Unveiling the Potential of Cyclin-Dependent Kinases 4 and 6 Inhibitors Beyond Progression in Hormone Receptor Positive/Human Epidermal Growth Factor Negative Advanced Breast Cancer - A Clinical Review

Abstract

Cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) have revolutionized the management of hormone receptor-positive (HR +) breast cancer. However, resistance to CDK4/6i remains an unavoidable challenge, with limited evidence to guide the choice of subsequent treatments. Continuation of CDK4/6 inhibition raises as a compelling treatment option and is currently an active area of research. This approach encompasses multifaceted strategies regarding CDK4/6i sequence (same or switched agent), endocrine therapy (ET) partner and potential combination with a third drug. Continuing CDK4/6 inhibition while targeting ET resistance in tumours still dependent on ER activity (i.e., ESR1 mutation) through a ctDNA-guided approach has the potential of becoming practice-changing, pending the results of ongoing phase III studies. Conversely, the efficacy of this strategy in cases of radiological progression in a biomarker-unselected population appears to be rather unsatisfactory. While some benefit, albeit modest, has been observed from switching to a different CDK4/6i after progression (e.g. ribociclib after palbociclib in the MAINTAIN trial and abemaciclib after both palbociclib and ribociclib in the postMONARCH trial), the current evidence (mainly with palbociclib) clearly argues against maintaining the same CDK4/6i. Biomarker analyses to optimally identify patients suitable for this approach yielded inconsistent findings that do not apply to daily clinical decision making. Attractive preliminary efficacy has recently emerged from combining a third agent (immunotherapy, AKT/ PIK3CA/mTOR inhibitor, new ET agents, CDK2 inhibitors) to CDK4/6i and ET, but further validation in larger ongoing trials is required to also determine the optimal timing for incorporating these agents into the therapeutic timeline. To date, CDK4/6i after CDK4/6i progression is far from being a standard of care. However, selected patients with indolent disease, prolonged exposure to previous CDK4/6i treatment (especially palbociclib) and without actionable molecular alterations, may be suitable for suchmaintenance strategy beyond progression. In this challenging and rapidly evolving treatment landscape, ongoing studies can refine the optimal approach and identify clinical and molecular factors to select the best treatment for the right patient.

Keywords: ESR1 mutation; Biomarkers; CDK4/6i maintenance; Cyclin-dependent kinases 4 and 6 inhibitors; Hormone receptor-positive breast cancer.

Fig. 1

Overview of the main mechanisms leading to resistance to CDK4/6i. The development of resistance to CDK4/6i occurs through complex pathways that are interconnected in multiple ways. One of the most important mechanisms of resistance is the reactivation of upstream signalling, mainly via tyrosine kinase receptor pathways such as FGFR and ERBB2 or via the heightened activity of the non-receptors src kinase family. These pathways converge on the MAPK and PIK3CA/Akt/mTOR pathways, ultimately leading to upregulation of cyclin D. Another relevant resistance pathway is the overactivation of the cyclin D-CDK4/6 axis, which can occur directly through gene amplification or indirectly through various other mechanisms. In addition, independent activation of downstream factors plays a crucial role in resistance. Events such as loss of Rb1, overactivation of CDK2 and aberrant cyclin E1 signalling disrupt the dependence on the cyclin D-CDK4/6 complex for G1-S progression. Finally, signalling pathways such as the upregulation of AURKA come into play, stimulating cell cycle progression independently of the cyclin D1-CDK4/6 axis and promoting G2-M phase transition. AURKA: Aurora Kinase A. Rb: retinoblastoma protein. The figure has been created with Biorender.com

Fig. 2

Strategies Exploiting Continuous CDK4/6 inhibition in HR + /HER2- ABC. Following the occurrence of radiological disease progression during treatment with CDK4/6i and ET, several approaches focusing on the sustained inhibition of CDK4/6 have been investigated. In the first strategy, the same CDK4/6i is maintained while the ET backbone is switched. The second approach involves switching both agents. The third strategy focuses on the continuation of CDK4/6i and ET (either the same or a switch), while introducing a third agent that targets resistance pathways or exhibits synergistic activity in a combined approach. In parallel, another promising strategy currently under investigation focuses on switching the ET backbone to an agent known to be effective against ESR1mutant tumour cells when an ESR1 mutation is detected by ctDNA analysis prior to radiological progression, while continuing the same CDK4/6i. AI: aromathase inhibitor; CDK4/6i: Cyclin-dependent kinases 4 and 6 inhibitors; ctDNA: circulating tumour DNA; ESR1: estrogen receptor 1; ET: endocrine therapy. The figure has been created with Biorender.com