title: Phosphorylation of AKT pathway proteins is not predictive of benefit of taxane therapy in early breast cancer.
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.
authors.affiliation: Ontario Institute for Cancer Research, MaRS Centre, South Tower, 101 College Street, Suite 800, Toronto, ON M5G 0A3, Canada. John.Bartlett@oicr.on.ca
authors.forename: John M S
authors.initials: JM
authors.lastname: Bartlett
authors.forename: Roger
authors.initials: R
authors.lastname: A'hern
authors.forename: Tammy
authors.initials: T
authors.lastname: Piper
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Mallon
authors.forename: David A
authors.initials: DA
authors.lastname: Cameron
authors.forename: Stephen
authors.initials: S
authors.lastname: Johnston
authors.forename: Judith M
authors.initials: JM
authors.lastname: Bliss
authors.forename: Paul
authors.initials: P
authors.lastname: Ellis
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Barrett-Lee
mesh_terms: D000328:Adult; D018943:Anthracyclines / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D008875:Middle Aged; D010766:Phosphorylation; D011237:Predictive Value of Tests; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D043823:Taxoids / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D018943:Anthracyclines; D015415:Biomarkers; D043823:Taxoids; D000077143:Docetaxel; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D058570:TOR Serine-Threonine Kinases