An analysis of available biomarker data for targeting cyclin-dependent kinases 4 and 6 (CDK4/6) in breast cancer

ABSTRACT

Introduction: Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are a standard of care for advanced estrogen receptor (ER)–positive breast cancer in combination with hormonal therapy. Recent data from large trials comprising these agents in different settings show that a proportion of patients do not actually achieve a clinical benefit from this class, without a clear-cut panorama of predictive biomarkers. Here, clinical and preclinical evidence regarding plausible alterations that have been studied as possible candidates for better steering the indications of CDK4/6i in clinical practice are reviewed and analyzed.

Areas covered: We explored cyclin D-related aberrations, ESR1 mutational profile, pRb levels/loss of RB1 function, cyclin E1-E2 overexpression, CDK6 amplification, PIK3CA/AKT/mTOR pathway interactions, and CDKN2A loss/CDK2 activity.

Expert opinion: The complex molecular pathway involving cell cycle regulation still hampers the validation of a single marker to rationally select patients who would benefit the most from CDK4/6i and avoid futile toxicity. We perceive that, through a combination of assembled molecular alterations, both patient and resource allocation can be optimized. In the meanwhile, paired and reproducible tumor analyses, as well as early ctDNA dynamics, are strongly supported through clinical trials.

KEYWORDS:

• CDK
• cyclin dependent kinase
• CDK4/6
• biomarker
• resistance
• breast cancer
• precision medicine

Article highlights

• The addition of CDK4/6i to endocrine therapy has resulted in the longest improvement in PFS seen to date in advanced ER-positive breast cancer;

• Exploratory analyses of key clinical trials indicate that a proportion of patients do not actually derive significant benefit from a CDK4/6i (i.e.: OR or event-free survival) and clear-cut clinical characteristics that set this population apart have not yet been identified;

• Wide, unrestricted prescription of high-priced, non-inert compounds equals exponential rise in global costs for cancer care and unavoidable toxicities, posing an urgent need to come up with reliable biomarkers of benefit/resistance to CDK4/6i;

• Despite cyclin D-related signatures appearing to be the most strongly predictive parameter for CDK4/6i sensitivity, the remaining majority still fall flat when evaluated as a single tool;

• Comprehensive signatures and panel testing, with simultaneous determination of multiple biomarkers in order to convey most promising results and overcome the single-alteration framework, may be crucial;

• Attention must be made over molecular alterations lying outside of the canonical pathways implicated in CDK4/6i efficacy (i.e.: dMMR);

• For the time being, a prudent position is to secure that paired, rational and reproducible tumor molecular analyses, as well as early ctDNA dynamics, are performed at its best, whenever possible, through future trials.

Declaration of interest

G Curigliano has received funding from Roche, Novartis, Pfizer and Lilly as speaker’s fees. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

B Duso has received financial support for this paper by Fondazione Istituto Europeo di Oncologia e Centro Cardiologico Monzino.