title: Do all patients with advanced HER2 positive breast cancer need upfront-chemo when receiving trastuzumab? Randomized phase III trial SAKK 22/99.
abstract: HER2-targeted therapy plus chemotherapy is standard treatment in advanced HER2+ breast cancer. Trastuzumab alone followed by addition of chemotherapy at disease progression versus upfront combination therapy has not been elucidated.
  
  
  
  One-hundred seventy-five patients with measurable/evaluable HER2+ advanced disease without previous HER2-directed therapy were randomized to trastuzumab alone followed, at disease progression, by the combination with chemotherapy (Arm A) or upfront trastuzumab plus chemotherapy (Arm B). Chemotherapy could be stopped after ≥6 cycles in responding patients, trastuzumab was continued until progression. The primary endpoint of this superiority trial was time to progression (TTP) on combined trastuzumab-chemotherapy (Combination-TTP) in both arms. Secondary endpoints included response rate, TTP, overall survival, quality of life and toxicity.
  
  
  
  Combination-TTP was longer than expected in both arms, 12.2 months in Arm A and 10.3 months in Arm B and not significantly different (hazard ratio [HR] 0.7; 95% CI 0.5-1.1; P =0.1). Overall survival was also not significantly different (HR 0.9; 95% CI 0.6-1.5; P = 0.55). In Arm A, the median TTP before introduction of chemotherapy was 3.7 months (95% CI 2.3-5.4), yet at 2 years 6% of patients were still on trastuzumab alone. Patients without visceral disease had a Combination-TTP of 21.8 months in arm A, compared with 10.1 months in arm B (unplanned analysis HR 2.1, 95% CI 1.1-4.2, P = 0.03). Patients with visceral disease showed no difference. Toxicity was chemotherapy-related.
  
  
  
  The outcome of patients receiving sequential trastuzumab-chemotherapy or upfront combination was similar. We failed to demonstrate superiority of the sequential approach. These results nevertheless suggest chemotherapy and its toxicity can be deferred, especially in patients with indolent, non-visceral disease. Despite a larger non-inferiority confirmatory study would be needed, these findings represent an additional proof of concept that de-escalation strategies can be discussed in individual patients.
authors.affiliation: Institute of Oncology and Breast Unit of Southern Switzerland, Bellinzona.
authors.forename: O
authors.initials: O
authors.lastname: Pagani
authors.affiliation: Swiss Group for Clinical Cancer Research, Coordinating Center, Bern.
authors.forename: D
authors.initials: D
authors.lastname: Klingbiel
authors.affiliation: Breast Center, St. Gallen, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Ruhstaller
authors.affiliation: European Institute of Oncology, Milano, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Nolè
authors.affiliation: Molecular Pathology, University Hospital, Basel.
authors.forename: S
authors.initials: S
authors.lastname: Eppenberger
authors.affiliation: Pathology, Kantonsspital, San Gallen.
authors.forename: C
authors.initials: C
authors.lastname: Oehlschlegel
authors.affiliation: International Breast Cancer Study Group Coordinating Center, Bern.
authors.forename: J
authors.initials: J
authors.lastname: Bernhard
authors.affiliation: Swiss Group for Clinical Cancer Research, Coordinating Center, Bern.
authors.forename: P
authors.initials: P
authors.lastname: Brauchli
authors.affiliation: Department of Internal Medicine, Kantonsspital, St.Gallen.
authors.forename: D
authors.initials: D
authors.lastname: Hess
authors.affiliation: Oncology, Kantonsspital, Aarau, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Mamot
authors.affiliation: European Institute of Oncology, Milano, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Munzone
authors.affiliation: Oncology, University Hospital, Zurich.
authors.forename: B
authors.initials: B
authors.lastname: Pestalozzi
authors.affiliation: Breast Unit, Inselspital, Bern.
authors.forename: M
authors.initials: M
authors.lastname: Rabaglio
authors.affiliation: Medical Oncology, Inselspital Bern, now at Luzerner Kantonsspital.
authors.forename: S
authors.initials: S
authors.lastname: Aebi
authors.affiliation: International Breast Cancer Study Group Coordinating Center, Bern.
authors.forename: K
authors.initials: K
authors.lastname: Ribi
authors.affiliation: Oncology, University Hospital, Basel.
authors.forename: C
authors.initials: C
authors.lastname: Rochlitz
authors.affiliation: Swiss Group for Clinical Cancer Research, Coordinating Center, Bern.
authors.forename: K
authors.initials: K
authors.lastname: Rothgiesser
authors.affiliation: Breast Center, St.Gallen.
authors.forename: B
authors.initials: B
authors.lastname: Thürlimann
authors.affiliation: Department of Medicine, Kantonsspital, Chur.
authors.forename: R
authors.initials: R
authors.lastname: von Moos
authors.affiliation: Breast Centre, University Hospital, Lausanne, Switzerland.
authors.forename: K
authors.initials: K
authors.lastname: Zaman
authors.affiliation: European Institute of Oncology, Milano, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Goldhirsch
mesh_terms: D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D000068878:Trastuzumab / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D018943:Anthracyclines; D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: HER2+; advanced breast cancer; breast cancer; chemotherapy; combination therapy; sequential therapy; trastuzumab