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Applying CDK46i in EBC
Applying CDK4/6 Inhibitors in High-Risk Early HR+/HER2- Breast Cancer: A Case-Based Discussion

Released: November 06, 2025

Elizabeth Diaz
Elizabeth Diaz, PA-C
Julia LaBarbera
Julia LaBarbera, MSN, RN, AGACNP-BC
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Key Takeaways
  • Adjuvant abemaciclib and ribociclib have both shown durable reductions in risk of HR-positive/HER2-negative breast cancer relapse, with abemaciclib also showing a significant improvement in overall survival.
  • Dose reductions of adjuvant CDK4/6 inhibitors do not appear to diminish efficacy.
  • Routinely asking patients how they are coping, both physically and emotionally, and addressing their needs is important to maintain CDK4/6 inhibitor adherence and to obtain full benefit.

In this commentary, we use a case study to illustrate our considerations and management of a patient with high-risk early-stage hormone receptor (HR)–positive/HER2-negative breast cancer using adjuvant CDK4/6 inhibitor therapy.

Elizabeth Diaz, PA-C:
Sally’s case is a great example of how we approach decision-making for patients with high-risk, HR-positive, HER2-negative early breast cancer. She is a 58-year-old woman who underwent a right mastectomy for stage III disease, followed by adjuvant docetaxel and cyclophosphamide for 6 cycles and radiation therapy. Now she’s sitting in front of us to discuss adjuvant endocrine therapy and whether to add a CDK4/6 inhibitor. Sally has hypertension that is controlled with hydrochlorothiazide and verapamil—a strong CYP3A inhibitor—and a mild baseline neutropenia with an absolute neutrophil count of 1.3. Her case illustrates the type of nuanced clinical reasoning we face in daily practice where guideline recommendations meet real-world complexity.

When we talk about “high-risk” early breast cancer, we are referring to a combination of clinicopathologic and molecular features that together predict a greater likelihood of recurrence following definitive treatment. These features include larger tumor size, nodal involvement, and high-grade histology, as well as biologic markers such as elevated Ki-67, which signals high proliferation. In addition, low estrogen or progesterone receptor expression and certain genomic alterations can drive aggressive behavior. The definitions of high risk also differ slightly between the clinical trials that have shaped our current use of CDK4/6 inhibitors in the adjuvant setting.

In the monarchE trial, abemaciclib combined with endocrine therapy was studied in patients who had either 4 or more positive axillary nodes or at least 1 positive node plus another high-risk feature such as tumor size greater than 5 cm, grade 3 disease, or high Ki-67. In contrast, the NATALEE trial that evaluated ribociclib plus endocrine therapy used broader inclusion criteria, allowing even some node-negative patients with high genomic or pathologic risk scores. This difference makes NATALEE particularly relevant to a wider range of early-stage patients.

The results of these studies have been practice changing. In monarchE, adding 2 years of abemaciclib to endocrine therapy reduced the risk of recurrence by approximately 30% after 5 years of follow-up, and the updated results recently presented at the 2025 ESMO Congress showed not only a sustained invasive disease–free survival benefit with nearly 6.5 years of follow-up but also, of importance, a statistically significant improvement in overall survival with approximately 16% reduction in the risk of death compared with endocrine therapy alone. That’s the first time we have seen a clear survival advantage with adjuvant CDK4/6 inhibition. Meanwhile, the latest NATALEE data also presented at the 2025 ESMO Congress confirmed a durable invasive disease–free survival benefit with a reduced the risk of recurrence of approximately 30% with ribociclib at 5 years of follow-up, extending across a broader risk spectrum, although overall survival data for that trial are still maturing. These 2 studies together demonstrate that CDK4/6 inhibitors can substantially alter long-term outcomes when used early in the treatment course.

Julia LaBarbera, MSN, RN, AGACNP-BC:
When I meet a patient like Sally, I think through both the evidence and the patient-specific factors that might steer us toward one CDK4/6 inhibitor over another. Both ribociclib and abemaciclib are now approved for high-risk, early-stage HR-positive/HER2-negative disease, but each comes with a unique safety profile and set of practical considerations. For ribociclib, the main issues we watch for are hepatotoxicity and QT prolongation, whereas for abemaciclib the most common concern is gastrointestinal toxicity, particularly diarrhea.

In Sally’s situation, her mild neutropenia and the fact that she’s taking verapamil—an established CYP3A inhibitor—raise immediate red flags. Verapamil can increase plasma concentrations of ribociclib, potentially heightening cardiac risk, including QT prolongation. Because of that, ribociclib wouldn’t be my choice as the best option for her. Abemaciclib, on the other hand, tends to cause less neutropenia and doesn’t carry the same cardiac cautions, so in this case, I think that it’s a more appropriate choice. Still, before prescribing, I would reach out to Sally’s cardiologist to discuss whether there’s a reasonable alternative to verapamil for her hypertension. That interprofessional coordination is critical because we want to manage comorbidities without compromising the efficacy or safety of cancer therapy.

Elizabeth Diaz, PA-C:
That’s an important point. Sometimes what makes a treatment “right” isn’t just its efficacy data but how well it fits into the patient’s overall clinical picture. Once we’ve settled on abemaciclib, patient education becomes the next crucial step. Before starting therapy, I spend time explaining what the drug does and what to expect in the first few weeks. Patients often do well, but the first couple of months can be rough if they’re not prepared. I talk about possible gastrointestinal side effects, fatigue, and the need for regular lab monitoring. I make sure they have loperamide on hand and that they understand how and when to use it. I also emphasize hydration, small frequent meals, and calling our office at the first sign of trouble. Early communication is everything; if we know what’s happening, we can intervene before problems escalate.

Julia LaBarbera, MSN, RN, AGACNP-BC:
Absolutely. I tell my patients that most side effects, if they’re going to occur, happen early and then often improve. I also reassure them that dose adjustments are part of good care, not a sign of failure. We check labs regularly—typically every 2 weeks for the first couple of months—and I like to schedule early follow-up visits, even if they’re virtual, to keep the lines of communication open. Patients are often relieved to know that we expect some bumps along the road and that we have strategies ready to help them manage.

Elizabeth Diaz, PA-C:
So, 2 months into treatment, Sally calls to report that she’s having 7 or 8 loose stools a day. Her appetite and weight are stable, but she’s fatigued and struggling to work. This pattern immediately raises concern for grade 3 diarrhea. Our first step is to have her stop abemaciclib temporarily until the diarrhea resolves to grade 1 or better. She should maintain hydration and use antidiarrheals aggressively. Once symptoms settle, we’ll restart abemaciclib at the next lower dose. This approach is supported by both clinical trial experience and current guidelines. The goal is to control symptoms and keep her on treatment, not to abandon therapy at the first sign of toxicity.

Julia LaBarbera, MSN, RN, AGACNP-BC:
That’s exactly right. Managing abemaciclib-induced diarrhea really depends on severity. For grade 1 (fewer than 4 stools above baseline) we just continue treatment with supportive care. For grade 2 (4-6 stools above baseline) we hold treatment if it lasts more than a day and resume once it improves. Persistent or recurrent grade 2 diarrhea calls for a dose reduction. For grade 3, as in Sally’s case, we always hold the drug until resolution and then restart at a reduced dose. I remind patients that diarrhea is a very common and manageable side effect and that we’ll work through it together. The worst thing they can do is try to tough it out without telling us.

I also point out that dose reductions of the CDK4/6 inhibitors did not appear to diminish efficacy in either the monarchE or NATALEE trials. That’s reassuring for both healthcare professionals and patients. What really affects outcomes is staying on therapy long term. Of interest, data show that most discontinuations due to side effects occur in the first 5 months of treatment, which tells us that early support and symptom management are key to keeping patients engaged.

There’s also emerging data from the TRADE trial looking at a gradual dose-escalation approach with abemaciclib. Patients started at 50 mg twice daily and increased the dose every 2 weeks to the full 150 mg twice daily. Approximately 70% of patients reached and maintained the full dose, with fewer discontinuations overall compared with what was seen in monarchE. I think that this is an intriguing strategy, particularly for older or more fragile patients, as it gives the body time to adjust to treatment.

Elizabeth Diaz, PA-C:
Once Sally’s diarrhea resolved and she restarted at the reduced dose, her symptoms remained manageable, and she was able to continue therapy successfully. That’s a great outcome, but it’s also a reminder that our job doesn’t stop at managing acute side effects. Maintaining adherence and ensuring that patients feel supported throughout the course of therapy are just as important.

Many factors can influence adherence: side effects, complexity of the regimen, cost, even the patient’s perception of benefit. Some patients struggle to appreciate the preventive intent of adjuvant therapy because they don’t have symptomatic disease and they feel fine overall, which can make them less motivated. Practical barriers, such as transportation or pharmacy delays, can also erode consistency. To counter that, we use a mix of strategies: pill organizers, medication calendars, phone alarms, and follow-up reminders. We encourage patients to take their medication at the same time every day and to build it into a daily routine.

Julia LaBarbera, MSN, RN, AGACNP-BC:
I agree. I also find that involving family members or caregivers can make a big difference. Having a support person who understands the treatment plan helps ensure that doses aren’t missed and that new symptoms are reported early. At our center, we rely heavily on nurse navigators and pharmacists who reinforce education and help troubleshoot access or insurance issues. We also encourage patients to use our electronic communication system to message us directly if they have concerns. It empowers them to take an active role in their care, and it helps us catch issues before they become serious.

Ongoing satisfaction with treatment is another aspect we can’t ignore. I routinely ask my patients how they’re coping, not just physically but emotionally. Adherence is closely tied to how supported a patient feels. If someone is frustrated, anxious, or financially stressed, that can easily translate into missed doses or skipped appointments. Part of our role is to assess those barriers regularly and connect patients with the right resources, whether that’s social work, financial counseling, or mental health support.

Elizabeth Diaz, PA-C:
Exactly. I often remind colleagues that adherence is a shared responsibility. We can’t assume that a prescription equals compliance. Every patient has a story behind how they take—or don’t take—their medication. Taking the time to listen, to ask open-ended questions, and to provide practical tools can make all the difference.

To wrap up, I want to highlight 2 resources that our readers might find helpful. The first is an interactive tool for managing adverse events with CDK4/6 inhibitors, which allows healthcare professionals to input patient information including the specific CDK4/6 inhibitor and type and severity of an adverse event and receive tailored recommendations for managing toxicities. This interactive tool is evidence based with expert insights and is perfect for quick consultation during a busy clinic day. The second is a 2-page handout that gives patients clear, concise information about what to expect during CDK4/6 inhibitor treatment, how to recognize potential side effects, and when to contact the care team.

Julia LaBarbera, MSN, RN, AGACNP-BC:
Those tools are helpful for bridging the gap between education and real-world practice. At the end of the day, success with CDK4/6 inhibition in early breast cancer isn’t just about selecting the right drug—it’s about building a partnership with our patients that allows them to stay on therapy long enough to realize its full benefit. Sally’s case illustrates beautifully that with individualized care, proactive management, and open communication, we can help our patients not just start these treatments but thrive on them.

Your Thoughts
Tell us about your experiences caring for patients with high-risk HR-positive/HER2-negative early breast cancer. Are there other things that your team does to help these patients stay on track with their treatment plan? Let us know in the comments.

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How often do you recommend switching from one adjuvant CDK4/6 inhibitor to the alternative in patients experiencing significant side effects rather than a dose reduction approach?

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