Assessing CDK4/6 Inhibitor Use in HR+ Breast Cancer Cases
Key Points
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CDK4/6 inhibitors are a standard treatment for hormone receptor (HR)-positive breast cancer, and abemaciclib and ribociclib have recently been approved in the adjuvant setting.
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Toxicities from CDK4/6 inhibitors can be managed with dose modifications without compromising patient outcomes.
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Comorbidities and drug interactions are major considerations when selecting a CDK4/6 inhibitor in the metastatic setting.
CDK4/6 Inhibitors in Adjuvant or Metastatic Breast Cancer
CDK4/6 inhibitors have been used in the metastatic HR-positive breast cancer setting for years. Recently, abemaciclib and ribociclib were approved in the adjuvant setting based on the monarchE and NATALEE trials, respectively. Medical oncologists, Adam Brufsky, MD, PhD, of UPMC Hillman Cancer Center, and Sara Tolaney, MD, MPH, of Dana-Farber Cancer Institute, joined the Oncology Brothers podcast to discuss two challenging cases of HR-positive breast cancer, focusing on the applications of CDK4/6 inhibitor therapies.
Adjuvant CDK4/6 Inhibitor Treatment for High-Risk Breast Cancer
The panel first considered a 68-year-old postmenopausal woman who presented with palpated axillary lymphadenopathy, after which imaging identified a 2.2 cm left breast mass staged as cT2cN2. Further workup confirmed a diagnosis of estrogen receptor and progesterone receptor (ER/PR)-positive, HER2 IHC 1+, grade 3 invasive ductal carcinoma without genetic mutations. The patient received neoadjuvant dose-dense doxorubicin and cyclophosphamide plus paclitaxel followed by surgery, but showed significant residual disease after surgery and underwent adjuvant radiation.
For this patient, the standard recommendation would be 7 to 10 years of aromatase inhibitor therapy and potentially bisphosphonate therapy, said Dr. Tolaney. When considering additional adjuvant CDK4/6 inhibition, Dr. Tolaney said she would prefer abemaciclib over ribociclib based on the more mature monarchE data if this patient meets the stricter eligibility criteria.
“The length of hormonal therapy, especially in an era of CDK4/6 inhibitors, really is a question that has not been answered,” Dr. Brufsky said. “There is a future where potentially we give people CDK4/6 and endocrine therapy only for a total of both for 5 years… or we somehow, with biomarkers, are able to select the people who really do benefit from the 10 years of endocrine therapy in spite of a CDK4/6.”
The doctors agreed that the adjuvant CDK4/6 inhibitors are more attractive than prior options, such as adjuvant capecitabine, based on the CREATE-X trial. Still, oncologists must be prepared to manage CDK4/6 inhibitor toxicities with dose modifications and supportive care. If a patient experienced significant toxicity with abemaciclib, switching to ribociclib may be an effective strategy, Dr. Brufsky said.
Metastatic Breast Cancer Treatment Selection
The second case described a 54-year-old postmenopausal woman who presented with ongoing back pain, sudden weight loss, and lab indications for hypercalcemia. The patient had a history of hypertension, hyperlipidemia, and diabetes mellitus type II. Imaging revealed a 1.5 cm left breast mass, axillary and mediastinal lymphadenopathy, and multiple bone lesions suggesting metastatic disease. Upon bone biopsy, the patient was diagnosed with ER/PR-positive, HER2 IHC2+, fluorescence in situ-negative stage IV metastatic breast cancer without actionable mutations.
When a patient presents with such advanced disease, there can be an instinct to start chemotherapy immediately; however, several randomized trials, such as RIGHT Choice, have shown that endocrine therapy plus CDK4/6 inhibition can yield better outcomes. While this patient had cardiac risk factors, ribociclib with monitoring could be appropriate if her baseline QTc interval was normal. If the patient was on other drugs that interacted with ribociclib, then abemaciclib might be the best choice, Dr. Tolaney said.
Among the three approved CDK4/6 inhibitors for metastatic disease—palbociclib, ribociclib, and abemaciclib—ribociclib has clear data supporting an overall survival (OS) benefit. While abemaciclib did not technically reach statistical significance for an OS benefit in the MONARCH 3 trial, it showed a “very clinically meaningful” difference of 13 months. Palbociclib has weaker OS data, but this may be due to the less informed designs of earlier trials, and real-world data suggest its benefit may be comparable to that of other CDK4/6 inhibitors, said Dr. Brufsky.
Ultimately, the choice of CDK4/6 inhibitor in the HR-positive metastatic breast cancer setting may hinge less on disease characteristics and more on the patient’s frailty and underlying comorbidities.