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  • Review Article
  • Published:

Mechanisms of aromatase inhibitor resistance

Nature Reviews Cancer volume 15, pages 261–275 (2015)Cite this article

Subjects

Key Points

  • Aromatase inhibitors (AIs) are frequently prescribed for patients with oestrogen receptor-positive (ER+) breast cancer to control advanced disease and to prevent relapse after treatment with localized breast cancer (adjuvant therapy). However, resistance to AI therapy is common, occurring in over 20% of patients with early-stage disease and is inevitable in patients with metastatic disease.

  • Resistance to AI therapy can be detected in primary tumours by measuring on-treatment tumour Ki67 expression. The idea of monitoring tumour Ki67 expression as a clinical tool is being prospectively evaluated for individualized treatment approaches that de-escalate therapy for responsive tumours (Ki67low after AI treatment) and escalate therapy for unresponsive tumours (Ki67high after treatment).

  • Genomic analyses of ER+ tumours have identified more than 30 significantly mutated genes the role of which in AI therapy responsiveness is under investigation. To date, TP53 has been associated with high levels of Ki67 both before and after therapy, and therefore with more aggressive disease, and MAP3K1 has the opposite pattern, and is therefore associated with more indolent disease. GATA3 mutation was associated with a greater fall in Ki67 expression with treatment, suggesting that GATA3-mutant tumours are more dependent on oestrogen than GATA3 wild-type tumours.

  • ERα ligand-binding domain mutations emerge after prolonged periods of AI therapy and are therefore an acquired resistance mechanism to AI therapy. Other genomic aberrations in the ESR1 locus have also been identified, including translocations, amplifications and localized gene rearrangements within the long arm of chromosome 6. The frequency of these findings in AI-resistant tumours and their role in AI resistance is under investigation.

  • Cancer cell-intrinsic mechanisms for AI resistance include loss of ER expression, upregulation of growth factor receptor pathways including the ERBB family of receptors, fibroblast growth factor receptor (FGFR), insulin-like growth factor 1 receptor (IGF1R) and their downstream signalling including MAPK and PI3K–AKT–mTOR, deregulation of apoptosis and cell cycle machinery.

  • Cancer cell-extrinsic mechanisms depend on interactions with other cell types within the tumour microenvironment (fibroblasts, immune cells, adipose cells and mesenchymal stem cells) that collectively orchestrate the development and maintenance of AI resistance.

  • Mechanism-based inhibitors against cyclin-dependent kinase 4 (CDK4) and CDK6, PI3K and histone deacetylases are among the most promising strategies being tested to overcome AI resistance in Phase III clinical trials.

  • Further advances in our understanding of AI-resistance mechanisms rely on prospective longitudinal studies of tumour samples collected at multiple disease time points and also on preclinical models that capture the full spectrum and biology of AI-resistance mechanisms.

Abstract

Oestrogen receptor-positive (ER+) breast cancer is a major cause of cancer death in women. Although aromatase inhibitors suppress the function of ER and reduce the risk of recurrence, therapeutic resistance is common and essentially inevitable in advanced disease. This Review considers both genomic and cell biological explanations as to why ER+ breast cancer cells persist, progress and cause an incurable, lethal, systemic disease. The design and outcomes of clinical trials are considered with the perspective that resistance mechanisms are heterogeneous, and therefore biomarker and somatic mutation-based stratification and eligibility will be essential for improvements in patient outcomes.

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Figure 1: Mechanism of action of AIs.
Figure 2: DiPSC plot illustrating correlations between mutations, biomarkers and subtypes.
Figure 3: Alterations in key cancer pathway components in luminal breast cancers.
Figure 4: Mutations in key cancer pathways in luminal breast cancers.
Figure 5: ESR1 mutation and ESR1-YAP1 translocation.
Figure 6: Growth factor receptor signalling, PI3K, MAPK, ER and the p53–RB pathway in ER+ breast cancer.
Figure 7: The tumour microenvironment and AI resistance.
Figure 8: The hallmarks of AI resistance.

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Acknowledgements

C.X.M. is supported by the National Cancer Institute (NCI) Cancer Clinical Investigator Team Leadership Award, the Breast Cancer Research Foundation, the Siteman Cancer Center, and the Susan G. Komen Foundation. All four authors were supported by the AVON visiting scholarship program during the development of the manuscript. M.J.E. is also supported by R01 CA095614, the Barnes-Jewish Foundation, the Breast Cancer Research Foundation, the Susan G. Komen Foundation, a McNair Scholarship, the Cancer Prevention Research Institute of Texas, Lester and Sue Smith, the Glen Smith Family and the Theresa Research Foundation for Metastatic Breast Cancer.

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Authors and Affiliations

  1. Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, 63110, Missouri, USA

    Cynthia X. Ma

  2. Department of Medical Oncology, Instituto Nacional de Câncer (INCA), Praça da Cruz Vermelha, 23, 20230–130, Rio de Janeiro, Brazil

    Tomás Reinert

  3. Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Jaczewskiego 8 St., 20–954, Lublin, Poland

    Izabela Chmielewska

  4. Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, 77030, Texas, USA

    Matthew J. Ellis

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Correspondence to Matthew J. Ellis.

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Competing interests

M.J.E. receives royalties for patent licensing to Nanostring for sales of the breast cancer prognostic test “Prosigna” and has stock in Bioclassifer LLC that advises Nanostring on Prosigna development. He is also paid as an ad hoc consultant for Novartis, Pfizer and AstraZeneca. C.X.M., T.R. and I.C. declare no competing interests.

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Glossary

Aromatase inhibitors

(AIs). A class of drugs, including non-steroidal AIs (for example, anastrozole and letrozole), and steroidal AIs (for example, exemestane), that lower oestrogen levels by inhibiting the enzyme aromatase.

Tamoxifen

A selective oestrogen receptor (ER) modulator (SERM), which antagonizes ER function in breast tissue but also acts as an ER agonist in other tissues, including the endometrium and blood coagulation system, resulting in side effects such as endometrial cancer and an increased risk of thrombosis, respectively.

Endocrine therapy

Targets the oestrogen receptor (ER) pathway for the treatment of ER+ breast cancer either by lowering oestrogen level or by antagonizing ER function.

Neoadjuvant

(also known as preoperative treatment). Refers to therapy administered before curative surgery of the primary cancer. This is often used to reduce tumour size and render large or locally advanced cancers operable.

Natural logarithm

The natural logarithm (loge) of 2.7% is ∼ 1. A natural scale based on multiples of loge = 1 was used in the preoperative endocrine prognostic index because it creates Ki67 intervals, measured during neoadjuvant aromatase inhibitor therapy, associated with significant stepwise increased risk of relapse and death.

Pathological complete response

(pCR). Commonly defined as the absence of residual invasive cancers in the breast and in the axillary lymph node following completion of neoadjuvant systemic therapy, but other definitions exist.

Luminal B

One of the five intrinsic molecular subtypes of breast cancer characterized by higher expression levels of proliferation genes and lower expression levels of oestrogen receptor (ER)-regulated genes compared with the luminal A subtype, and is associated with a poor prognosis.

Luminal A

One of the five intrinsic subtypes of breast cancer characterized by high expression levels of oestrogen receptor (ER) pathway genes and low expression levels of proliferation genes, and associated with a good prognosis.

Patient-derived xenografts

(PDXs). Xenograft models generated by engrafting the cancerous tissue from a patient into an immunodeficient mouse to generate an individualized model of their disease.

Synthetic lethality

The simultaneous perturbation of two genes or processes that results in cellular or organism death, whereas loss of either alone does not.

Epithelial-to-mesenchymal transition

(EMT). A process by which epithelial cells lose their cell polarity and cell–cell adhesion, and gain migratory and invasive properties.

Plasmacytoid DCs

Innate immune cells that circulate in the blood and that are found in peripheral lymphoid organs, specialized in rapid and massive secretion of type I interferon (IFNα/β) in response to foreign nucleic acids.

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Ma, C., Reinert, T., Chmielewska, I. et al. Mechanisms of aromatase inhibitor resistance. Nat Rev Cancer 15, 261–275 (2015). https://doi.org/10.1038/nrc3920

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