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Physicians' Education Resource®, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Physicians' Education Resource®, LLC designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Physicians' Education Resource®, LLC, is approved by the California Board of Registered Nursing, Provider #16669, for 1.0 Contact Hour.

Acknowledgement of Commercial Support

This activity is supported by an educational grant from Novartis Pharmaceuticals Corporation.

Community Practice Connections: Oncology Best Practice™ Targeting Cell Cycle Progression: The Latest Advances on CDK4/6 Inhibition in Metastatic Breast Cancer

Release Date: October 31, 2017
Expiration Date: October 31, 2018
Media: Internet - based


Activity Overview

The expanding arsenal of targeted therapies available for the treatment of patients with metastatic breast cancer is allowing us to continually hone treatment and personalize care. While novel therapies and combinations— including those utilizing oral, CDK4/6 inhibitors—undeniably benefit patients with breast cancer, they also add markedly to the complexity of care. It is key for practitioners to be able to assimilate the latest clinical evidence, thus optimizing efficacy and mitigating the chance for toxicities for these most difficult-to-treat patients. This activity provides recent clinical data and expert perspectives regarding CDK4/6 inhibitors and their use in the management of patients with estrogen-receptor positive, metastatic breast cancer, which can help the multidisciplinary team to further establish state-of-the-art treatment practices.

Acknowledgement of Commercial Support

This activity is supported by an educational grant from Novartis Pharmaceuticals Corporation.

CME/CE Activity Table of Contents

  • Understanding of the Role of CDK4/6 Inhibition in the Treatment of Metastatic Breast Cancer
  • CDK4/6 Inhibition: Clinical Applications and Supporting Evidence
  • Optimizing the Safety of CDK4/6 Inhibitor Application
  • Individualizing CDK4/6 Inhibitor Therapy and Future Applications

Instructions for This Activity and Receiving Credit

  • You will need to login to participate in the activity.
  • Each presentation may contain an interactive question(s). You may move forward through the presentation; however, you may not go back to change answers or review videos/content until you finish the presentation.
  • At the end of the activity, “educational content/video files” will be available for your reference.
  • In order to receive a cme/ce certificate, participants must complete the activity.
  • Complete the posttest and pass with a score of 70% or higher, complete the evaluation and then click on request for credit. Participants may immediately download a cme/ce certificate upon completion of these steps.

Target Audience

This activity is directed toward medical, surgical and radiation oncologists who treat or manage patients with breast cancer. Fellows, nurses, nurse practitioners, physician assistants, researchers, pharmacists and other healthcare professionals interested in the treatment or management of these tumors are also invited to participate.

Learning Objectives

At the conclusion of this activity, you should be better prepared to:

  • Assess pharmacodynamics properties of cyclin-dependent kinase (CDK) 4/6 inhibition and how that is currently applied to the management of metastatic breast cancer
  • Discuss pivotal trial results concerning the use of CDK4/6 inhibitors in the treatment of metastatic breast cancer
  • Translate evolving evidence to apply CDK4/6 inhibitor approaches to the care of patients with metastatic breast cancer
  • Identify strategies that can be integrated by multidisciplinary teams in institutions for the mitigation and management of predictable adverse events associated with emerging CDK4/6 inhibitory therapies in the management of metastatic breast cancer

Faculty, Staff, and Planners' Disclosures


Francisco J. Esteva, MD, PhD
Professor of Medicine (Oncology)
Director, Breast Medical Oncology Program
Associate Professor of Clinical Investigation
Laura and Isaac Perlmutter Cancer Center
New York University Langone Medical Center
New York, NY

Disclosure: Consultant: Novartis, Genentech; Grant/Research Support: Novartis, Merrimack, Kadmon, Pfizer.

Sara Hurvitz, MD
Associate Professor of Medicine
Division of Hematology/Oncology
Director, Breast Cancer Clinical Research Program
Outpatient Hematology/Oncology
University of California, Los Angeles
Santa Monica, CA

Disclosure: Grant/Research Support: Amgen, Bayer, Boehringer Ingelheim, Genentech, GSK, Pfizer, Roche, Biomarin, Merrimack, OBI Pharm, PUMA, Dignitana, Medivation, Lilly, Novartis, OBI.

The staff of PER® have no relevant financial relationships with commercial interests to disclose.

Disclosure Policy and Resolution of Conflicts of Interest (COI)

As a sponsor accredited by the ACCME, it is the policy of PER® to ensure fair balance, independence, objectivity, and scientific rigor in all of its CME/CE activities. In compliance with ACCME guidelines, PER® requires everyone who is in a position to control the content of a CME/CE activity to disclose all relevant financial relationships with commercial interests. The ACCME defines “relevant financial relationships” as financial relationships in any amount occurring within the past 12 months that creates a COI.

Additionally, PER® is required by ACCME to resolve all COI. PER® has identified and resolved all COI prior to the start of this activity by using a multistep process.

Off-Label Disclosure and Disclaimer

This CME/CE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME/CE activity is for continuing medical and nursing education purposes only, and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER®.

PER Pulse™ Recap

PER Pulse Recap (1 of 3)

Understanding of the Role of CDK4/6 Inhibition in the Treatment of Metastatic Breast Cancer

Cyclin-dependent kinases (CDK) are key components of cell cycle regulation, controlling the transitions between phases of the cell cycle. CDK4 and CDK6 interact with cyclin D1, and when activated, they phosphorylate the retinoblastoma gene product, inactivating it and allowing the cell cycle to progress with transcription of S-phase–specific target genes.1 In cancer cells, cell cycle progression becomes dysregulated, with uncontrolled cellular proliferation, and the cyclin D1:CDK4/6 axis is an essential component of breast cancer maintenance and progression. In breast cancer, peptide and steroid growth factors push proliferation by the activation of cyclin D/CDK4/6.1 Inhibitors of cyclin-dependent kinase have been shown in preclinical and clinical studies to be effective in the treatment of hormone receptor–positive breast cancer by blocking the hyperphosphorylation of the retinoblastoma protein, inducing arrest of the cycle in the G1 phase.1.2 In addition, results of preclinical studies also show activity in HER2-positive lines of breast cancer.

In this activity, Sara Hurvitz, MD and Francisco Esteva, MD, PhD, discuss  current understanding of the role of CDK4/6 inhibitors in the treatment of patients with breast cancer and several other key topics. For more information, please go to


  1. Finn RS, Aleshin A, Slamon DJ. Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers. Breast Cancer Res. 2016;18(1):17. doi: 10.1186/s13058-015-0661-5.
  2. Finn RS, Dering J, Conklin D, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11(5):R77. doi: 10.1186/bcr2419.

PER Pulse Recap (2 of 3)

CDK4/6 Inhibition: The Latest Evidence for Current and Potential Clinical Applications

There are many factors to consider when developing treatment plans for patients with newly diagnosed estrogen receptor–positive metastatic breast cancer. Age, comorbidities, concurrent medications, and previous lines of therapy are just a few of the items that need to be addressed. Systemic endocrine therapy is the preferred treatment option for patients with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer in most cases. Current National Comprehensive Cancer Network (NCCN) guidelines recommend 3 lines of consecutive endocrine therapy for patients with HR-positive advanced breast cancer who lack visceral symptoms.1 Suggested options include anastrozole, letrozole, exemestane, exemestane plus everolimus, ribociclib and letrozole, palbociclib and letrozole, fulvestrant, palbociclib and fulvestrant, tamoxifen, and toremifene.1 Patients with visceral metastases who are symptomatic may require other treatments, such as upfront chemotherapy.1 Several clinical studies have demonstrated the efficacy and safety of CDK4/6 inhibitors in the treatment of HR-positive metastatic breast cancer, leading to the approval of 3 agents: palbociclib, ribociclib, and abemaciclib.

The emergence of treatment resistance is likely, and new studies are examining switching endocrine therapy or CDK4/6 inhibitors with the addition of other drugs to disrupt treatment resistance pathways. According to NCCN guidelines, if disease progression occurs while a patient is taking a CDK4/6 inhibitor and letrozole, there are no data to support an additional line of therapy with another CDK4/6 inhibitor regimen.1 Several clinical trials are examining approaches to overcoming treatment resistance. Among these strategies are (1) implementation of a CDK inhibitor-free period followed by rechallenge; (2) incorporation of additional agents that address pathways, such as PI3K and mTOR; and (3) switching of endocrine therapies. CDK4/6 inhibitors continue to be explored in the curative and metastatic settings.

In this educational activity, Drs Hurvitz and Esteva discuss several of the key clinical trials leading to the approval of CDK4/6 inhibitor therapy for patients with metastatic breast cancer, as well as considerations for potential future applications and the studies that are being conducted to shed further light on this class of therapy. For more information, please visit


  1. NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. Version 2. 2017. Accessed October 12, 2017.

PER Pulse™ Recap (3 of 3)

Optimizing the Safety of CDK4/6 Inhibitor Application

Grade 3 and 4 neutropenia has been associated with the use of approved CDK4/6 inhibitors, leading to establishment of a dosing schedule of 3 weeks on, 1 week off for palbociclib and ribociclib.1,2 Febrile neutropenia and infections are uncommon, and the treatment-associated neutropenia has been shown to decline over time. Complete blood counts should take place before initiating ribociclib and palbociclib, with subsequent blood count monitoring according to the prescribing information.1,2 In the PALOMA-3 study, no difference in progression-free survival was seen between patients who had ≥1 neutropenia-related dose reduction and those who had no dose reduction.3 Results from this study indicate that palbociclib-associated neutropenia may be managed in a variety of ways, including dose delay, dose reduction, and dose interruption, without influencing treatment efficacy.3 QTc prolongation is an additional consideration for patients who are treated with ribociclib, necessitating EKG monitoring.2

Abemaciclib is given on continuous dosing, with less grade 3 and 4 neutropenia than that seen in palbociclib and ribociclib; adverse gastrointestinal side effects such as diarrhea have been seen more commonly with abemaciclib, which may be controlled with treatment.4 Hepatotoxicity and venous thromboembolism formation have also been observed in patients taking abemaciclib, necessitating assessment of blood counts, liver function tests, and monitoring for signs and symptoms of thrombosis and pulmonary embolism.4

It is important for different healthcare providers to be educated regarding these side effects. Blood count monitoring is necessary for approved CDK4/6 inhibitors. Close communication among healthcare providers and patients can help to optimize outcomes for patients who may be candidates for CDK4/6 therapy. In this activity, Drs Hurvitz and Esteva discuss key safety considerations for CDK4/6 inhibitors and strategies to optimize their use. For more information, please visit


  1. Ibrance [prescribing information]. New York, NY: Pfizer Inc; 2017.  Accessed October 24, 2017.
  2. Kisqali [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2017. Accessed October 24, 2017.
  3. Verma S, Bartlett CH, Schnell P, et al. Palbociclib in combination with fulvestrant in women with hormone receptor-positive/HER2-negative advanced metastatic breast cancer: detailed safety analysis from a multicenter, randomized, placebo-controlled, phase III study (PALOMA-3). Oncologist. 2016;21(10):1165-1175. doi: 10.1634/theoncologist.2016-0097
  4. Verzenio [prescribing information]. Indianapolis, IN: Lilly USA, LLC; 2017. Accessed October 24, 2017.

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