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Celebrating Women Chair in Breast Cancer Research
Director, Breast Cancer Research Program
Baylor University Medical Center
US Oncology Network
Joyce O’Shaughnessy, MD: consultant/advisor/speaker: AbbVie, Agendia, Amgen Biotechnology, Aptitude Health, AstraZeneca, Athenex, Bayer, Bristol-Myers Squibb, Carrick Therapeutics, Celgene, Daiichi Sankyo, Eisai, G1 Therapeutics, Genentech, Genzyme, Gilead Sciences, GRAIL, Halozyme Therapeutics, Heron Therapeutics, Immunomedics, Ipsen Biopharmaceuticals, Lilly, Merck, Myriad, Nektar Therapeutics, Novartis, Ontada, Pfizer, Pharmacyclics, Pierre Fabre, Prime Oncology, Puma Biotechnology, Roche, Samsung Bioepis, Sandoz, Sanofi, Seagen, Syndax, Synthon, Taiho Oncology, Takeda.
Several therapies are available for patients with hormone receptor (HR)-positive/HER2‑negative early breast cancer (EBC) who are at high risk of recurrence, including adjuvant abemaciclib or olaparib. But questions remain about how to best identify which patients are at greatest risk of recurrence and, once identified, the optimal therapeutic approach to minimize the risk of recurrence.
Patients who have endocrine therapy (ET) resistance early in the course of their disease are at higher risk of recurrence. These patients frequently receive adjuvant chemotherapy, then adjuvant ET, but they are at risk for recurrence in the first 5-8 years with more highly proliferative, genomically unstable, luminal B breast cancer, for which ET resistance is a key feature. Patients with difficulty adhering to ET who prematurely cease therapy also are at higher risk of recurrence. Another group is patients with late disease recurrence, for whom we have less knowledge of risk factors. Fundamentally, we need better strategies for these patients beyond 5-10 years of ET.
Identifying Patients With High‑Risk HR-Positive/HER2‑Negative EBC
Patients at high risk for early recurrence generally have a mixture of high‑risk anatomic and biologic features in their breast cancer and a spike in recurrence risk in the first 2‑4 years that remains elevated, particularly in those who are node positive.
Tools such as the 21-gene recurrence score or the 70-gene signature help identify patients at high risk of recurrence due to genomic features. Patients with high scores on these genomic assessments tend to derive limited benefit from ET and are usually prescribed chemotherapy. High Ki-67 expression, especially a Ki-67 score ≥20%, is another factor that predicts for higher risk of early recurrence.
Patients with grade 3 disease are at higher risk of early recurrence, as are those with progesterone receptor–negative disease. Higher nodal status (≥4 nodes) predicts for a high risk of recurrence but not necessarily an early recurrence.
Adjuvant Abemaciclib Plus ET in High-Risk HR-Positive/HER2-Negative EBC
Several trials have explored the efficacy of 2-3 years of CDK4/6 inhibition plus ET as adjuvant therapy given the success of CDK4/6 inhibitors in HR-positive metastatic disease. The phase III monarchE trial enrolled patients with early-stage estrogen receptor (ER)-positive/HER2-negative breast cancer and node-positive disease. The eligible patient population had to have either ≥4 positive nodes or 1-3 positive nodes and either T3 or T4 breast cancer, grade 3 disease, or a high centrally confirmed Ki-67 score ≥20%. Patients were randomized to receive ET with or without 2 years of adjuvant abemaciclib. ET was continued for 5-10 years per physician’s choice. Premenopausal women received physician’s choice of ovarian suppression, primarily a luteinizing hormone-releasing hormone agonist.
With a median follow-up of 27 months, there was a statistically significant improvement in the 3-year invasive disease–free survival (iDFS) rate in the intention-to-treat population with abemaciclib plus ET vs ET alone. There was a 5.4% lower chance of developing a recurrence or dying of breast cancer with abemaciclib, and abemaciclib improved iDFS regardless of Ki-67 level. The rate of distant relapse-free survival also was improved by 4.2%.
I am optimistic that we are going to see long‑term benefit with the addition of abemaciclib to ET even in patients with ET‑sensitive disease because 60% of patients enrolled on monarchE had ≥4 positive nodes, and among those patients, 55% had low Ki-67 scores. In the group of patients with 4‑9 positive nodes who are at very high risk of recurrence, the hazard ratio for 3-year iDFS was 0.6—a 40% reduction in risk of recurrence. Thus, abemaciclib showed a positive impact both in patients with elevated early risk of recurrence and in patients at later risk of recurrence. Data for overall survival are immature, showing no differences yet between the study arms.
Unfortunately, we did not see the same iDFS benefit in the clinical trials of adjuvant palbociclib (PALLAS and PENELOPE-B), and palbociclib is currently not an option for patients in the adjuvant setting. The results of 3 years of adjuvant ribociclib plus ET from the phase III NATALEE trial (NCT03701334) are eagerly awaited.
Based on the current monarchE data, it is possible that with longer follow-up, not only will abemaciclib favorably impact the iDFS outcome of patients with primary ET‑resistant disease or very high–risk, highly proliferative, genomically unstable, luminal B breast cancer, but—we hope—the iDFS curves also will continue to separate, and we will see a reduction in the risk of late recurrence with the addition of abemaciclib. That remains to be seen, but I am encouraged based on the current results of abemaciclib in patients with low Ki-67 scores.
Abemaciclib is now approved by the FDA in combination with ET (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with HR-positive/HER2-negative, node-positive EBC at high risk of recurrence and a Ki-67 score ≥20% as determined by an FDA-approved test. Both the American Society of Clinical Oncology and National Comprehensive Cancer Network guidelines recommend adjuvant abemaciclib for patients meeting the inclusion criteria of the monarchE trial.
Gaps in Use of Adjuvant Abemaciclib
One of the unanswered questions about the use of adjuvant abemaciclib focuses on whether the benefit can be extended to patients who did not fit the monarchE eligibility criteria. For example, a patient who has 3 positive nodes and other adverse features, such as lymphovascular invasion, but who has T2, grade 2 breast cancer would not have been eligible for the monarchE trial unless her Ki-67 was ≥20%. But if her Ki-67 is 15%, she falls into a gray zone where she is still at high risk, but adjuvant abemaciclib is not indicated. There are other planned or ongoing clinical trials to examine adjuvant abemaciclib in lower‑risk populations, including a comparison with chemotherapy.
Another issue is whether patients can receive adjuvant abemaciclib later post surgery. In monarchE, patients needed to be within 16 months of their breast surgery and have ≤3 months of prior adjuvant ET following their most recent non-ET breast cancer therapy before starting adjuvant abemaciclib. A patient at 1 year beyond surgery would still be eligible for adjuvant abemaciclib, but we do not know if a patient at high-risk who underwent surgery 2 years ago might benefit from abemaciclib.
Olaparib in High-Risk ER-Positive/HER2-Negative EBC With BRCA Mutations
The other option for our high‑risk ER‑positive/HER2‑negative patients is 1 year of the PARP inhibitor olaparib if they harbor a germline BRCA1/2 mutation. The OlympiA trial enrolled patients with ER‑positive/HER2‑negative or triple-negative breast cancer and a germline BRCA1/2 mutation. Additional criteria for enrollment for patients with ER-positive/HER2-negative disease were either ≥4 positive lymph nodes for patients with prior adjuvant chemotherapy or no pathologic complete response and a CPS + EG score ≥3 for those with prior neoadjuvant chemotherapy. Patients were randomized to receive adjuvant olaparib or placebo after ≥6 cycles of neoadjuvant or adjuvant chemotherapy. There was an approximately 8.8% improvement in 3‑year iDFS with olaparib vs placebo in the OlympiA trial.
These are important results for this population of patients. In my practice, I would prioritize olaparib over abemaciclib for patients with a germline BRCA1/2 mutation because the PARP inhibitor is synthetically lethal in the context of germline BRCA mutation.
You can learn more about managing patients with EBC at our symposium titled, “Precision Medicine Advances in Early Breast Cancer: The Role of Biomarkers in Neo/Adjuvant Therapy” at the 2022 San Antonio Breast Cancer Symposium. Register here.
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