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Can predictive biomarkers in breast cancer guide adjuvant endocrine therapy?

Abstract

Personalized medicine for oestrogen receptor-α (ERα)-positive breast cancer requires predictive biomarkers for broad endocrine resistance as well as biomarkers capable of predicting resistance to a specific agent. In addition, biomarkers could be used to select patients that might benefit from the addition of treatments that do not target ERα. However, biomarker identification studies seem to be far from consistent and identified biomarkers seldom face an introduction into clinical practice. Importantly, most of the studies that seek to identify biomarkers have been performed using material from consecutive series of patients treated with tamoxifen (the most commonly prescribed ERα antagonist). Consequently, the predictive value of any biomarker identified is confounded by its prognostic value. Another important issue is the lack of differentiation between premenopausal and postmenopausal patients with breast cancer. The hormonal environment of a tumour in patients who are premenopausal is intrinsically distinct from those arising in postmenopausal women. Biomarkers of different biological mechanisms might enable the prediction of either broad endocrine resistance or resistance to a specific agent in each of these patient subtypes. Ultimately, improvements to study design are needed to establish the clinical validity of the most promising biomarkers to predict benefit from endocrine therapy.

Key Points

  • Predictive biomarkers for resistance to tamoxifen and/or aromatase inhibitors are essential to select the optimal adjuvant treatment for oestrogen receptor-α (ERα)-positive breast cancer and increase patient survival rates

  • As oestrogen signalling is different between premenopausal and postmenopausal patients with breast cancer, these subgroups should be analysed separately when testing the clinical validity of potential predictive biomarkers

  • Although additional activated signalling pathways circumvent ERα signalling in vitro, a validated biomarker that predicts the activation status of these pathways and resistance to endocrine therapies is not yet clinically available

  • Targeted agents to these signalling pathways have shown promise in metastatic breast cancer and might provide an additional treatment modality in personalized breast cancer treatment

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Figure 1: The functional behaviour of ERα in mediating gene transcription.
Figure 2: Hypothetical examples of erroneous conclusions from cohort studies of patients with breast cancer treated with tamoxifen.
Figure 3: Central components of the PI3K and MAPK pathways.
Figure 4: Effect of tamoxifen and aromatase inhibitors on cell-cycle regulators.

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Acknowledgements

The authors are supported by TI Pharma (project number T3-502) and by Pink Ribbon/A Sister's Hope.

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K. Beelen researched the data and wrote the article. All authors contributed to the discussion of the article content and edited the manuscript before submission.

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Correspondence to Sabine C. Linn.

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Supplementary information

Supplementary Table 1

Promising biomarkers for adjuvant endocrine therapy resistance in premenopausal and postmenopausal women with oestrogen-receptor-positive breast cancer (DOC 124 kb)

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Beelen, K., Zwart, W. & Linn, S. Can predictive biomarkers in breast cancer guide adjuvant endocrine therapy?. Nat Rev Clin Oncol 9, 529–541 (2012). https://doi.org/10.1038/nrclinonc.2012.121

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