Expanding the Clinical Use of CDK4/6 Inhibitors in the Treatment of Hormone Receptor-Positive, HER2-Negative Breast Cancer from Metastatic Setting to Adjuvant Setting

Abstract

More than two-thirds of patients with breast cancer present with hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative disease at their initial diagnosis. HR-positive breast cancer’s growth depends on Cyclin D1, a direct transcriptional target of estrogen receptors (ER). The recent introduction of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors (palbociclib, ribociclib, and abemaciclib) has revolutionized the treatment of metastatic HR-positive, HER2-negative breast cancer in both endocrine-sensitive and endocrine-resistant settings and in both pre-and post-menopausal women. Multiple large randomized clinical trials had demonstrated improvement in progression-free survival (PFS) and, more recently, in overall survival (OS). Adjuvant endocrine therapy (ET) significantly reduces the risk of recurrence and death among patients with HR-positive early-stage breast cancer (EBC). However, up to 20% of these patients will experience local, regional or distal recurrences in the first ten years. Such resistance to ET motivated researchers to try CDK4/6 inhibitors in EBC, both in adjuvant and neoadjuvant settings. While many clinical trials are still ongoing, at least one study and two meta-analyses had shown beneficial results, based on which the US Food and Drug Administration had recently approved the use of one of these agents, abemaciclib, in combination with ET for the adjuvant therapy of patients with high-risk EBC. In this paper, we review the recently published and ongoing landmark clinical trials attempting to expand the use of CDK4/6 inhibitors, in combination with ET, in the adjuvant setting of EBC.

Anti-cancer Therapies in Adults and Their Effects on Cardiovascular System: A Review

“…However, this was reversible and effectively managed by interrupting or reducing the dose, without any noticeable clinical consequences. it was strongly advised to avoid the concurrent administration of Ribociclib with drugs that were recognized to prolong the QT interval [58]. Because of the increased risk of QT prolongation, combining Ribociclib with Tamoxifen (endocrine therapy, see chapter 3.5) was not recommended.…”

CDK4/6 inhibitors: basics, pros, and major cons in breast cancer treatment with specific regard to cardiotoxicity – a narrative review

“…Finally, the randomized trials of ribociclib revealed that some patients experienced QTc interval prolongation, which was reversible and effectively managed through dose interruption and reduction, without any discernible clinical repercussions. 139 Therefore, the administration of ribociclib is advised solely for individuals whose QTc interval is less than 450 ms. It is imperative to avoid administering ribociclib to patients who are at a heightened risk of developing QTc prolongation and uncontrolled cardiac diseases.…”