Neoadjuvant Nivolumab and Chemotherapy in Early Estrogen Receptor-Positive Breast Cancer

Academic Background

Breast cancer is one of the most common cancers among women worldwide, with estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2−) breast cancer accounting for the majority of cases. Although ER+/HER2− breast cancer is sensitive to endocrine therapy, its pathological complete response rate (pCR) to chemotherapy is relatively low, especially in high-risk patients. In recent years, immune checkpoint inhibitors have shown significant effects in the treatment of various cancers, particularly in triple-negative breast cancer (TNBC). However, their role in ER+/HER2− breast cancer remains unclear.

This study aims to investigate whether adding the anti-programmed death 1 (PD-1) drug Nivolumab to a neoadjuvant chemotherapy regimen can improve pCR rates in patients with early-stage high-risk ER+/HER2− breast cancer. Through this research, the investigators hope to provide a new treatment paradigm for ER+/HER2− breast cancer patients and further explore the potential of immunotherapy in this subtype.

Source of the Paper

This paper was co-authored by Sherene Loi and several other researchers from institutions such as the Peter MacCallum Cancer Centre, University of Melbourne, and European Institute of Oncology. The paper was published in February 2025 in the journal Nature Medicine, titled “Neoadjuvant nivolumab and chemotherapy in early estrogen receptor-positive breast cancer: a randomized phase 3 trial”. The study was funded by Bristol Myers Squibb.

Research Process

Study Design and Patient Screening

This study is a randomized, multicenter, double-blind phase 3 clinical trial (NCT04109066), designed to evaluate the efficacy of Nivolumab combined with neoadjuvant chemotherapy in high-risk ER+/HER2− breast cancer patients. A total of 830 patients were screened, and ultimately 510 patients were randomly assigned, with 257 receiving Nivolumab plus chemotherapy and 253 receiving placebo plus chemotherapy. All patients were newly diagnosed with high-risk ER+/HER2− breast cancer, with tumor grades of 3 or grade 2 with ER expression between 1% and ≤10%.

Treatment Regimen

Patients received weekly paclitaxel treatment over 12 weeks, followed by Nivolumab (360 mg) or placebo every three weeks combined with anthracycline and cyclophosphamide. All patients underwent surgery within four weeks after completing neoadjuvant treatment. Post-surgery, patients continued with Nivolumab (480 mg) combined with endocrine therapy for up to seven cycles.

Primary and Secondary Endpoints

The primary endpoint of the study was pCR (ypT0/is, ypN0), meaning no invasive residual disease in the breast and lymph nodes post-surgery. Secondary endpoints included residual cancer burden (RCB) class 0 or I rates, event-free survival (EFS), and safety assessments. Additionally, the researchers evaluated PD-L1 expression using Ventana SP142 and Dako 28-8 immunohistochemistry and assessed the proportion of tumor-infiltrating lymphocytes (TILs) via H&E staining.

Main Results

Significant Increase in pCR Rates

In the Nivolumab group, the pCR rate was 24.5%, significantly higher than the 13.8% in the placebo group (p=0.0021). This result was particularly prominent in patients with high PD-L1 expression (SP142 ≥1%), where the pCR rate in the Nivolumab group was 44.3%, compared to only 20.2% in the placebo group. Additionally, in patients with higher TIL levels, the pCR rate in the Nivolumab group was also significantly higher than in the placebo group.

Improvement in RCB Class 0 or I Rates

The RCB class 0 or I rate in the Nivolumab group was 30.7%, higher than the 21.3% in the placebo group. This result aligns with the improvement in pCR rates, indicating that Nivolumab significantly reduces the burden of residual tumors post-surgery.

Safety Assessment

The safety profile of the Nivolumab group was consistent with its known safety profile, with no new safety signals identified. However, there were two drug toxicity-related deaths in the Nivolumab group, due to pneumonia and hepatitis. Additionally, the incidence of immune-related adverse events was higher in the Nivolumab group, warranting further attention.

Conclusion and Significance

This study shows that in high-risk early-stage ER+/HER2− breast cancer patients, Nivolumab combined with neoadjuvant chemotherapy significantly improves pCR rates, particularly in patients with high PD-L1 expression or higher TIL levels. This finding provides a new direction for the treatment of ER+/HER2− breast cancer, emphasizing the potential role of immunotherapy in this subtype. Furthermore, the results suggest that PD-L1 and TILs may serve as biomarkers predicting the efficacy of Nivolumab, aiding in the development of further personalized treatment strategies.

Highlights of the Study

1. Significant Increase in pCR Rates: Nivolumab combined with chemotherapy significantly improved pCR rates in high-risk ER+/HER2− breast cancer patients, especially in those with high PD-L1 expression.
2. Exploration of Biomarkers: PD-L1 and TILs were confirmed as important biomarkers for predicting the efficacy of Nivolumab, providing a basis for personalized treatment.
3. Safety Assessment: Although the safety profile of Nivolumab was consistent with its known profile, the incidence of immune-related adverse events was higher, requiring further attention.

Other Valuable Information

This study also explored the impact of ER and progesterone receptor expression levels on the efficacy of Nivolumab, finding that patients with lower ER and progesterone receptor expression benefited more from Nivolumab. This finding suggests that patients with lower ER and progesterone receptor expression may share similar immune characteristics with TNBC patients, warranting further investigation.

This study provides new insights into the treatment of ER+/HER2− breast cancer, highlighting the potential of immunotherapy in this subtype and offering important reference points for future research.