Kazuki Nozawa, MD
Question: Based on NATALEE and monarchE data, is there still a need for neoadjuvant chemotherapy in hormone receptor (HR)-positive, HER2-negative early breast cancer?
Answer: In monarchE trial, the CDK4/6 inhibitor abemaciclib combined with endocrine therapy demonstrated long-term efficacy in patients with HR-positive, HER2-negative, early breast cancer at high risk of recurrence.1 Additionally, the U.S. Food and Drug Administration (FDA) has approved the CDK4/6 inhibitor ribociclib for HR-positive, HER2-negative early breast cancer, based on the 4-year outcomes update data of the NATALEE trial, presented at the European Society for Medical Oncology (ESMO) Congress 2024.2
Although the NATALEE trial includes patients with breast cancer who are at a lower risk of recurrence than those in the monarchE trial, this update showed the invasive disease–free survival benefit continued to increase from 2.7% in 3 years to 4.9% in 4 years, showing benefits after the end of 3 years of ribociclib treatment. In this 4-year landmark analysis, ribociclib demonstrated an invasive disease–free survival benefit over endocrine therapy alone by reducing the risk of disease recurrence by 28.5% (hazard ratio = 0.715).
After the positive results of the monarchE and NATALEE trials, the necessity of neoadjuvant chemotherapy is being questioned in HR-positive, HER2-negative early breast cancer. However, in the monarchE trial, 95% of patients had a history of chemotherapy (37% neoadjuvant and 58% adjuvant). In the NATALEE trial, 88% had prior chemotherapy (42% neoadjuvant and 48% adjuvant). Only some cases had prior chemotherapy, and due to limited data, definitive conclusions cannot be made at this time.
Learning From Genomic Profiling
Results of the RxPONDER and TAILORx trials have informed systemic chemotherapy recommendations for HR-positive, HER2-negative early breast cancer. However, few data have proven the efficacy of adding CDK4/6 inhibitors in this patient population, according to OncotypeDX.
Data on genomic and transcriptomic profiling of primary tumors from patients with HR-positive, HER2-negative, node-positive, high-risk early breast cancer in the monarchE trial were presented at the 2023 San Antonio Breast Cancer Symposium. In this study, abemaciclib was effective even in patients with a low-risk score using inferred 21-gene Oncotype-RNA signatures (the 4-year rate of invasive disease–free survival was 90.2%).3 This result indicates we may potentially omit adjuvant chemotherapy in patients with low-risk scores.
More From monarchE and NATALEE
One disadvantage of neoadjuvant chemotherapy is that it can cause tumor shrinkage and the disappearance of axillary lymph node metastases, making accurate staging and evaluation of lymph node involvement challenging. However, a prespecified exploratory analysis in monarchE showed that treatment with adjuvant abemaciclib demonstrated benefit for patients who received neoadjuvant chemotherapy before trial enrollment.4
A subgroup analysis of the NATALEE trial presented at the ESMO Congress 2024 focused on younger patients with breast cancer. Of these patients, 60% had received prior neoadjuvant chemotherapy. The analysis demonstrated that 3 years of adjuvant ribociclib therapy consistently provided benefits in this younger patient population, aligning with the overall trial results. These data showed the benefit of adding CDK4/6 inhibitors even if the patients received neoadjuvant chemotherapy.
What Next?
There is an ongoing study of neoadjuvant endocrine therapy, and it is anticipated that combining ribociclib may allow for the omission of chemotherapy.5 The ongoing WSG ADAPTcycle trial is currently assigning patients with HR-positive, HER2-negative early breast cancer—who have an uncertain benefit from chemotherapy (intermediate risk)—to receive either adjuvant ribociclib plus endocrine therapy or adjuvant chemotherapy followed by endocrine therapy. On the other hand, several ongoing trials combining immune checkpoint inhibitors with chemotherapy may show the benefit of escalation of treatment in patients with HR-positive, HER2-negative early breast cancer.
CheckMate 7FL (ClinicalTrials.gov identifier NCT04109066) is a prospective, randomized, multicenter, double-blind, placebo-controlled trial investigating the benefit of the PD- 1inhibitor nivolumab in combination with neoadjuvant chemotherapy and adjuvant endocrine therapy in patients with high-risk, high-grade estrogen receptor (ER)-positive, HER2-negative early breast cancer. Adding nivolumab to neoadjuvant chemotherapy resulted in a statistically significant improvement in pathologic complete response rate (the primary endpoint) in the overall population; the residual cancer burden 0–1 rate was also improved.
The MK-3475/KEYNOTE-756 trial (NCT03725059) showed that adding the PD-1 inhibitor pembrolizumab to neoadjuvant chemotherapy demonstrated increased pathologic complete response rates vs chemotherapy alone in patients with high-risk, high-grade ER-positive, HER2-negative early breast cancer. The development of oral selective estrogen receptor degraders is also progressing, and advances in endocrine therapy are anticipated. These developments highlight the need for more individualized treatment approaches to contribute to more precise, patient-specific treatment decisions.
DISCLOSURE: Dr. Nozawa has received lecture fees from Daiichi Sankyo, Eli Lilly, and Chugai Pharmaceutical Co.
REFERENCES
1. Rastogi P, O’Shaughnessy J, Martin M, et al: Adjuvant abemaciclib plus endocrine therapy for hormone receptor–positive, human epidermal growth factor receptor 2–negative, high-risk early breast cancer: Results from a preplanned monarchE overall survival interim analysis, including 5-year efficacy outcomes. J Clin Oncol 42:987-993, 2024.
2. Fasching PA, Stroyakovskiy D, Yardley D, et al: Adjuvant ribociclib plus nonsteroidal aromatase inhibitor in patients with HR+/HER2− early breast cancer: 4-Year outcomes from the NATALEE trial. ESMO Congress 2024. Abstract LBA13. Presented September 16, 2024.
3. Turner N, Reis-Filho J, Goetz M, et al: Genomic and transcriptomic profiling of primary tumors from patients with HR+, HER2–, node-positive, high-risk early breast cancer in the monarchE trial. 2023 San Antonio Breast Cancer Symposium. Abstract GS03-06. Presented December 5, 2023.
4. Martin M, Hegg R, Kim SB, et al: Treatment with adjuvant abemaciclib plus endocrine therapy in patients with high-risk early breast cancer who received neoadjuvant chemotherapy: A prespecified analysis of the monarchE randomized clinical trial. JAMA Oncol 8:1190-1194, 2022.
5. Harbeck N, Gluz O, Christgen M, et al: ADAPTcycle: Adjuvant dynamic marker-adjusted personalized therapy (ADAPT) comparing endocrine therapy plus ribociclib versus chemotherapy in intermediate-risk HR+/HER2– early breast cancer. 2020 ASCO Annual Meeting I. Abstract TPS601.
Dr. Nozawa works at the Department of Advanced Clinical Research and Development at the Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan.
Disclaimer: This perspective represents the author's opinion and does not necessarily reflect the views of ASCO or The ASCO Post.
