Ursa Brown-Glaberman, MD
University of New Mexico Comprehensive Cancer Center, Albuquerque

Key Takeaways

  • Incorporating cyclin-dependent kinase (CDK)4/6 inhibitors into adjuvant treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) breast cancer requires personalized tailoring based on patient characteristics, risk factors, side-effect tolerance, target specificity, toxicity, and synergy with endocrine therapy.
  • Providing patient education, support, and careful management of side effects are essential in the adjuvant setting to prevent treatment discontinuation and ensure optimal patient outcomes.
  • Ribociclib has demonstrated enhanced 3-year invasive disease-free survival rates, minimal side effects, and potential comparability to abemaciclib benefits.
  • To manage abemaciclib-associated diarrhea, implementing strategies such as educating patients about potential risks and closely monitoring side effects during the early stages can optimize abemaciclib tolerability and patient-reported outcomes.

Breast cancer is a relatively common form of cancer, and approximately 70% of breast cancers are classified as HR+/HER2− breast cancer.1 Significant progress has been made in understanding and refining adjuvant therapy strategies to reduce the risk for recurrence in patients with early breast cancer without lymph node involvement, specifically those with HR+/HER2− tumors.
There is a significant risk for recurrence in HR+/HER2− breast cancer; approximately 1 in 6 women with HR+/HER2− breast cancer who are already receiving endocrine therapy will face recurrence or death within 5 years of initiating treatment.2 Emerging research in this field has illuminated novel approaches to customizing treatment duration, optimizing the incorporation of drug classes, and enhancing patient-specific considerations.
Estrogen receptor signaling plays a crucial role in regulating various genes, including proteins that control cell-cycle progression, such as cyclins and CDKs. In HR+/HER2− breast cancer, 3 selective CDK4/6 inhibitors — ribociclib, abemaciclib, and palbociclib — have been developed.3 CDK4/6 inhibitors play a crucial role in the G1-to-S-phase cell-cycle transition, and when combined with endocrine therapy, selective CDK4/6 inhibitors offer improved effectiveness and fewer adverse effects compared with nonselective inhibition of CDKs.4
Palbociclib, which was the first-in-class of the CDK4/6 inhibitors, was evaluated in the PALLAS trial (ClinicalTrials.gov identifier: NCT02513394). However, the trial yielded disappointing results, possibly attributed to high discontinuation rates.5
The monarchE trial (ClinicalTrials.gov identifier: NCT03155997), which evaluated the use of abemaciclib, led to the US Food and Drug Administration (FDA) approval of adjuvant abemaciclib in combination with endocrine therapy for high-risk node-positive HR+ early breast cancer. Abemaciclib was first approved only for patients with Ki-67 scores of 20% or greater, but the Ki-67 score requirement was removed in March 2023.6 The American Society of Clinical Oncology guidelines endorse the use of adjuvant abemaciclib for node-positive patients with a high risk for recurrence, based on the monarchE trial population.7
Results from the MONALEESA-2 trial (ClinicalTrials.gov identifier: NCT01958021) suggest ribociclib may significantly improve overall survival in patients with HR+/HER2− breast cancer, and patients receiving ribociclib experienced 12.5 months longer median survival than did patients receiving placebo.8
For patients with HR+/HER2− breast cancer, abemaciclib and ribociclib offer promising treatment options for those with the highest risk for recurrence. Ongoing research aims to further identify the specific patient subgroups who benefit most from this treatment approach.
Ursa Brown-Glaberman, MD, is a practicing board-certified oncologist at the University of New Mexico Cancer Comprehensive Center in Albuquerque, where she holds the position of associate professor in the Department of Internal Medicine, Division of Hematology/Oncology. Dr Brown-Glaberman leads the Breast Clinical Working Group and serves as the medical director for the Clinical Research Office. In this article, Dr Brown-Glaberman presents an insightful exploration of emerging research on adjuvant therapy in early breast cancer. She sheds light on the efficacy of these therapies in reducing the risk for recurrence in HR+/HER2− early breast cancer cases.

How does the use of CDK4/6 inhibitors as an adjuvant therapy to reduce recurrence risk in HR+/HER2 early breast cancer differ from their use in advanced metastatic breast cancer? Can you elaborate on any specific challenges or considerations when incorporating this drug class into an adjuvant setting?

There is currently only 1 approved CDK4/6 inhibitor, abemaciclib, for use in the adjuvant setting.9 Another inhibitor, ribociclib, is expected to receive approval soon. Unlike in the metastatic setting, where these drugs are taken for as long as they effectively control the cancer, they are taken for a specified duration in the adjuvant setting (2 years for abemaciclib and 3 years for ribociclib). Additionally, the dose of ribociclib that was used in the adjuvant setting is lower than the dose that is currently approved for use in the metastatic setting.10,11
When considering the use of this drug class in the adjuvant setting, it is crucial to take into account the individual patient’s overall risk for breast cancer recurrence, their other medical conditions, their tolerance for side effects, and their likelihood of compliance. It is also important to note that all adjuvant CDK4/6 inhibitors are used in combination with endocrine therapy, which serves as the backbone and the most critical component of treatment. I view the CDK4/6 inhibitors as complementary to this backbone.
When discussing treatment options with a patient, it is vital to guide them through the decision-making process and provide ongoing support once treatment begins. The worst-case scenario is that a patient feels overwhelmed and unsupported, leading them to discontinue all adjuvant therapy.

It is also important to note that all adjuvant CDK4/6 inhibitors are used in combination with endocrine therapy, which serves as the backbone and the most critical component of treatment. I view the CDK4/6 inhibitors as complementary to this backbone.

In 1 study, researchers mention that ribociclib is currently the only CDK4/6 inhibitor approved in combination with fulvestrant for the treatment of premenopausal, perimenopausal, and postmenopausal women with HR+/HER2 advanced or metastatic breast cancer.12 Are there any specific response-related differences to ribociclib that a patient may experience, dependent on their current stage of menopause?

Each CDK4/6 inhibitor presents a slightly different side-effect profile. With ribociclib, it is important to monitor a patient’s blood cell count, fatigue, QT, and liver function. Side effects can occur regardless of menopausal status, but overall, ribociclib is well tolerated.12 In the treatment of advanced or metastatic breast cancer, CDK4/6 inhibitors are always used in combination with endocrine therapy. Hot flashes, night sweats, and vaginal dryness are all side effects of hormone therapies, and premenopausal women may experience disruption of their menstrual cycle.13

Routine testing for patients receiving ribociclib
Patients on ribociclib should be monitored for blood cell count, QT, liver function, and fatigue.

In a 2021 study, researchers discussed at length the differences between CDK4/6 inhibitors in terms of target specificity, dosing schedules, central nervous system (CNS) penetration, and toxicity.14 How might these factors impact treatment strategies among clinicians deciding whether to initiate their patient on palbociclib, ribociclib, or abemaciclib?

Clinicians are increasingly recognizing subtle differences among these 3 medications and making prescribing decisions based on the individual patient they are treating. Sometimes, the choice comes down to the preference and experience of the physician. There is some evidence of an overall survival advantage with ribociclib. However, it is important to note that ribociclib has unique side effects, such as QTc prolongation; therefore, if a patient has a prolonged QTc unrelated to cancer at baseline, ribociclib may not be the initial choice.14
On the other hand, abemaciclib is associated with a higher incidence of diarrhea.
In patients with a significant burden of gastrointestinal symptoms at baseline, it may not be the most suitable choice. However, there are data suggesting that abemaciclib may have better penetration in the CNS.14 Although this is still an area of ongoing research, abemaciclib may be a favorable option for women with known brain metastasis. As the first available CDK4/6 inhibitor, physicians have gained considerable experience with palbociclib compared with the other 2 medications. Palbociclib is known for its excellent tolerability and is often chosen as the initial treatment for older patients.15

Treatment strategies tested in the phase 3 NATALEE trial (ClinicalTrials.gov identifier: NCT03701334) added ribociclib to endocrine therapy in patients with HR+/HER2 early breast cancer. Patients who received ribociclib in combination with standard-of-care endocrine therapy achieved an invasive disease-free survival rate of 90.4%, compared with 87.1% among patients treated with endocrine therapy alone.10 Could you provide details on the efficacy and safety data for ribociclib in this setting and how they compare with other approved treatments?

While the results of the NATALEE trial are undeniably exciting and encouraging, it is premature to draw definitive conclusions about the efficacy of ribociclib in the adjuvant setting, as it has not yet received approval for this indication. Therefore, it is imperative that we observe the long-term outcomes of these patients before making any decisions regarding its usage.
That being said, the initial findings from the NATALEE trial are highly promising. Notably, the dosage of ribociclib used in this trial is lower than the initial dosage employed in the metastatic setting, with a daily intake of 400 mg compared with 600 mg, and overall side effects were minimal.10,11
Regarding its efficacy, the preliminary results suggest that ribociclib is at least as effective as abemaciclib at the same stage of evaluation.14 It is important, however, to exercise caution and await further data to establish a more conclusive assessment.

Considering the evolving landscape of adjuvant therapy for early breast cancer, what are some of the challenges and opportunities in incorporating CDK4/6 inhibitors into standard treatment regimens? Can you expound upon some factors that might guide treatment decisions for individual patients?

The availability of adjuvant CDK4/6 inhibitors has revolutionized the treatment of early-stage breast cancer. This breakthrough offers immense potential to positively impact the lives of millions of women. It is important to note that no medication is without side effects. Therefore, close monitoring, including regular lab tests, is crucial when using these drugs. By the time women begin endocrine therapy, they have often undergone extensive treatment, including surgery, chemotherapy, and radiation. Many may feel overwhelmed by the prospect of adding more medications to their regimen. Therefore, it is paramount that physicians provide diligent monitoring and ample support to help women initiate and adhere to adjuvant CDK4/6 inhibitor treatment.
In my practice, I typically commence with backbone endocrine therapy and then introduce the adjuvant CDK4/6 inhibitor once tolerance is established. Once the appropriate dose is determined and side effects are managed, the majority of women can successfully complete the full 2 to 3 years of CDK4/6 inhibitor treatment. In addition to stage, other pre-existing medical conditions and baseline symptoms play a crucial role in guiding treatment decisions.

Considering the relatively significant side effects associated with abemaciclib and its potential impact on patients’ quality of life during adjuvant treatment,14 what strategies can be implemented to optimize patient-reported outcome assessments and ensure a comprehensive understanding of the treatment’s tolerability and impact on quality of life within the first 3 months and beyond? How can the findings from these assessments influence treatment decision-making and patient counseling regarding adjuvant therapy options?

Diarrhea is a significant side effect associated with abemaciclib,14 typically occurring early in treatment and improving over time. Simple medications, such as loperamide, can effectively manage this issue.16 Before initiating abemaciclib, women should be informed about this potential risk and the planned management approach. Regular monitoring of side effects, particularly in the early stages, is crucial, with the medical oncologist playing a key role, supported by the breast cancer team, including advanced practice providers, pharmacists, clinic nurses, and nurse navigators. Ribociclib, when approved for adjuvant use, has fewer gastrointestinal side effects and may be considered as an alternative for patients experiencing intolerable side effects, despite optimal support from the medical team.14

This Q&A was edited for clarity and length.


Ursa Brown-Glaberman, MD, reported affiliations with Sanofi-Aventis US, LLC; Gilead Sciences, Inc; Menarini Group; Criterium, Inc; and Seagen, Inc.


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Reviewed September 2023