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Revisiting the estrogen receptor pathway and its role in endocrine therapy for postmenopausal women with estrogen receptor-positive metastatic breast cancer

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Abstract

Endocrine therapy (ET) is the most commonly administered first-line systemic therapy for estrogen receptor-positive (ER+) metastatic breast cancer (MBC). Manipulation of hormone levels was one of the earliest ET approaches. However, treatment modalities have since evolved with the growing understanding of estrogen biosynthesis and ER biology. The current armamentarium of ET includes selective estrogen receptor modulation, aromatase inhibition, and selective estrogen receptor downregulation. However, intrinsic or acquired resistance to ET is frequently observed. Significant strides have been made in recent years in our understanding of the mechanisms of resistance to ET, and several targeted approaches including inhibitors against the phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway and cyclin-dependent kinase 4/6 (CDK4/6) have shown great promise. The mTOR inhibitor, everolimus, is already in clinical use for the treatment of resistant ER+MBC. However, multiple levels of evidence indicate that ER signaling remains as an important therapeutic target even in the resistance setting, providing the rationale for sequencing multiple lines and combinations of ET. In addition, recurrent mutations in estrogen receptor 1 (ESR1), the gene that encodes the ER, have been identified in the genomic studies of metastatic ER+ breast cancer. ESR1 mutations are an important mechanism for acquired resistance, and effective ER targeting in this setting is particularly important.

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Abbreviations

AIs:

Aromatase inhibitors

CDK:

Cyclin-dependent kinase

CBR:

Clinical benefit rate

ER+:

Estrogen receptor-positive

ERG:

Estrogen-responsive genes

ESR1:

Estrogen receptor 1

ET:

Endocrine therapy

FAK:

Focal adhesion kinase

GF:

Growth factor

GnRH:

Gonadotropin-releasing hormone

HER:

Human epidermal growth-factor receptor

IM:

Intramuscular

JNK:

c-Jun N-terminal kinase

LD:

Loading dose

MBC:

Metastatic breast cancer

mTOR:

Mammalian target of rapamycin

mTORc1:

Mammalian target of rapamycin complex 1

mTORc2:

Mammalian target of rapamycin complex 2

ORR:

Objective response rate

OS:

Overall survival

PDX:

Patient-derived xenograft

PFS:

Progression-free survival

PI3K:

Phosphatidylinositol 3-kinase

PI3KCA:

PI3K alpha catalytic subunit

RB1:

Retinoblastoma susceptibility

RTK:

Receptor tyrosine kinase

SERMS:

Selective estrogen receptor modulators

SWOG:

Southwest Oncology Group

TTP:

Time to progression

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Acknowledgments

The authors independently created the initial draft of the manuscript. Editorial services were provided by SCI Scientific Communications & Information, Parsippany, NJ. Funding was provided by AstraZeneca LP.

Conflict of interest

Gayathri Nagaraj, MD, reported no disclosures. Cynthia Ma, MD, PhD, is a consultant/advisory role for Novartis and receives funding from Novartis, Puma, and Pfizer.

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Authors and Affiliations

  1. Division of Medical Oncology & Hematology, Department of Medicine, Loma Linda University, 11175 Campus Street, CSP 11015, Loma Linda, CA, USA

    Gayathri Nagaraj

  2. Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA

    Cynthia Ma

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  1. Gayathri Nagaraj
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  2. Cynthia Ma
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Correspondence to Gayathri Nagaraj.

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Nagaraj, G., Ma, C. Revisiting the estrogen receptor pathway and its role in endocrine therapy for postmenopausal women with estrogen receptor-positive metastatic breast cancer. Breast Cancer Res Treat 150, 231–242 (2015). https://doi.org/10.1007/s10549-015-3316-4

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  • DOI: https://doi.org/10.1007/s10549-015-3316-4

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