Abstract
PurposeTo provide an overview of clinical data supporting the use of cyclin-dependent kinases 4 and 6 (CDK 4/6) inhibitors in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−), metastatic breast cancer (mBC), from the perspective of the practicing oncologist community.MethodsA recent roundtable discussion was convened by The Breast Cancer Therapy Expert Group (BCTEG) to review existing data on this topic and its impact on their current practice.ResultsLevel 1 evidence now supports use of a CDK 4/6 inhibitor in combination with endocrine therapy for patients with HR+, HER2−, mBC. Currently, there are no biomarkers that reliably define patients who will, or will not, benefit from the addition of a CDK 4/6 inhibitor to their endocrine therapy. Additional research is needed to identify the optimal sequencing of CDK 4/6 inhibitors in relation to other therapies as well as the optimal duration of therapy; at present, evidence suggests that use in the upfront setting is better than waiting for a later line of therapy, or adding after endocrine therapy has started.ConclusionsThus far, three CDK 4/6 inhibitors—palbociclib, ribociclib, and more recently, abemaciclib—have been approved for use in the setting of HR+, HER2−, mBC. The degrees to which these agents differ in terms of CDK4/6 affinity, side-effect profiles, dosing, degree of central nervous system (CNS) penetration, optimal use in combination with antiestrogen therapy, and across other subsets of breast cancer, remain an active area of investigation.
Highlights
Dysregulation of the cell cycle is recognized as a salient feature of cancer cells [2,3,4]
The group viewed the addition of cyclin-dependent kinases 4 and 6 (CDK 4/6) inhibitors as a valuable therapeutic option available to women with HR+, HER2−, metastatic breast cancer (mBC), with the caveat that additional research is needed to gain clarification on several important issues such as treatment biomarkers, optimal duration of therapy, continuation of CDK4/6 inhibitors, and/or a switch to a different drug in the same class following disease progression
Financial considerations may limit the use of these agents, and treatment-related toxicities such as diarrhea and fatigue may be dose limiting; neutropenia is a frequent occurrence with these agents, the rate of febrile neutropenia is low
Summary
Dysregulation of the cell cycle is recognized as a salient feature of cancer cells [2,3,4]. Preclinical work in breast cancer cell lines from Finn and coworkers showed that estrogen receptorpositive (ER+) cell lines were most sensitive to CDK 4/6 inhibition, and evidence for an apparent synergism between CDK 4/6 inhibitors and endocrine therapy (tamoxifen) [2]. These findings have led to the development of CDK 4/6 inhibitors as potential therapeutic agents in breast cancer. The seminal clinical data supporting the use of CDK 4/6 inhibitors in combination with endocrine therapy for mBC are summarized, and includes the PALOMA-1, -2, and 3, MONALEESA-2 and -7, and MONARCH-1, -2, and -3 studies for palbociclib, ribociclib, and abemaciclib, respectively. An overall survival (OS) advantage has not yet been documented in the setting of mBC (Table 1); the choice of which therapeutic line in which to initiate a CDK 4/6 inhibitor is not mandated
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