Systematic Review of Molecular Biomarkers Predictive of Resistance to CDK4/6 Inhibition in Metastatic Breast Cancer

Author:

Asghar Uzma S.1234ORCID,Kanani Ruhi5ORCID,Roylance Rebecca6,Mittnacht Sibylle7ORCID

Affiliation:

1. Breast Unit, Royal Marsden Hospital, Sutton, United Kingdom

2. Croydon University Hospital, Thornton Heath, United Kingdom

3. Concr LTD, Babraham Research Campus Limited, Babraham Research Campus, Cambridge, United Kingdom

4. Cohort Innovation Space, Southport, QLD, Australia

5. University College London Hospital, London, United Kingdom

6. NIHR Biomedical Research Centre UCLH/UCL, and Breast Unit, University College London Hospital, London, United Kingdom

7. UCL Cancer Institute, University College London, London, United Kingdom

Abstract

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have revolutionized the treatment of hormone-positive metastatic breast cancers (mBCs). They are currently established as standard therapies in combination with endocrine therapy as first- and second-line systemic treatment options for both endocrine-sensitive and endocrine-resistant mBC populations. In the first-line metastatic setting, the median progression-free survival for the three currently approved CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, with aromatase inhibitors is greater than 2 years (palbociclib 27.6 months; ribociclib 25.3 months; and abemaciclib 28.18 months). Although CDK4/6 inhibitors have significant clinical benefits and enable physicians to delay starting chemotherapy, they are expensive and can be associated with drug toxicities. Here, we have performed a systemic review of the reported molecular markers predictive of drug response including intrinsic and acquired resistance for CDK4/6 inhibition in mBC. The rapidly emerging molecular landscape is captured through next-generation sequencing of breast cancers (DNA with or without RNA), liquid biopsies (circulating tumor DNA), and protein analyses. Individual molecular candidates with robust and reliable evidence are discussed in more depth.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

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