title: Time-Varying Effects of Breast Cancer Adjuvant Systemic Therapy.
abstract: BACKGROUND
  The benefits of breast cancer adjuvant systemic treatments are generally assumed to be proportional (or constant) over time, but limited data suggest that some treatment effects may vary with time. We therefore systematically assessed the proportional hazards assumption across all 19 breast cancer adjuvant systemic therapy trials in the National Surgical Adjuvant Breast and Bowel Project (NSABP) database.
  
  
  METHODS
  The NSABP breast cancer trials were tested for the proportionality of hazard rates between randomized treatment groups for five endpoints: overall survival, disease-free survival and recurrence, local-regional recurrence, or distant recurrence as first events. When the proportional hazards assumption did not hold, a "change point for the relative risk" technique was used to identify the temporal breakdown of the treatment effect.
  
  
  RESULTS
  Time-varying treatment effects were observed in nearly half of the trials (nine of 19). In six (B-05, B-11, B-12, B-14, B-16, and B-20), novel treatment benefits diminished statistically significantly at specific time points following surgery. In B-09 and B-31, novel treatment benefits were delayed and emerged more than one year after surgery (1.57 and 1.32 years correspondingly), but the benefit in B-09 reversed after the third year of follow-up. In one trial (B-23), the initial advantage and subsequent disadvantage of one of the regimens was evident.
  
  
  CONCLUSIONS
  Breast cancer adjuvant systemic therapy can have statistically significant time-varying effects, which should be considered in the design, analysis, reporting, and translation of clinical trials. These time-dependent effects will have greater relevance as the number of long-term breast cancer survivors increases.
authors.affiliation: NRG Oncology/ National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA (IJ, EHR, EPM, NW); Department of Surgery University of Texas Health Science Center, San Antonio, TX (IJ); NRG Oncology Statistics & Data Management Center, and the Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA (HB, JHJ); NIH/NCI/Division of Cancer Epidemiology and Genetics, Bethesda, MD (WFA); Markey Cancer Center, University of Kentucky, Lexington, KY (EHR); UF Cancer Center at Orlando Health, Orlando, FL (EPM); Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh, PA (NW). jatoi@uthscsa.edu.
authors.forename: Ismail
authors.initials: I
authors.lastname: Jatoi
authors.affiliation: NRG Oncology/ National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA (IJ, EHR, EPM, NW); Department of Surgery University of Texas Health Science Center, San Antonio, TX (IJ); NRG Oncology Statistics & Data Management Center, and the Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA (HB, JHJ); NIH/NCI/Division of Cancer Epidemiology and Genetics, Bethesda, MD (WFA); Markey Cancer Center, University of Kentucky, Lexington, KY (EHR); UF Cancer Center at Orlando Health, Orlando, FL (EPM); Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh, PA (NW).
authors.forename: Hanna
authors.initials: H
authors.lastname: Bandos
authors.affiliation: NRG Oncology/ National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA (IJ, EHR, EPM, NW); Department of Surgery University of Texas Health Science Center, San Antonio, TX (IJ); NRG Oncology Statistics & Data Management Center, and the Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA (HB, JHJ); NIH/NCI/Division of Cancer Epidemiology and Genetics, Bethesda, MD (WFA); Markey Cancer Center, University of Kentucky, Lexington, KY (EHR); UF Cancer Center at Orlando Health, Orlando, FL (EPM); Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh, PA (NW).
authors.forename: Jong-Hyeon
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: NRG Oncology/ National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA (IJ, EHR, EPM, NW); Department of Surgery University of Texas Health Science Center, San Antonio, TX (IJ); NRG Oncology Statistics & Data Management Center, and the Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA (HB, JHJ); NIH/NCI/Division of Cancer Epidemiology and Genetics, Bethesda, MD (WFA); Markey Cancer Center, University of Kentucky, Lexington, KY (EHR); UF Cancer Center at Orlando Health, Orlando, FL (EPM); Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh, PA (NW).
authors.forename: William F
authors.initials: WF
authors.lastname: Anderson
authors.affiliation: NRG Oncology/ National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA (IJ, EHR, EPM, NW); Department of Surgery University of Texas Health Science Center, San Antonio, TX (IJ); NRG Oncology Statistics & Data Management Center, and the Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA (HB, JHJ); NIH/NCI/Division of Cancer Epidemiology and Genetics, Bethesda, MD (WFA); Markey Cancer Center, University of Kentucky, Lexington, KY (EHR); UF Cancer Center at Orlando Health, Orlando, FL (EPM); Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh, PA (NW).
authors.forename: Edward H
authors.initials: EH
authors.lastname: Romond
authors.affiliation: NRG Oncology/ National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA (IJ, EHR, EPM, NW); Department of Surgery University of Texas Health Science Center, San Antonio, TX (IJ); NRG Oncology Statistics & Data Management Center, and the Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA (HB, JHJ); NIH/NCI/Division of Cancer Epidemiology and Genetics, Bethesda, MD (WFA); Markey Cancer Center, University of Kentucky, Lexington, KY (EHR); UF Cancer Center at Orlando Health, Orlando, FL (EPM); Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh, PA (NW).
authors.forename: Eleftherios P
authors.initials: EP
authors.lastname: Mamounas
authors.affiliation: NRG Oncology/ National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA (IJ, EHR, EPM, NW); Department of Surgery University of Texas Health Science Center, San Antonio, TX (IJ); NRG Oncology Statistics & Data Management Center, and the Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA (HB, JHJ); NIH/NCI/Division of Cancer Epidemiology and Genetics, Bethesda, MD (WFA); Markey Cancer Center, University of Kentucky, Lexington, KY (EHR); UF Cancer Center at Orlando Health, Orlando, FL (EPM); Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh, PA (NW).
authors.forename: Norman
authors.initials: N
authors.lastname: Wolmark
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000517:prevention & control* / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D055502:Secondary Prevention / Q000379:methods; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D004317:Doxorubicin; D003520:Cyclophosphamide