title: Activation of Akt, mTOR, and the estrogen receptor as a signature to predict tamoxifen treatment benefit.
abstract: The frequent alterations of the PI3K/Akt/mTOR-growth signaling pathway are proposed mechanisms for resistance to endocrine therapy in breast cancer, partly through regulation of estrogen receptor α (ER) activity. Reliable biomarkers for treatment prediction are required for improved individualized treatment. We performed a retrospective immunohistochemical analysis of primary tumors from 912 postmenopausal patients with node-negative breast cancer, randomized to either tamoxifen or no adjuvant treatment. Phosphorylated (p) Akt-serine (s) 473, p-mTOR-s2448, and ER phosphorylations-s167 and -s305 were evaluated as potential biomarkers of prognosis and tamoxifen treatment efficacy. High expression of p-mTOR indicated a reduced response to tamoxifen, most pronounced in the ER+/progesterone receptor (PgR) + subgroup (tamoxifen vs. no tamoxifen: hazard ratio (HR), 0.86; 95 % confidence interval (CI), 0.31-2.38; P = 0.78), whereas low p-mTOR expression predicted tamoxifen benefit (HR, 0.29; 95 % CI, 0.18-0.49; P = 0.000002). In addition, nuclear p-Akt-s473 as well as p-ER at -s167 and/or -s305 showed interaction with tamoxifen efficacy with borderline statistical significance. A combination score of positive pathway markers including p-Akt, p-mTOR, and p-ER showed significant association with tamoxifen benefit (test for interaction; P = 0.029). Cross-talk between growth signaling pathways and ER-signaling has been proposed to affect tamoxifen response in hormone receptor-positive breast cancer. The results support this hypothesis, as an overactive pathway was significantly associated with reduced response to tamoxifen. A clinical pre-treatment test for cross-talk markers would be a step toward individualized adjuvant endocrine treatment with or without the addition of PI3K/Akt/mTOR pathway inhibitors.
authors.affiliation: Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University & County Council of Östergötland, SE-581 85, Linköping, Sweden. josefine.bostner@liu.se
authors.forename: Josefine
authors.initials: J
authors.lastname: Bostner
authors.forename: Elin
authors.initials: E
authors.lastname: Karlsson
authors.forename: Muneeswaran J
authors.initials: MJ
authors.lastname: Pandiyan
authors.forename: Hanna
authors.initials: H
authors.lastname: Westman
authors.forename: Lambert
authors.initials: L
authors.lastname: Skoog
authors.forename: Tommy
authors.initials: T
authors.lastname: Fornander
authors.forename: Bo
authors.initials: B
authors.lastname: Nordenskjöld
authors.forename: Olle
authors.initials: O
authors.lastname: Stål
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D006801:Humans; D008875:Middle Aged; D010766:Phosphorylation; D017698:Postmenopause; D011237:Predictive Value of Tests; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D012189:Retrospective Studies; D012694:Serine / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen; D013629:Tamoxifen; D012694:Serine; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases