Subscribe

Subscribe Today!

To sign up for our newsletter or print publications, please enter your contact information below.

I'd like to receive:

Resistance Mechanisms to CDK4/6 Blockade in Advanced HR-Positive, HER2-Negative Breast Cancer and Emerging Therapeutic Opportunities

2021 Year in Review - Breast Cancer - Breast Cancer

The most common breast cancer subtype is hormone receptor (HR)-positive, HER2-negative breast cancer, and endocrine therapy is still the most effective treatment. The addition of cyclin-dependent kinase (CDK)4/6 inhibitors (ie, palbociclib, ribociclib, abemaciclib) to endocrine therapy has significantly improved the outcomes of patients with HR-positive advanced breast cancer.1

Several preclinical and translational studies have begun to offer light on the genetic and molecular landscape underlying resistance to these drugs. Changes affecting cell-cycle mediators and activation of oncogenic signal transduction pathways are 2 major drivers of CDK4/6 inhibitor treatment resistance. Next-generation sequencing of resistant tumor biopsies in the clinic identified the resistance drivers with the greatest translational evidence supporting their hypothesized role, which were then verified in laboratory models of HR-positive breast cancer. The mitotic spindle regulator Aurora Kinase A (AURKA), as well as the AKT/MAPK signaling pathways, have all been identified as common, therapeutically actionable resistance nodes. Precision-guided therapy techniques are currently being tested in clinical trials based on these findings.2

The main target of CDK4/6 is the tumor suppressor retinoblastoma. In preclinical studies, loss of retinoblastoma was found to be a driver of CDK4/6 inhibitor resistance.1

CDK4/6 inhibitors revolutionized the treatment of HR-positive, HER2-negative metastatic breast cancer, improving critical clinical outcomes while maintaining a manageable safety profile. The mechanism of action of CDK4/6 inhibitors and their implications in contemporary clinical practice are being studied to fully understand all the mechanisms of resistance.1

References

  1. Roberto M, Astone A, Botticelli A, et al. CDK4/6 inhibitor treatments in patients with hormone receptor positive, HER2 negative advanced breast cancer: potential molecular mechanisms, clinical implications and future perspectives. Cancers (Basel). 2021;13:332.
  2. Lloyd MR, Spring LM, Bardia A, Wander SA. Mechanisms of resistance to CDK4/6 blockade in advanced hormone receptor-positive, HER2-negative breast cancer and emerging therapeutic opportunities. Clin Cancer Res. 2021 Nov 1. Epub ahead of print.
Related Items
Enhertu Received Regular FDA Approval for Patients with Unresectable or Metastatic Breast Cancer
JHOP - June 2022 Vol 12, No 3 published on June 16, 2022 in FDA Oncology Update, Breast Cancer
Pembrolizumab plus Chemotherapy for Neoadjuvant and Adjuvant Therapy in Early Triple-Negative Breast Cancer: KEYNOTE-522
Robert J. Ignoffo, PharmD, FASHP, FCSHP, FHOPA
JHOP - April 2022 Vol 12, No 2 published on May 3, 2022 in From the Literature, Breast Cancer, Checkpoint Inhibitors
Lynparza Receives FDA Approval for Adjuvant Treatment of High-Risk Early Breast Cancer with BRCA Mutation
JHOP - April 2022 Vol 12, No 2 published on May 3, 2022 in FDA Oncology Update, Breast Cancer
Evaluating Adverse Events in Patients with Breast Cancer and HIV Infection Receiving Concomitant Antiretroviral Therapy and Chemotherapy with Curative Intent
Donyika Joseph, PharmD, BCOP, Farnaz Foolad, PharmD, BCPS, Neelam K. Patel, PharmD, BCOP, Meghan Karuturi, MD, MSc, Jaime Kaushik, PharmD, BCOP
JHOP - April 2022 Vol 12, No 2 published on May 2, 2022 in Original Article, Adverse Events, Breast Cancer, Infections
Advances in Breast Cancer Treatments: Are We Extending Patients’ Survival?
Meg Barbor, MPH
JHOP - June 2019 Vol 9, No 2 published on April 28, 2022 in HOPA Highlights, Breast Cancer
Development and Implementation of a Pharmacist-Led Virtual Clinic Improve the Management of Patients with Metastatic Breast Cancer Receiving CDK4/6 Inhibitors
JHOP - March 2022 Vol 12 Special Feature published on March 22, 2022 in HOPA Abstracts, Breast Cancer
Time to Treatment Initiation and Outcomes for Patients with Nonmetastatic Breast Cancer Before and During the COVID-19 Pandemic at Community Cancer Centers
JHOP - March 2022 Vol 12 Special Feature published on March 22, 2022 in HOPA Abstracts, Breast Cancer
Spontaneous Tumor Lysis Syndrome in a Patient with Stage IV HER2-Positive Breast Cancer: Case Report
Blake T. Robbins, PharmD, MBA , Alexander M. Kreimer, PharmD, BCPS , Reema A. Patel, MD, Allison R. Butts, PharmD, BCOP
JHOP - February 2022 Vol 12, No 1 published on March 1, 2022 in Case Reports, Tumor Lysis Syndrome, Breast Cancer
Sacituzumab Govitecan Moves to Second-Line Therapy for Metastatic Triple-Negative Breast Cancer: Applying the Lessons from Clinical Trials to Clinical Practice
February 2022 Clinical Trials to Clinical Practice published on February 3, 2022 in Clinical Trials, Breast Cancer
A Subanalysis of the Phase 3 MONARCH 3 Study of Abemaciclib as Initial Therapy for HR-Positive, HER2-Negative Advanced Breast Cancer
2021 Year in Review - Breast Cancer published on January 21, 2022 in Breast Cancer
© Amplity Health. All rights reserved.