title: Neoadjuvant chemotherapy with sequential anthracycline-docetaxel with gemcitabine for large operable or locally advanced breast cancer: ANZ 0502 (NeoGem).
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cancer Care Services, Royal Brisbane and Women's Hospital, Butterfield St, Herston, Brisbane, QLD 4029, Australia; University of Queensland, Brisbane, QLD, Australia. Electronic address: NMcCarthy@iconcancercare.com.au.
authors.forename: N
authors.initials: N
authors.lastname: McCarthy
authors.affiliation: The Mater Hospital, Sydney, NSW, Australia; University of Sydney, Sydney, NSW, Australia.
authors.forename: F
authors.initials: F
authors.lastname: Boyle
authors.affiliation: Australia and New Zealand Breast Cancer Trials Group, Newcastle, NSW, Australia; University of Newcastle, Newcastle, NSW, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Zdenkowski
authors.affiliation: Australia and New Zealand Breast Cancer Trials Group, Newcastle, NSW, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Bull
authors.affiliation: Australia and New Zealand Breast Cancer Trials Group, Newcastle, NSW, Australia.
authors.forename: E
authors.initials: E
authors.lastname: Leong
authors.affiliation: Wellington Cancer Centre, Wellington Hospital, Wellington, New Zealand.
authors.forename: A
authors.initials: A
authors.lastname: Simpson
authors.affiliation: Ballarat Oncology and Haematology Service, Ballarat, VIC, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Kannourakis
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Department of Medicine, St. Vincent's Hospital, University of Melbourne, VIC, Australia.
authors.forename: P A
authors.initials: PA
authors.lastname: Francis
authors.affiliation: University of Newcastle, Newcastle, NSW, Australia; Box Hill Hospital, Box Hill, VIC, Australia; Maroondah Breast Clinic, Maroondah Hospital, Ringwood East, VIC, Australia; Monash University, VIC, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Chirgwin
authors.affiliation: Tweed Hospital, Tweed Heads, NSW, Australia; Griffith University- Gold Coast, Southport, QLD, Australia.
authors.forename: E
authors.initials: E
authors.lastname: Abdi
authors.affiliation: National Health and Medical Research Council Clinical Trials Centre, Sydney, NSW, Australia.
authors.forename: V
authors.initials: V
authors.lastname: Gebski
authors.affiliation: National Health and Medical Research Council Clinical Trials Centre, Sydney, NSW, Australia.
authors.forename: A S
authors.initials: AS
authors.lastname: Veillard
authors.affiliation: National Health and Medical Research Council Clinical Trials Centre, Sydney, NSW, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Zannino
authors.affiliation: Westmead Cancer Care Centre, Westmead Hospital, University of Sydney, NSW, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Wilcken
authors.affiliation: Australia and New Zealand Breast Cancer Trials Group, Newcastle, NSW, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Reaby
authors.affiliation: Australia and New Zealand Breast Cancer Trials Group, Newcastle, NSW, Australia.
authors.forename: D F
authors.initials: DF
authors.lastname: Lindsay
authors.affiliation: Australia and New Zealand Breast Cancer Trials Group, Newcastle, NSW, Australia.
authors.forename: H D
authors.initials: HD
authors.lastname: Badger
authors.affiliation: Australia and New Zealand Breast Cancer Trials Group, Newcastle, NSW, Australia; University of Newcastle, Newcastle, NSW, Australia; Department of Surgical Oncology, Calvary Mater Newcastle, Newcastle, NSW, Australia.
authors.forename: J F
authors.initials: JF
authors.lastname: Forbes
mesh_terms: D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003520:Cyclophosphamide / Q000009:adverse effects / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018572:Disease-Free Survival; D000077143:Docetaxel; D015251:Epirubicin / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D043823:Taxoids / Q000009:adverse effects / Q000627:therapeutic use*; D000068878:Trastuzumab; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D018943:Anthracyclines; D061067:Antibodies, Monoclonal, Humanized; D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; D015251:Epirubicin; D003520:Cyclophosphamide; D000068878:Trastuzumab; D000093542:Gemcitabine
keywords: Gemcitabine; Locally advanced breast cancer; Neoadjuvant chemotherapy; Pathologic complete response; Phase 2