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Managing non-proportionality of hazards (PH) within TNT: a randomised phase III trial of carboplatin compared to docetaxel for patients with metastatic or recurrent locally advanced triple negative (TN) or brca1/2 breast cancer (BC)

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Trials201516 (Suppl 2) :P150

  • Published:


  • Breast Cancer
  • Breast Cancer
  • Breast Cancer Patient
  • Docetaxel
  • Carboplatin


TNT is a trial comparing carboplatin with docetaxel for advanced TN or BRCA1/2 BC patients. TNBC is heterogeneous; median progression-free survival (PFS) is short but some patients have prolonged PFS following treatment. BRCA1/2 patients were hypothesised to respond better to carboplatin. This interaction, with the heterogeneous population, was expected to cause a failure of PH assumptions required for Cox-PH analysis. Therefore, TNT required alternative analysis methods.


376 patients were randomised (1:1) to carboplatin or docetaxel for 6-8 cycles or until progression. Primary endpoint was objective response; PFS was a secondary endpoint. Restricted mean survival (RMS) was used to deal with non-PH. A cut-off of 15months was used. Treatment groups were compared using a t-test. A Cox-PH landmark analysis (LA) splitting data at 3, 6 and 9months and a time-dependent Cox model were also applied.


Kaplan-Meier curves crossed and the PH assumption didn't hold (p=0.02). RMS indicated no difference in PFS between groups; difference=0.4 months (-1.1-0.3); p=0.29. Within each period of the LA, PH assumptions held. Between 0-3months PFS is better for patients on docetaxel (HR=1.73, p=0.001) however for patients with PFS> 6months this reversed (HR=0.63, p=0.05). Beyond 9months there is no significant difference (HR=0.82, p=0.56). A time-dependent Cox model resulted in the same HRs as the LA.


Lack of PH is a common issue in metastatic cancer trials. Often this is ignored and standard Cox regression applied or modelling avoided. TNT has shown that RMS is a suitable alternative for comparing groups in the presence of non-PH.

Authors’ Affiliations

Institute of Cancer Research Clinical Trials & Statistics Unit (ICR-CTSU), London, UK
King's College London School of Medicine, London, UK


© Tovey et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.


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