Resistance Mechanisms to Combined CDK4/6 Inhibitors and Endocrine Therapy in ER+/HER2− Advanced Breast Cancer: Biomarkers and Potential Novel Treatment Strategies

The introduction of CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) has revolutionized the treatment landscape for patients with estrogen receptor-positive (ER+) advanced breast cancer (ABC) and has become the new standard treatment. However, resistance to this combined therap...

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Autores principales:	Abeer J. Al-Qasem, Carla L. Alves, Henrik J. Ditzel
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	breast cancer CDK4/6 inhibitor biomarkers resistance mechanisms liquid biopsy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/e0d512c167784d4ab2aa38eb43b5651e
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spelling	oai:doaj.org-article:e0d512c167784d4ab2aa38eb43b5651e2021-11-11T15:29:58ZResistance Mechanisms to Combined CDK4/6 Inhibitors and Endocrine Therapy in ER+/HER2− Advanced Breast Cancer: Biomarkers and Potential Novel Treatment Strategies10.3390/cancers132153972072-6694https://doaj.org/article/e0d512c167784d4ab2aa38eb43b5651e2021-10-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5397https://doaj.org/toc/2072-6694The introduction of CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) has revolutionized the treatment landscape for patients with estrogen receptor-positive (ER+) advanced breast cancer (ABC) and has become the new standard treatment. However, resistance to this combined therapy inevitably develops and represents a major clinical challenge in the management of ER+ ABC. Currently, elucidation of the resistance mechanisms, identification of predictive biomarkers, and development of novel effective combined targeted treatments to overcome the resistance are active areas of research. Given the heterogeneity of the resistance mechanisms towards combined CDK4/6i and ET, identification of a single universal predictive biomarker of resistance is unlikely. Novel approaches are being explored, including examination of multiple genetic alterations in circulating cell-free tumor DNA in liquid biopsies from ABC patients with disease progression on combined CDK4/6i and ET treatment. Here, we review the molecular basis of the main known resistance mechanisms towards combined CDK4/6i and ET and associated potential biomarkers. As inhibiting key molecules in the pathways driving resistance may play an important role in the selection of therapeutic strategies for patients who experience disease progression on combined CDK4/6i and ET, we also review preclinical and early phase clinical data on novel combination therapies for these patients.Abeer J. Al-QasemCarla L. AlvesHenrik J. DitzelMDPI AGarticlebreast cancerCDK4/6 inhibitorbiomarkersresistance mechanismsliquid biopsyNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5397, p 5397 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	breast cancer CDK4/6 inhibitor biomarkers resistance mechanisms liquid biopsy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	breast cancer CDK4/6 inhibitor biomarkers resistance mechanisms liquid biopsy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Abeer J. Al-Qasem Carla L. Alves Henrik J. Ditzel Resistance Mechanisms to Combined CDK4/6 Inhibitors and Endocrine Therapy in ER+/HER2− Advanced Breast Cancer: Biomarkers and Potential Novel Treatment Strategies
description	The introduction of CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) has revolutionized the treatment landscape for patients with estrogen receptor-positive (ER+) advanced breast cancer (ABC) and has become the new standard treatment. However, resistance to this combined therapy inevitably develops and represents a major clinical challenge in the management of ER+ ABC. Currently, elucidation of the resistance mechanisms, identification of predictive biomarkers, and development of novel effective combined targeted treatments to overcome the resistance are active areas of research. Given the heterogeneity of the resistance mechanisms towards combined CDK4/6i and ET, identification of a single universal predictive biomarker of resistance is unlikely. Novel approaches are being explored, including examination of multiple genetic alterations in circulating cell-free tumor DNA in liquid biopsies from ABC patients with disease progression on combined CDK4/6i and ET treatment. Here, we review the molecular basis of the main known resistance mechanisms towards combined CDK4/6i and ET and associated potential biomarkers. As inhibiting key molecules in the pathways driving resistance may play an important role in the selection of therapeutic strategies for patients who experience disease progression on combined CDK4/6i and ET, we also review preclinical and early phase clinical data on novel combination therapies for these patients.
format	article
author	Abeer J. Al-Qasem Carla L. Alves Henrik J. Ditzel
author_facet	Abeer J. Al-Qasem Carla L. Alves Henrik J. Ditzel
author_sort	Abeer J. Al-Qasem
title	Resistance Mechanisms to Combined CDK4/6 Inhibitors and Endocrine Therapy in ER+/HER2− Advanced Breast Cancer: Biomarkers and Potential Novel Treatment Strategies
title_short	Resistance Mechanisms to Combined CDK4/6 Inhibitors and Endocrine Therapy in ER+/HER2− Advanced Breast Cancer: Biomarkers and Potential Novel Treatment Strategies
title_full	Resistance Mechanisms to Combined CDK4/6 Inhibitors and Endocrine Therapy in ER+/HER2− Advanced Breast Cancer: Biomarkers and Potential Novel Treatment Strategies
title_fullStr	Resistance Mechanisms to Combined CDK4/6 Inhibitors and Endocrine Therapy in ER+/HER2− Advanced Breast Cancer: Biomarkers and Potential Novel Treatment Strategies
title_full_unstemmed	Resistance Mechanisms to Combined CDK4/6 Inhibitors and Endocrine Therapy in ER+/HER2− Advanced Breast Cancer: Biomarkers and Potential Novel Treatment Strategies
title_sort	resistance mechanisms to combined cdk4/6 inhibitors and endocrine therapy in er+/her2− advanced breast cancer: biomarkers and potential novel treatment strategies
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/e0d512c167784d4ab2aa38eb43b5651e
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Resistance Mechanisms to Combined CDK4/6 Inhibitors and Endocrine Therapy in ER+/HER2− Advanced Breast Cancer: Biomarkers and Potential Novel Treatment Strategies

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