What Are CDK4/6 Inhibitors?
CDK4/6 inhibitors, such as abemaciclib and ribociclib, are changing breast cancer treatment for HR+/HER2- early-stage patients. Specifically, these drugs target a key cell growth pathway to tackle hormone therapy resistance, a major issue in high-risk cases. For example, Dr. Austin Williams, a breast surgeon at Fox Chase Cancer Center, explains in a recent interview that these drugs work inside cells to boost treatment success.
How Do These Drugs Work?
In simple terms, CDK4/6 inhibitors stop a protein complex that drives cell growth, halting tumor cells in their tracks. As a result, they prevent cancer from spreading, especially when hormone therapy alone fails due to changes in the hormone receptor pathway. Consequently, drugs like abemaciclib and ribociclib make hormone therapy more effective, lowering the chance of cancer returning.
monarchE Trial: Abemaciclib
The monarchE trial tested abemaciclib with hormone therapy in high-risk HR+/HER2- early breast cancer patients. Notably, high-risk patients were those with:
- 4 or more positive lymph nodes, or
- 1–3 positive nodes with risk factors like larger tumors, higher grade, or elevated Ki-67 levels.
Key Results:
- Greatly improved invasive disease-free survival (IDFS), meaning patients stayed cancer-free longer.
- No overall survival (OS) benefit yet, because the data are still developing (31-month follow-up).
- Approved by the FDA in October 2021; later, the Ki-67 requirement was dropped, so more patients qualify.
Importantly, studies, including one by Dr. Williams, show that lymph node surgery (ALND) shouldn’t be done just to qualify for abemaciclib, as it offers little benefit in this case.
NATALEE Trial: Ribociclib
Meanwhile, the NATALEE trial studied ribociclib with hormone therapy in stage II–III HR+/HER2- breast cancer, using broader high-risk criteria:
- Stage IIA with at least 1 positive node, or
- No positive nodes but with grade 2 disease, high Ki-67, or high genetic risk.
Key Results:
- Improved IDFS, similar to monarchE.
- Shorter follow-up than monarchE, so no OS benefit yet.
- FDA approval in September 2024, allowing treatment for a wider group.
As a result, NATALEE’s broader criteria reduce the need for extra surgeries like ALND, making treatment decisions easier.
monarchE vs. NATALEE: What’s Different?
Although both trials show IDFS benefits, they differ in key ways:
- Patient Groups: monarchE had stricter high-risk rules, while NATALEE included earlier-stage patients with fewer nodes affected.
- Treatment Time: Abemaciclib lasted 2 years; ribociclib, 3 years.
- Follow-Up: monarchE has longer data, but both trials need more time for OS results.
Therefore, these differences help doctors choose the best treatment for each patient.
Why Did Palbociclib Fail?
In contrast, palbociclib, tested in PALLAS and PENELOPE-B trials, didn’t improve IDFS or OS in early breast cancer. Reasons include:
- Trials didn’t focus enough on high-risk patients.
- Treatment was shorter (1 year in PENELOPE-B vs. 2–3 years in monarchE/NATALEE).
Thus, palbociclib isn’t approved for early breast cancer.
The Future of CDK4/6 Inhibitors
Looking ahead, Dr. Williams highlights new research:
- Before Surgery: Testing these drugs before surgery to shrink tumors in HR+/HER2- cancers.
- Combined Treatments: Trials like monarchHER pair CDK4/6 inhibitors with HER2 drugs, while others explore adding immunotherapy.
In short, these studies aim to make breast cancer treatment more tailored and effective.
What Surgeons Should Know
For surgeons, key points include:
- Don’t perform ALND just to qualify patients for these drugs.
- Work with oncologists to identify high-risk patients using trial criteria.
- Keep up with new uses, like before-surgery treatments.
Conclusion
In summary, CDK4/6 inhibitors like abemaciclib and ribociclib are advancing breast cancer treatment by fighting hormone therapy resistance in HR+/HER2- cases. The monarchE and NATALEE trials show they keep cancer at bay longer, and future research will expand their role. Stay informed to help patients get the best care.
Related Links:
https://www.breastsurgeons.org