Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Apr 20;39(12):1383-1388.
doi: 10.1200/JCO.20.03565. Epub 2021 Mar 11.

Next-Generation Endocrine Therapies for Breast Cancer

Donald P McDonnell  1 , Suzanne E Wardell  1 , Ching-Yi Chang  1 , John D Norris  1
Affiliations

Next-Generation Endocrine Therapies for Breast Cancer

Donald P McDonnell et al. J Clin Oncol. .
No abstract available

PubMed Disclaimer

Conflict of interest statement

Donald P. McDonnellEmployment: Duke UniversityStock and Other Ownership Interests: Zentalis, G1 Therapeutics, Viba Therapeutics, Rappta Therapeutics, X-RAD TherapeuticsHonoraria: NovartisConsulting or Advisory Role: Zentalis, G1 therapeutics, Bristol-Myers Squibb, Rappta TherapeuticsResearch Funding: Bristol-Myers Squibb, Novartis, ZentalisPatents, Royalties, Other Intellectual Property: Inventor on two patents (assigned to Duke) licensed to Radius Health covering the use of Rad1901 for Breast cancer. I am an inventor on two patents (assigned to Duke) that covers the use of lasofoxifene for ESR1-mutant breast cancers. Licensed to SermonixTravel, Accommodations, Expenses: Bristol-Myers Squibb Suzanne E. WardellConsulting or Advisory Role: ZentalisResearch Funding: Zentalis, Bristol-Myers SquibbPatents, Royalties, Other Intellectual Property: I am listed as an inventor on a patent for the use of RAD1901 in metastatic breast cancer Ching-Yi ChangResearch Funding: Novartis Institutes for BioMedical Research, Bristol-Myers SquibbPatents, Royalties, Other Intellectual Property: Sermonix. Patent application for the use of lasofoxifene as treatment for breast cancer John D. NorrisConsulting or Advisory Role: G1 Pharmaceuticals, CelgeneResearch Funding: G1 Therapeutics, CelgeneNo other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Endocrine therapy landscape for ER-positive breast cancer. SERMs such as tamoxifen inhibit ER-positive breast tumor growth by competitively blocking estrogen binding to the receptor, whereas AIs function by blocking the production of estrogens from androgens. These treatments are not curative as growth factor signaling pathways can mediate resistance by activating the receptor-CoA complex in the absence of hormone or when the receptor is occupied by an SERM. Treatment escape following AI therapy, and to a lesser extent SERM therapy, is also often accompanied by the expression of constitutively active ER mutants, most commonly ER-D538G and ER-Y537S. SERDs, such as fulvestrant and elacestrant (RAD1901), can circumvent some of the therapeutic liabilities of SERMs and AIs by degrading both wild-type and mutant receptors. AIs, aromatase inhibitors; AKT, protein kinase B; CoA, coactivator; EGF, epidermal growth factor; ER, estrogen receptor; GRB2, growth factor receptor-bound protein 2; IGF1, insulin-like growth factor 1; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; PI3K, phosphoinositide 3-kinase; RAF, Raf oncogene; RAS, Ras oncogene; SERD, selective estrogen receptor downregulator or degrader; SERM, selective estrogen receptor modulator; SOS, son of sevenless homolog 1.
FIG 2.
FIG 2.
ER modulators that are currently approved for use in the treatment or prevention of ER-positive breast cancers or that are currently in clinical development. Those drugs (SERDs and SERMs) that are currently approved for clinical use in breast cancer are highlighted in green. Investigational drugs that are currently in development for breast cancer are as follows: AZD9833 (NCT04588298; SERENA-3), RG6171 (giredestrant) (NCT04576455), SAR439859 (amcenestrant) (NCT03284957; AMEERA-1), ZN-c5 (NCT03560531), G1T48 (rintodestrant) (NCT03455270), LY3844356 (NCT04188548; EMBER), D-0502 (NCT03471663), SHR9549 (NCT03596658), OP-1250 (NCT04505826), LSZ102 (NCT02734615), ARV-471 (NCT04072952), bazedoxifene (NCT02448771), RAD1901 (elacestrant) (NCT03778931; EMERALD), lasofoxifene (NCT03781063; ELAINE-1), and H3B-6545 (NCT04288089). The relative SERD or SERM activity reflects the authors' summary of the available literature and may change as more data become available from comparative studies. ER, estrogen receptor; SERD, selective estrogen receptor downregulator or degrader; SERM, selective estrogen receptor modulator.
See this image and copyright information in PMC

References

    1. Beatson G.On the treatment of inoperable cases of carcinoma of the mamma: Suggestions for a new method of treatment with illustrative cases Lancet 2162–1651896 - PMC - PubMed
    1. Boyd S.On oophorectomy in the treatment of cancer Br Med J 2890–8961987 - PMC - PubMed
    1. Glascock RF, Hoekstra WG.Selective accumulations of tritium-labelled hexoestrol by the reproductive organs of immature female goats and sheep Biochem J 72673–6821959 - PMC - PubMed
    1. Jensen EV, Jacobson HI.Basic guides to the mechanism of estrogen action Rec Prog Horm Res 18387–4141962
    1. Toft D, Gorski J.A receptor molecule for estrogens: Isolation from the rat uterus and preliminary characterization Proc Natl Acad Sci U S A 551574–15811966 - PMC - PubMed

Publication types

MeSH terms

Substances