Akt Phosphorylation at Ser473 Predicts Benefit of Paclitaxel Chemotherapy in Node-Positive Breast Cancer

Yang, Sherry X.; Costantino, Joseph P.; Kim, Chungyeul; Mamounas, Eleftherios P.; Nguyen, Dat; Jeong, Jong‐Hyeon; Wolmark, Norman; Kidwell, Kelley M.; Paik, Soonmyung; Swain, Sandra M.

doi:10.1200/jco.2009.26.1602

Cited by 59 publications

(45 citation statements)

References 34 publications

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“…Taxanes have demonstrated great efficiency in the treatment of breast cancer and are widely used in the adjuvant, neo-adjuvant, and metastatic settings [2][3][4][5][6][7]. However, predicting taxane benefit [8][9][10][11][12][13] using conventional histoclinical factors has been controversial and no molecular predictor has been clearly identified [14][15][16][17][18]. Thus, ER, HER2, b-tubulin isotypes, p53, or MAP-Tau expression, which all had been suggested to regulate Taxsensitivity, were not validated as surrogate markers for drug efficacy and none is currently used in the clinic for selecting Tax treatment [4,8,9,16,[19][20][21].…”

Section: Introductionmentioning

confidence: 98%

Gene expression profiling of breast tumor cell lines to predict for therapeutic response to microtubule-stabilizing agents

Kadra

Finetti

Toiron

et al. 2011

Breast Cancer Res Treat

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Microtubule-targeting agents, including taxanes (Tax) and ixabepilone (Ixa), are important components of modern breast cancer chemotherapy regimens, but no molecular parameter is currently available that can predict for their efficiency. We sought to develop pharmacogenomic predictors of Tax- and Ixa-response from a large panel of human breast tumor cell lines (BTCL), then to evaluate their performance in clinical samples. Thirty-two BTCL, representative of the molecular diversity of breast cancers (BC), were treated in vitro with Tax (paclitaxel (Pac), docetaxel (Doc)), and ixabepilone (Ixa), then classified as drug-sensitive or resistant according to their 50% inhibitory concentrations (IC50s). Baseline gene expression data were obtained using Affymetrix U133 Plus 2.0 human oligonucleotide microarrays. Gene expression set (GES) predictors of response to taxanes were derived, then tested for validation internally and in publicly available gene expression datasets. In vitro IC50s of Pac and Doc were almost identical, whereas some Tax-resistant BTCL retained sensitivity to Ixa. GES predictors for Tax-sensitivity (333 genes) and Ixa-sensitivity (79 genes) were defined. They displayed a limited number of overlapping genes. Both were validated by leave-n-out cross-validation (n = 4; for overall accuracy (OA), P = 0.028 for Tax, and P = 0.0005 for Ixa). The GES predictor of Tax-sensitivity was tested on publicly available external datasets and significantly predicted Pac-sensitivity in 16 BTCL (P = 0.04 for OA), and pathological complete response to Pac-based neoadjuvant chemotherapy in BC patients (P = 0.0045 for OA). Applying Tax and Ixa-GES to a dataset of clinically annotated early BC patients identified subsets of tumors with potentially distinct phenotypes of drug sensitivity: predicted Ixa-sensitive/Tax-resistant BC were significantly (P < 0.05, Fischer's exact test) more frequently ER/PR-positive, Ki67-negative, and luminal subtype than predicted Ixa-resistant/Tax-sensitive BC. Genomic predictors for Tax- and Ixa-sensitivity can be derived from BTCL and may be helpful for better selecting cytotoxic treatment in BC patients.

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Section: Introductionmentioning

confidence: 98%

Gene expression profiling of breast tumor cell lines to predict for therapeutic response to microtubule-stabilizing agents

Kadra

Finetti

Toiron

et al. 2011

Breast Cancer Res Treat

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“…Another analysis by my group of the B28 study looked at Akt phosphorylation, finding that patients with tumors that were Akt ϩ ER Ϫ did have a benefit with taxane therapy whereas those whose tumors were phosphorylated Akt Ϫ did not [26] (Fig. 6).…”

Section: Other Biomarkers and Response To Therapymentioning

confidence: 99%

Chemotherapy: Updates and New Perspectives

Swain¹

2011

The Oncologist

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Treatment options for patients with breast cancer have progressively improved over the past 40 years, from an era of no chemotherapy to the introduction of taxanes, hormonal therapy, and biologic therapy. These advances have resulted in substantial, 15%-20% improvements in clinical outcomes. However, progress has yet to be made to improve the prognosis in many breast cancer patients, and research is currently under way to test new tools, or new applications of older tools, to advance breast cancer management. Chemotherapy clearly remains a cornerstone of adjuvant breast cancer treatment, because breast cancer can be very sensitive to the currently available agents. Meanwhile, the era of a one-size-fits-all approach to breast cancer management is over, and the maximum potential of chemotherapy should now be reached by targeting specific populations. Effective biomarkers are therefore needed to optimize chemotherapy, define more selective populations, and clearly tailor treatment. This paper discusses recent data, including new trials that are more fully incorporating current knowledge with respect to molecular markers and the underlying biology of breast cancer. The Oncologist 2011;16(suppl 1):30 -39

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“…This finding was echoed by Grell et al ,37 who showed that patients with HER2-positive metastatic breast cancer that expressed cytoplasmic and nuclear pAkt treated with trastuzumab had a better overall survival. Furthermore, Yang et al 38 demonstrated that patients with pAkt-positive breast cancers have a 26% improvement in disease-free survival or a 20% improvement in overall survival, with the sequential addition of paclitaxel to doxorubicin plus cyclophosphamide adjuvant chemotherapy in patients with node-positive early breast cancer. These apparent discrepancies in the outcome of patient with pAkt expression tumours may relate to differences in patient cohort characteristics, for example, breast cancer versus NSCLC, early versus late disease, as well as to variations in methodology and antibody selection.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylated Akt expression is a prognostic marker in early-stage non-small cell lung cancer

et al. 2013

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Akt Phosphorylation at Ser473 Predicts Benefit of Paclitaxel Chemotherapy in Node-Positive Breast Cancer

Abstract: pAkt significantly predicts disease-free benefit from the sequential addition of paclitaxel to AC chemotherapy in patients with node-positive breast cancer. Patients with pAkt-negative breast tumors do not appear to benefit from the addition of paclitaxel.

Cited by 59 publications

References 34 publications

Gene expression profiling of breast tumor cell lines to predict for therapeutic response to microtubule-stabilizing agents

Gene expression profiling of breast tumor cell lines to predict for therapeutic response to microtubule-stabilizing agents

Chemotherapy: Updates and New Perspectives

Phosphorylated Akt expression is a prognostic marker in early-stage non-small cell lung cancer

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