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Phosphorylation of AKT pathway proteins is not predictive of benefit of taxane therapy in early breast cancer

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Abstract

Results from the NSABP B-28 trial suggest AKT activation may predict reduced benefit from taxanes following standard anthracycline therapy. Pre-clinical data support a link between PI3 K/AKT signalling and taxane resistance. Using the UK taxotere as adjuvant chemotherapy trial (TACT), we tested the hypothesis that activation of AKT or downstream markers, p70S6K or p90RSK, identifies patients with reduced benefit from taxane chemotherapy. TACT is a multi-centre open-label phase III trial comparing four cycles of standard FEC (fluorouracil, epirubicin, cyclophosphamide) followed by four cycles of docetaxel versus eight cycles of anthracycline-based chemotherapy. Samples from 3,596 patients were available for the current study. We performed immunohistochemical analysis of activation of AKT, p70S6 K and p90RSK. Using a training set with multiple cut-offs for predictive values (10 % increments in expression), we found no evidence for a treatment by marker interaction for pAKT473, pS6 or p90RSK. pAKT473, pS6 and p90RSK expression levels were weakly correlated. A robust, preplanned statistical analysis in the TACT trial found no evidence that pAKT473, pS6 or p90RSK identifies patients deriving reduced benefit from adjuvant docetaxel. This result is consistent with the recent NASBP B28 study where the pAKT473 effect is not statistically significant for the treatment interaction test. Therefore, neither TACT nor NASBP-B28 provides statistically robust evidence of a treatment by marker interaction between pAKT473 and taxane treatment. Alternative methods for selecting patients benefitting from taxanes should be explored.

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Acknowledgements

This study was conducted with the support of the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. The TACT trial is jointly funded by Cancer Research UK (CRUK/01/001) and educational Grants from Aventis, Roche and Pfizer. Storage, construction of microarrays and tissue HER2 testing were funded by an educational grant from Roche. This analysis was funded by a Cancer Research UK grant. Grateful thanks is due to all the patients who agreed to enter the TACT trial and donated their tumour tissue for this research. We also thank the many UK pathologists who sent tumour tissue samples to the central laboratories for storage and future biological research.

Conflict of interest

In the last year, Judith M Bliss has received support from Roche towards travel to attend the San Antonio Breast Cancer Symposium. Peter J Barrett-Lee has received honoraria in the past for advisory boards for Sanofi-Aventis and Pfizer. John MS Bartlett, Roger A’Hern, Tammy Piper, Ian O Ellis, Mitch Dowsett, Elizabeth A Mallon, David A Cameron, Stephen Johnston and Paul Ellis have no conflicts of interest.

Ethical standards

The experiments comply with the current laws of the United Kingdom.

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Authors and Affiliations

  1. Ontario Institute for Cancer Research, MaRS Centre, South Tower, 101 College Street, Suite 800, Toronto, ON, M5G 0A3, Canada

    John M. S. Bartlett

  2. Endocrine Cancer Group, Edinburgh University Cancer Research Centre, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XU, UK

    John M. S. Bartlett & Tammy Piper

  3. ICR-CTSU Division of Clinical Studies, The Institute of Cancer Research, Sutton, Surrey, UK

    Roger A’Hern & Judith M. Bliss

  4. Histopathology Department, Nottingham University Hospitals NHS Trust, Nottingham, UK

    Ian O. Ellis

  5. Royal Marsden NHS Trust, Fulham Road, London, SW3 6JJ, UK

    Mitch Dowsett

  6. Department of Pathology, Western Infirmary, Dumbarton Road, Glasgow, G11 6NT, UK

    Elizabeth A. Mallon

  7. Edinburgh Cancer Research Centre, Western General Hospital, Lothian University Hospitals Trust, Crewe Road, Edinburgh, EH4 2XU, UK

    David A. Cameron

  8. Consultant Medical Oncologist, Department of Medicine, Breast Unit, Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK

    Stephen Johnston

  9. Consultant Medical Oncologist, Department of Medical Oncology, Guy’s & St Thomas’ NHS Trust, London, UK

    Paul Ellis

  10. Academic Breast Unit, Velindre Cancer Center, Velindre NHS Trust, Cardiff, CF14 2TL, UK

    Peter J. Barrett-Lee

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  1. John M. S. Bartlett
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Correspondence to John M. S. Bartlett.

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10549_2013_2489_MOESM1_ESM.doc

Supplementary Table 1: Table comparing patient characteristics of the overall trial and biomarker subset: N = number of cases per category; percent–percentage. All population = all patients eligible for the TACT trial. Biomarker sub-group = patients with available biomarker data. Non-biomarker sub-group = patients with no biomarker data either due to exclusion from tissue collection or missing data on biomarker analysis.(DOC 59 kb)

10549_2013_2489_MOESM2_ESM.doc

Supplementary Table 2: Treatment by marker interaction terms for breast cancer sub-groups: Interaction (treatment by marker) hazard ratios for tumour sub-groups defined as ER+/HER2−ve (ER positive and HER2 negative), HER2+ (HER2 positive and either ER positive or negative) and ER-/HER2-ve (ER negative and HER2 negative). A ratio of less than 1 indicates that the hazard ratio for taxane benefit is less in patients with biomarkers scores above the median. None of the effects reach statistical significance, but a majority of confidence intervals include values that would be of clinical interest (e.g. below 0.7 or above 1.4) if they represented the real effect size.(DOC 36 kb)

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Bartlett, J.M.S., A’Hern, R., Piper, T. et al. Phosphorylation of AKT pathway proteins is not predictive of benefit of taxane therapy in early breast cancer. Breast Cancer Res Treat 138, 773–781 (2013). https://doi.org/10.1007/s10549-013-2489-y

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