title: Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2 study.
abstract: BACKGROUND
  Previous results suggest that docetaxel plus cyclophosphamide improves disease-free survival (DFS) and overall survival compared with doxorubicin plus cyclophosphamide in early stage breast cancer. We assessed the addition of 1 year of trastuzumab to a non-anthracycline regimen, docetaxel plus cyclophosphamide, in patients with HER2-amplified early stage breast cancer and examined whether this regimen was equally effective in patients with TOP2A-amplified and TOP2A-non-amplified disease.
  
  
  METHODS
  This was an open-label, single-group, phase 2 study. Eligible patients were aged 18-75 years; had Eastern Cooperative Oncology Group performance status of 1 or less; HER2-amplified early stage breast cancer; operable, histologically confirmed, invasive carcinoma of the breast; adequate tumour specimen available for FISH analysis of TOP2A status; and adequate haematological, renal, hepatic, and cardiac function. Patients received four 21-day cycles of intravenous docetaxel 75 mg/m(2), plus intravenous cyclophosphamide 600 mg/m(2), plus intravenous trastuzumab 4 mg/kg (loading dose) on day 1 and 2 mg/kg on days 1, 8, and 15 during chemotherapy, followed by trastuzumab 6 mg/kg every three weeks for the remainder of 1 year. The primary endpoint was 2-year DFS in TOP2A-amplified and TOP2A-non-amplified patients; the primary analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00493649.
  
  
  RESULTS
  493 patients were enrolled between June 15, 2007, and Aug 5, 2009. After a median follow-up of 36·1 months (IQR 35·5-36·7), 2-year DFS was 97·8% (95% CI 94·2-99·2) and 2-year overall survival was 99·5% (95% CI 96·2-99·9) for the 190 patients with TOP2A-amplified disease; 2-year DFS was 97·9% (95% CI 94·9-99·1) and 2-year overall survival was 98·8% (95% CI 96·2-99·6) for the 248 patients with TOP2A-non-amplified disease; 55 patients were not assessable for TOP2A status. In the 486 patients who received at least one dose of study drug, the most common adverse events of any grade were fatigue (284 patients, 58·4%), neutropenia (250, 51·4%), and nausea (217, 44·7%). The most common grade 3-4 toxic effects were neutropenia (229, 47·1%), febrile neutropenia (30, 6·2%), fatigue (21, 4·3%), and diarrhoea (16, 3·3%). Cardiac dysfunction occurred in 29 (6·0%) patients (12 [2·5%] grade 1, 15 [3·1%] grade 2, and two [0·4%] grade 3). 23 patients had at least one study-related serious adverse event. 16 patients stopped trastuzumab because of cardiac dysfunction.
  
  
  CONCLUSIONS
  A short, four-cycle regimen of docetaxel and cyclophosphamide combined with trastuzumab could be an option for adjuvant treatment of women with lower risk HER2-amplified early breast cancer, irrespective of TOP2A status.
  
  
  BACKGROUND
  Sanofi.
authors.affiliation: US Oncology Research, McKesson Specialty Health, The Woodlands, TX, USA. Electronic address: steve.jones@usoncology.com.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Jones
authors.affiliation: US Oncology Research, McKesson Specialty Health, The Woodlands, TX, USA; New York Oncology Hematology, Albany, NY, USA.
authors.forename: Rufus
authors.initials: R
authors.lastname: Collea
authors.affiliation: US Oncology Research, McKesson Specialty Health, The Woodlands, TX, USA; Rocky Mountain Cancer, Denver, CO, USA.
authors.forename: Devchand
authors.initials: D
authors.lastname: Paul
authors.affiliation: US Oncology Research, McKesson Specialty Health, The Woodlands, TX, USA; Rocky Mountain Cancer, Denver, CO, USA.
authors.forename: Scot
authors.initials: S
authors.lastname: Sedlacek
authors.affiliation: US Oncology Research, McKesson Specialty Health, The Woodlands, TX, USA; Virginia Cancer Specialists, Fairfax, VA, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Favret
authors.affiliation: US Oncology Research, McKesson Specialty Health, The Woodlands, TX, USA; Alabama Oncology, Birmingham, AL, USA.
authors.forename: Ira
authors.initials: I
authors.lastname: Gore
authors.affiliation: US Oncology Research, McKesson Specialty Health, The Woodlands, TX, USA; Arizona Oncology, Sedona, AZ, USA.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Lindquist
authors.affiliation: US Oncology Research, McKesson Specialty Health, The Woodlands, TX, USA; Texas Oncology, Houston Memorial City, Houston, TX, USA.
authors.forename: Frankie Ann
authors.initials: FA
authors.lastname: Holmes
authors.affiliation: US Oncology Research, McKesson Specialty Health, The Woodlands, TX, USA; Comprehensive Cancer Centers of Nevada, Henderson, NV, USA.
authors.forename: Mary Ann K
authors.initials: MAK
authors.lastname: Allison
authors.affiliation: US Oncology Research, McKesson Specialty Health, The Woodlands, TX, USA; Texas Oncology, Medical City Dallas, Dallas, TX, USA.
authors.forename: Barry D
authors.initials: BD
authors.lastname: Brooks
authors.affiliation: US Oncology Research, McKesson Specialty Health, The Woodlands, TX, USA; Texas Oncology, El Paso West, El Paso, TX, USA.
authors.forename: Raul M
authors.initials: RM
authors.lastname: Portillo
authors.affiliation: US Oncology Research, McKesson Specialty Health, The Woodlands, TX, USA; Texas Oncology-Tyler, Tyler, TX, USA.
authors.forename: Svetislava J
authors.initials: SJ
authors.lastname: Vukelja
authors.affiliation: US Oncology Research, McKesson Specialty Health, The Woodlands, TX, USA; Virginia Oncology Associates, Virginia Beach, VA, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Steinberg
authors.affiliation: US Oncology Research, McKesson Specialty Health, The Woodlands, TX, USA; Texas Oncology, Plano East, Plano, TX, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Stokoe
authors.affiliation: US Oncology Research, McKesson Specialty Health, The Woodlands, TX, USA.
authors.forename: Maria W
authors.initials: MW
authors.lastname: Crockett
authors.affiliation: US Oncology Research, McKesson Specialty Health, The Woodlands, TX, USA.
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: US Oncology Research, McKesson Specialty Health, The Woodlands, TX, USA.
authors.forename: Lina
authors.initials: L
authors.lastname: Asmar
authors.affiliation: US Oncology Research, McKesson Specialty Health, The Woodlands, TX, USA; Virginia Cancer Specialists, Fairfax, VA, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Robert
authors.affiliation: US Oncology Research, McKesson Specialty Health, The Woodlands, TX, USA; Texas Oncology, Baylor-Sammons Cancer Center, Dallas, TX, USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: O'Shaughnessy
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000951:Antigens, Neoplasm / Q000235:genetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D000077143:Docetaxel; D005260:Female; D005500:Follow-Up Studies; D005784:Gene Amplification; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D000075223:Poly-ADP-Ribose Binding Proteins; D016133:Polymerase Chain Reaction; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage; D000068878:Trastuzumab; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D003520:Cyclophosphamide; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D000077143:Docetaxel; D000075223:Poly-ADP-Ribose Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C000618811:TOP2A protein, human