What to Know About CDK4/6 Inhibitors as Breast Cancer Treatment: Weighing the Risks vs. Benefits

Dr. Eleonora Teplinsky, a medical oncologist specializing in breast and gynecologic cancer at Valley Health System, tells SurvivorNet that it’s important for patients to understand, when making treatment decisions, that these drugs may have slightly different side effect profiles and a discussion on the risks vs. benefits for each individual patient is critical.

“There’s going to be different situations where we might want to use one drug versus the other,” Dr. Teplinsky explains.

What are CDK4/6 Inhibitors?

CDK4/6 inhibitors are a class of medicines used to treat certain types of hormone receptor-positive, HER2-negative breast cancer. These medicines interrupt the process through which breast cancer cells divide and multiply. They target specific proteins known as the cyclin-dependent kinases 4 and 6, abbreviated as CDK4/6, which are crucial in cell division and growth. Therefore, they are often referred to as targeted therapies.

If a breast cancer is hormone receptor-positive, it means the cancer’s growth is fueled by the hormones estrogen, progesterone, or both. HER2-negative cancers have tested negative for a protein called human epidermal growth factor receptor 2, or HER2, which promotes cancer cell growth. So HER2-negative cancers don’t respond to treatments that target the HER2 protein (such as Herceptin). More than two out of every three breast cancers are both hormone receptor-positive and HER2-negative.

How Do CDK4/6 Inhibitors Work?

The CDK4/6 proteins, found in both healthy cells and cancer cells, control how quickly cells grow and divide. In breast cancer, these proteins can become overactive and cause the cells to grow and divide uncontrollably. CDK4/6 inhibitors interrupt these proteins to slow or even stop the cancer cells from growing.

Currently, there are three CDK4/6 inhibitors used to treat breast cancer:

• Ibrance (chemical name: palbociclib)
• Kisqali (chemical name: ribociclib)
• Verzenio (chemical name: abemaciclib)

All three CDK4/6 inhibitors are pills taken by mouth, but they are used a little bit differently. Verzenio is a pill that you take every day, either alone or with other treatments. It appears to affect the CDK4 protein more than the CDK6 protein.

Ibrance and Kisqali affect both CDK4 and CDK6 and have to be taken along with hormonal therapy. They are also given in four-week cycles that include a week-long break — so you would take the medicine for three weeks and then take one week off.

Choosing a CDK4/6 Inhibitor: Which One is Right for You?

Ibrance, Kisqali, and Verzenio have not been directly compared to each other in a clinical trial. Still, doctors consider them to work equally well. Your treatment team can help you decide which one is right for your situation. This may depend on factors such as:

• The stage of the breast cancer (early or advanced)
• Treatments you have had in the past, if any
• How quickly the cancer grew after previous treatment
• If you are a woman, whether you are pre-menopausal or post-menopausal
• The side effects associated with each CDK4/6 inhibitor
• Whether you or your treatment team prefer that you take medicine continuously, as you would with Verzenio, or on a three-week on/one-week off cycle (Ibrance and Kisqali)
• Whether your health insurance favors one of the medications over the others

Each CDK4/6 inhibitor is approved by the U.S. Food and Drug Administration (FDA) to treat certain stages of hormone receptor-positive HER2-negative breast cancer in different groups of people. Keep in mind that these approvals are likely to change over time, as clinical trials are still ongoing to determine if CDK4/6 inhibitors can benefit additional groups.

Dr. Teplinsky tells SurvivorNet that the future of CDK4/6 inhibitors likely involves more approvals.

“In terms of the space of CDK4/6 inhibitors in early stage breast cancer, we’re talking stage one through three because these drugs are all approved in the metastatic setting. But for stage one through three, abemaciclib is approved by the FDA. But ribociclib is not yet approved by the FDA.”

“We do have robust data and ASCO just put out a rapid guideline update that does offer ribociclib as a potential option.

“I think that when we talk to patients, it’s important to tell them this and it’s important to have this conversation. This is not yet FDA approved, here are the risks of the medication. And I will say that between the two CDK4/6 inhibitors inhibitors, they have slightly different side effect profiles. Verzenio (abemaciclib), for example, causes more diarrhea. Ribociclib requires cardiovascular monitoring for the first few doses. So there’s going to be different [recommendations] based on a person’s medical condition, side effects.”

Common Side Effects of CDK4/6 Inhibitors

“I think it’s really important to say, ‘Look, we have this new medication, here are the benefits, here are the side effects,” Dr. Teplinsky adds. “Then really work through each individual patient about whether it’s something that is going to be right for them.”

Potential side effects include:

• Neutropenia, which is a low count of a type of white blood cell called neutrophils, which helps fight certain infections
• Nausea or vomiting
• Fatigue
• Diarrhea or upset stomach
• Alopecia, a type of hair loss
• Headache
• Constipation
• Rash
• Cough

“[Verzenio] is not the easiest drug in the world to take. Diarrhea is the big one, but fatigue, joint pain and low blood counts also. But we know that you can safely reduce the [dosage of the] medication without sacrificing efficacy. And that’s very important,” adds Dr. Teplinsky.

Managing Side Effects

Managing the side effects of CDK4/6 inhibitors is crucial for maintaining quality of life during treatment. Here are some strategies that can help:

• Regular Monitoring: Regular blood tests and liver function tests are essential to monitor the body’s response to CDK4/6 inhibitors. These tests help catch any potential issues early, allowing for prompt management.
• Diet and Hydration: Maintaining a healthy diet and staying hydrated can help manage common side effects such as nausea and diarrhea. Small, frequent meals and avoiding spicy or greasy foods may reduce gastrointestinal discomfort.
• Medication Adjustments: If side effects become too challenging, your doctor may adjust the dosage or switch you to a different CDK4/6 inhibitor. Open communication with your healthcare team is vital to finding the right balance.
• Supportive Medications: Medications like anti-diarrheal drugs, anti-nausea medications, and supplements to boost white blood cell counts can help manage side effects and maintain treatment efficacy.
• Physical Activity: Gentle exercise, such as walking or yoga, can help manage fatigue and improve overall well-being. Tailor your activity level to what feels comfortable for you.
• Emotional Support: Speaking with a counselor or joining a support group can provide emotional support and practical advice for managing side effects and navigating treatment.

In Early Breast Cancer: How Does Kisqali Help Prevent Recurrence?

According to the new study, adding Kisqali for women with earlier stage disease can improve outcomes: it reduced the risk of progression or death by about 25%. However, this may not be quite as significant as it seems for all patients.

“What that translates into, is that about 93% of patients who received ribociclib and regular endocrine therapy were alive without recurrence or death compared to about 90% of patients who received regular endocrine therapy alone,” explains Dr. Teplinsky.

“It’s all in the nuances and in the details. Because a lot of the big headlines are going to read new drug reduces risk of recurrence by 25%, right? And that’s true, it’s a relative risk reduction. But people seeing that are going to say, ‘wow, this is great.’

“Then you translate that into an absolute gain, only about 3% [will have] benefit. Meaning that out of a hundred women, three more will not experience disease recurrence or death or progression. I will have some patients that say to me, I will do everything to not experience a recurrence. So for me, that 3% is worth it. And other women will say, I appreciate that benefit, but I don’t want to risk the toxicity. Or they’ve tried it and they’ve experienced toxicity and they want to stop. And so that’s where it’s that individual shared decision making as well,” Dr. Teplinsky explains.

Coping with a Breast Cancer Diagnosis

Receiving a breast cancer diagnosis is undoubtedly one of the most challenging moments in a person’s life. It’s essential to remember that you are not alone. Many resources and support systems are available to help you cope with this diagnosis and navigate your treatment journey.

Here is some practical guidance on how to move forward from SurvivorNet’s experts:

• Seek Support: Reach out to support groups, both in-person and online. Connecting with others who are going through similar experiences can provide comfort and practical advice.
• Communicate with Your Healthcare Team: Your doctors, nurses, and other healthcare professionals are there to help you. Don’t hesitate to ask questions, express your concerns, and discuss your treatment options. Understanding your treatment plan can empower you and alleviate some of your anxiety.
• Take Care of Your Mental Health: Coping with cancer is not just a physical battle but an emotional one as well. Consider speaking with a counselor or therapist who specializes in cancer care. Practices such as mindfulness, meditation, and gentle exercise can also help manage stress and improve your overall well-being.
• Educate Yourself: Knowledge is power. Educate yourself about your specific type of breast cancer and the treatments available. Reliable sources of information can include your healthcare team, reputable cancer organizations, and medical literature.
• Lean on Loved Ones: Your family and friends want to support you. Let them know how they can help, whether it’s accompanying you to appointments, helping with daily tasks, or simply being there to listen.

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