Treatment strategies for hormone receptor (HR)-positive, HER2-negative breast cancer are rapidly evolving, influenced by pivotal trials such as KEYNOTE-756, monarchE, and NATALEE. These studies are impacting how clinicians approach adjuvant therapy and the integration of novel agents like CDK4/6 inhibitors and immunotherapy.
Immunotherapy in HR-positive, HER2-negative Breast Cancer: The KEYNOTE-756 Trial
The KEYNOTE-756 trial investigated the addition of immunotherapy to neoadjuvant chemotherapy in high-risk HR-positive, HER2-negative breast cancer patients, defined as having a grade 3 tumor. The study demonstrated an improvement in pathologic complete response (PCR) rates, with approximately 24% in the immunotherapy arm compared to 13% in the chemotherapy-only arm. However, event-free survival data is still pending, which is critical to determining the long-term benefit of this approach.
"Even though there has been a clear improvement in PCR favoring immunotherapy, I don't yet know whether or not the administration of immunotherapy decreases the likelihood that the patient in front of me would actually have a recurrence of their breast cancer," explains Dr. Erin Cobain, associate professor at the University of Michigan Rogel Cancer Center.
A significant consideration is the use of adjuvant endocrine therapy in HR-positive disease, which may rescue patients with residual disease post-neoadjuvant treatment. Additionally, the KEYNOTE-756 trial design included adjuvant immunotherapy, which may complicate the interpretation of results given the current landscape of adjuvant CDK4/6 inhibitors.
CDK4/6 Inhibitors in the Adjuvant Setting: monarchE and NATALEE Trials
The monarchE trial led to the approval of adjuvant abemaciclib for high-risk HR-positive, HER2-negative early-stage breast cancer. Patients in monarchE had four or more involved axillary lymph nodes or one to three nodes with additional high-risk features like a T3 tumor or grade 3 tumor. Four-year follow-up data showed a 6% absolute difference in invasive disease-free survival favoring abemaciclib plus endocrine therapy.
Recently, the FDA approved ribociclib based on the NATALEE trial, which included a broader patient population, including those with any lymph node involvement or even node-negative disease with other high-risk features. A key difference between the trials is the duration of CDK4/6 inhibitor therapy: two years for abemaciclib in monarchE versus three years for ribociclib in NATALEE.
Navigating Treatment Decisions with CDK4/6 Inhibitors
The availability of both abemaciclib and ribociclib has broadened the treatment options for HR-positive, HER2-negative breast cancer. However, it also presents challenges in selecting the most appropriate agent for individual patients. Factors to consider include side effect profiles (particularly diarrhea with abemaciclib), treatment duration, and individual risk factors.
"I think that the most challenging discussions are with patients who are eligible for both drugs... We have to have a conversation about differences in side effect profiles as well as differences in the duration of therapy," notes Dr. Cobain. For lower-risk patients eligible only for ribociclib, the decision involves weighing the potential benefits against the toxicity of additional therapy, given their generally favorable prognosis.
Longer-term follow-up data from both the NATALEE and monarchE trials are anticipated to further refine treatment strategies and inform clinical decision-making in the adjuvant setting for HR-positive, HER2-negative breast cancer.
