be recommended.
Keyword Locally advanced breast cancer
Neoadjuvant chemotherapy
Gemcitabine
Pathologic complete response
Surgical Adjuvant Breast
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 455513
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
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