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
Review
. 2022 Jun 22;5(3):727-748.
doi: 10.20517/cdr.2022.37. eCollection 2022.

Liquid biopsies to predict CDK4/6 inhibitor efficacy and resistance in breast cancer

Sasha C Main  1   2 , David W Cescon  1   3 , Scott V Bratman  1   2   4
Affiliations
Review

Liquid biopsies to predict CDK4/6 inhibitor efficacy and resistance in breast cancer

Sasha C Main et al. Cancer Drug Resist. .

Abstract

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors combined with endocrine therapy have transformed the treatment of estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer. However, some patients do not respond to this treatment, and patients inevitably develop resistance, such that novel biomarkers are needed to predict primary resistance, monitor treatment response for acquired resistance, and personalize treatment strategies. Circumventing the spatial and temporal limitations of tissue biopsy, newly developed liquid biopsy approaches have the potential to uncover biomarkers that can predict CDK4/6 inhibitor efficacy and resistance in breast cancer patients through a simple blood test. Studies on circulating tumor DNA (ctDNA)-based liquid biopsy biomarkers of CDK4/6 inhibitor resistance have focused primarily on genomic alterations and have failed thus far to identify clear and clinically validated predictive biomarkers, but emerging epigenetic ctDNA methodologies hold promise for further discovery. The present review outlines recent advances and future directions in ctDNA-based biomarkers of CDK4/6 inhibitor treatment response.

Keywords: Breast cancer; CDK4/6 inhibitors; cell-free DNA; circulating biomarkers; circulating tumor DNA; liquid biopsy; predictive biomarkers; resistance mechanisms.

PubMed Disclaimer

Conflict of interest statement

Main SC has no conflicts of interest to declare. Cescon DW reports consultancy and advisory fees from AstraZeneca, Exact Sciences, Eisai, Gilead, GlaxoSmithKline, Merck, Novartis, Pfizer and Roche; research funding to their institution from GlaxoSmithKline, Inivata, Merck, Pfizer and Roche; is a member of a trial steering committee for AstraZeneca, Merck and GlaxoSmithKline; and holds a holds a patent (US62/675,228) for methods of treating cancers characterized by a high expression level of spindle and kinetochore associated complex subunit 3 (ska3) gene. Bratman SV is inventor on patents related to cell-free DNA mutation and methylation analysis technologies that are unrelated to this work and have been licensed to Roche Molecular Diagnostics and Adela, respectively. Bratman SV is a co-founder of, has ownership in, and serves in a leadership role at Adela.

Figures

Figure 1
Figure 1
Overview of CDK4/6 inhibitor treatment and liquid biopsy in ER+/HER2- metastatic breast cancer patients. CDK4/6 inhibitors prevent the phosphorylation of Rb and downstream activation of the transcriptional profile required for progression to the S-phase of the cell cycle. In the anti-CDK4/6 therapy clinical setting, a liquid biopsy may be used to direct therapy, monitor patient response over time, and detect progression. Currently, research efforts focused on monitoring genetic alterations in cfDNA through liquid biopsy have made limited progress. Epigenetic profiling of cfDNA may reveal new biomarkers of CDK4/6 inhibitor efficacy or resistance.
See this image and copyright information in PMC

References

    1. Hart CD, Migliaccio I, Malorni L, Guarducci C, Biganzoli L, Di Leo A. Challenges in the management of advanced, ER-positive, HER2-negative breast cancer. Nat Rev Clin Oncol. 2015;12:541–52.. doi: 10.1038/nrclinonc.2015.99. - DOI - PubMed
    1. Pan H, Gray R, Braybrooke J, et al. 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med. 2017;377:1836–46.. doi: 10.1056/nejmoa1701830. - DOI - PMC - PubMed
    1. Mehta RS, Barlow WE, Albain KS, et al. Overall survival with fulvestrant plus anastrozole in metastatic breast cancer. N Engl J Med. 2019;380:1226–34.. doi: 10.1056/nejmoa1811714. - DOI - PMC - PubMed
    1. Burstein HJ, Somerfield MR, Barton DL, et al. Endocrine treatment and targeted therapy for hormone receptor–positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: ASCO Guideline update. J Clin Oncol. 2021;39:3959–77.. doi: 10.1200/JCO.21.01392. - DOI - PMC - PubMed
    1. Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375:1925–36.. doi: 10.1056/NEJMoa1607303. - DOI - PubMed

LinkOut - more resources