SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. The American Cancer Society estimates that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence.
The integration of Immune Checkpoint Inhibitors (ICIs) into early-stage breast cancer treatment, particularly when combined with neoadjuvant chemotherapy, represents a significant advancement in oncology. Recent studies have explored combining ICIs with neoadjuvant chemotherapy to improve pathologic Complete Response (pCR) rates and survival outcomes. While ICIs have revolutionized treatment in metastatic settings, their role in early-stage breast cancer remains debated. This meta-analysis aims to evaluate the optimal approach for incorporating ICIs into early-stage breast cancer therapy by assessing their impact on pCR, Event-Free Survival (EFS), and safety profiles.
This study utilized the PubMed database, with a search conducted on December 10, 2023, to identify relevant randomized clinical trials (RCTs). Inclusion criteria focused on RCTs assessing the efficacy of neoadjuvant or adjuvant ICI plus chemotherapy in early-stage breast cancer. The studies had to provide data on pCR, EFS, and adverse events. Two independent reviewers extracted data from the selected RCTs. An individual patient data meta-analysis and a trial-level random-effect meta-analysis were conducted to synthesize findings. Nine RCTs involving 5114 patients were included. The population comprised 2097 patients with Triple-Negative Breast Cancer (TNBC), 1924 patients with Hormone Receptor–positive/HER2-negative (HR+/HER2-negative) tumors, and 1115 patients with HER2-positive tumors.
The Primary objectives of this study were to 1) Evaluate the association of neoadjuvant ICIs with pCR (defined as ypT0/is ypN0) across different molecular phenotypes of breast cancer 2) Quantify EFS assessed in patients with and without pCR and 3) Evaluate the severity of Adverse Events associated with ICIs including Grade 3 or higher immune-related Adverse Events (irAEs).
Efficacy of Neoadjuvant ICIs:
TNBC: Neoadjuvant ICIs led to a significant improvement in pCR rates, with an absolute increase of more than 10%. The efficacy was consistent across different PD-L1 expression statuses. Neoadjuvant ICIs also improved EFS for both patients achieving pCR (HR=0.65) and those with residual disease (HR=0.77). In patients with TNBC achieving a pCR, the addition of ICIs was associated with a 5-year EFS of 92.0% compared with 88.0% without them. In patients with residual disease, treatment with ICIs resulted in 5-year EFS of 63.3%, and 56.1% without them.
HR+/HER2-negative Tumors: ICIs improved pCR rates predominantly in the PD-L1+ subgroup, with an absolute increase of 12.2%. No significant benefit was observed in the PD-L1 negative subgroup or in HER2-positive tumors.
Adjuvant ICI Therapy:
No numerical improvement was observed with adjuvant ICI therapy, regardless of whether patients had achieved pCR or had residual disease. Hazard ratios were greater than 1, suggesting a lack of benefit.
The incidence of Grade 3 or higher irAEs during neoadjuvant therapy was 10.3%. This was consistent with known AEs of ICIs. Chemotherapy-related AEs, such as gastrointestinal and hematologic complications, was not significantly increased with ICI addition.
In conclusion, this meta-analysis indicates that neoadjuvant ICI therapy is beneficial in enhancing pCR rates and improving survival outcomes in early-stage TNBC and PD-L1+ HR+/HER2-negative tumors. The results suggest a preference for neoadjuvant over adjuvant ICI therapy, given the lack of benefit from adjuvant ICIs. Future research should focus on optimizing patient selection for neoadjuvant ICIs and exploring whether adjuvant therapy can be safely omitted, potentially reshaping treatment paradigms in early-stage breast cancer.
Neoadjuvant Immune Checkpoint Inhibitors Plus Chemotherapy in Early Breast Cancer: A Systematic Review and Meta-Analysis. Villacampa G, Navarro V, Matikas A, et al. JAMA Oncol. Published online August 29, 2024. doi:10.1001/jamaoncol.2024.3456.
