title: HannaH phase III randomised study: Association of total pathological complete response with event-free survival in HER2-positive early breast cancer treated with neoadjuvant-adjuvant trastuzumab after 2 years of treatment-free follow-up.
abstract: In the phase III, open-label, randomised HannaH study, fixed-dose neoadjuvant-adjuvant subcutaneous trastuzumab for human epidermal growth factor receptor 2 (HER2)-positive early breast cancer was non-inferior to standard weight-based intravenous infusion in terms of serum trough concentration and pathological complete response (pCR). Evidence suggests that pCR, particularly total pCR (tpCR), is likely to predict clinical benefit. We report associations between tpCR and event-free survival (EFS) from HannaH (the largest population from a single study of patients presenting with newly diagnosed HER2-positive breast cancer treated with neoadjuvant-adjuvant trastuzumab to date) plus long-term efficacy and safety.
  
  
  
  Eligible patients received four cycles of neoadjuvant docetaxel followed by four cycles of fluorouracil/epirubicin/cyclophosphamide administered concurrently with 3-weekly subcutaneous (600 mg fixed dose) or intravenous trastuzumab (8 mg/kg loading, 6 mg/kg maintenance doses). Post-surgery, patients received adjuvant trastuzumab as randomised to complete 1 year of standard treatment. In exploratory analyses, we used Cox regression to assess associations between tpCR and EFS. EFS rates per subgroup were estimated using the Kaplan-Meier method.
  
  
  
  Three-year EFS rates were 76% for subcutaneous and 73% for intravenous trastuzumab (unstratified hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.69-1.30; intention-to-treat population). Three-year overall survival rates were 92% for subcutaneous and 90% for intravenous trastuzumab (unstratified HR 0.76, 95% CI 0.44-1.32). tpCR was associated with a reduced risk of an EFS event: subcutaneous arm HR 0.38 (95% CI 0.22-0.65); intravenous arm HR 0.32 (95% CI 0.18-0.60). Results were similar for subgroups, including oestrogen receptor status. The few additional adverse events occurring during treatment-free follow-up were balanced between arms.
  
  
  
  Long-term efficacy supports the established non-inferiority of subcutaneous trastuzumab, and its safety profile remains consistent with the known intravenous profile. In each of HannaH's treatment arms, tpCR was associated with improved EFS, adding to evidence that tpCR is associated with clinical benefit in HER2-positive early breast cancer.
authors.affiliation: Sana Klinikum Offenbach GmbH, Department of Obstetrics and Gynecology & Breast Cancer and Gynecology Cancer Center, Starkenburgring 66, D-63069, Offenbach, Germany. Electronic address: christian.jackisch@sana.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Jackisch
authors.affiliation: Hospital Pérola Byington and FMUSP, Department of Gynecology and Obstetrics, Avenida Brigadeiro Luís Antônio, 683 - Bela Vista, São Paulo - SP, 01317-000, Brazil.
authors.forename: Roberto
authors.initials: R
authors.lastname: Hegg
authors.affiliation: City Clinical Oncology Hospital 62, Chemotherapeutic Department, Moscow, 143423, Russia.
authors.forename: Daniil
authors.initials: D
authors.lastname: Stroyakovskiy
authors.affiliation: Samsung Medical Center, Sungkyunkwan University School of Medicine, Department of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, South Korea.
authors.forename: Jin-Seok
authors.initials: JS
authors.lastname: Ahn
authors.affiliation: Palacký University Medical School & Teaching Hospital, Department of Oncology, I. P. Pavlova 185/6, 779 00, Olomouc, Czech Republic.
authors.forename: Bohuslav
authors.initials: B
authors.lastname: Melichar
authors.affiliation: Chang Gung Memorial Hospital, Department of Surgery, No. 123, Dinghu Rd, Guishan District, Taoyuan, Taiwan.
authors.forename: Shin-Cheh
authors.initials: SC
authors.lastname: Chen
authors.affiliation: Asan Medical Center, University of Ulsan College of Medicine, Department of Oncology, 88 Olympic-ro, 43-gil, Songpa-gu, Seoul, South Korea.
authors.forename: Sung-Bae
authors.initials: SB
authors.lastname: Kim
authors.affiliation: NN Blokhin Cancer Research Center, Russian Academy of Medical Sciences, Kashirskoye Shosse 24, 115478, Moscow, Russia.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Lichinitser
authors.affiliation: St. John's Cancer Center, 20-090, Lublin, Poland.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Starosławska
authors.affiliation: St. Johannes Hospital, Johannesstraße 9-13, 44137, Dortmund, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Kunz
authors.affiliation: Hospital Nacional Edgardo Rebagliati Martins, Av. Rebagliati 490, Jesús María, Lima 11, Peru.
authors.forename: Silvia
authors.initials: S
authors.lastname: Falcon
authors.affiliation: Changhua Christian Hospital, No. 135, Nanhsiao St, Changhua City, Changhua County, Taiwan.
authors.forename: Shou-Tung
authors.initials: ST
authors.lastname: Chen
authors.affiliation: F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland.
authors.forename: Aulde
authors.initials: A
authors.lastname: Crepelle-Fléchais
authors.affiliation: F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland.
authors.forename: Dominik
authors.initials: D
authors.lastname: Heinzmann
authors.affiliation: Genentech, Inc., Global Pharma Development, 1 DNA Way, South San Francisco, CA, 94080, USA.
authors.forename: Mona
authors.initials: M
authors.lastname: Shing
authors.affiliation: CHU Jean Minjoz, Chemotherapy - Oncology, 3 Boulevard Alexandre Fleming, 25030, Besançon, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Pivot
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007279:Injections, Subcutaneous; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D000068878:Trastuzumab / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D000068878:Trastuzumab
keywords: Herceptin; Neoadjuvant chemotherapy; Pathological complete response; Subcutaneous; Trastuzumab