Jin Feng, Yu Xinmiao, Zheng Ang Department of Breast Surgery, The First Hospital of China Medical University
Editor’s Note At the 2025 San Antonio Breast Cancer Symposium (SABCS 2025), a study entitled “Gene Expression–based Subtyping of Early Triple-Negative Breast Cancer for Prediction of Response to Neoadjuvant Immune-chemotherapy in the NSABP B-59/GBG-96-GeparDouze Trial” (Abstract No. RF3-02) was presented. This study provides an in-depth analysis of the heterogeneity of benefit from immunotherapy in early-stage triple-negative breast cancer (TNBC), highlighting the predictive value of tumor-infiltrating lymphocytes (TILs) and TNBC molecular subtypes. Oncology Frontier invited Professor Jin Feng and his colleagues Professor Yu Xinmiao and Professor Zheng Ang from the First Hospital of China Medical University to introduce and comment on the study in detail, offering important evidence and clinical insights for precision immunotherapy in TNBC.Study Overview
Study Title Clinical Outcomes of Gene Expression–Based Subtyping in Early Triple-Negative Breast Cancer for Predicting Response to Neoadjuvant Immune-chemotherapy in the NSABP B-59/GBG-96-GeparDouze Trial
Background In recent years, immunotherapy represented by PD-1 and PD-L1 inhibitors has significantly reshaped the treatment landscape of triple-negative breast cancer. The KEYNOTE-522 trial demonstrated that neoadjuvant immunotherapy combined with chemotherapy can significantly improve the pathological complete response (pCR) rate in patients with early high-risk TNBC. However, not all TNBC patients derive benefit from immunotherapy. Against this background, the NSABP B-59/GBG-96-GeparDouze trial evaluated the addition of the PD-L1 inhibitor atezolizumab to standard neoadjuvant chemotherapy, followed by continuation in the adjuvant setting. The trial showed that adding atezolizumab did not significantly improve event-free survival (EFS) in the overall population.
This overall negative result reignited a critical question: even if immunotherapy does not demonstrate survival benefit in the overall population, could specific molecular subgroups still benefit? Identifying predictive biomarkers and molecular features that enable precise patient selection is key to addressing this issue. Tumor-infiltrating lymphocytes play an important role in the tumor microenvironment by modulating antitumor immune responses and have been considered important predictors of immunotherapy efficacy. This study therefore asked whether TIL levels and more refined molecular subtypes could predict response to immunochemotherapy. By analyzing gene expression profiles from pretreatment biopsy samples, the investigators systematically evaluated the role of TILs and TNBC molecular subtypes in predicting response to neoadjuvant immunochemotherapy, aiming to provide new evidence for individualized treatment strategies in TNBC.
Methods The study enrolled 1,520 patients with TNBC with tumors larger than 2 cm and/or clinically node-positive disease. Patients were randomly assigned to receive neoadjuvant chemotherapy plus placebo or neoadjuvant chemotherapy plus atezolizumab. TIL levels were assessed in all patients, and gene expression profiling was performed in 482 cases.
Patients were stratified by TIL levels into low (<10%), intermediate (10–29%), and high (≥30%) groups. TNBC molecular subtypes based on immune-related gene expression were classified as basal-like immune-activated (BLIA), basal-like immune-suppressed (BLIS), luminal androgen receptor (LAR), and mesenchymal (MES). The primary endpoints were pathological complete response and event-free survival.
Results The results showed a clear association between higher TIL levels and improved response to treatment. Patients with high TIL levels achieved a pCR rate of 68.6%, which was significantly higher than the 39.7% observed in patients with low TIL levels. Event-free survival was also significantly better in the high-TIL group, underscoring the importance of immune infiltration in antitumor response.
TIL levels were predictive of incremental benefit from immunotherapy. In the high-TIL subgroup, the addition of atezolizumab increased the pCR rate from 65.4% to 71.9% and resulted in a statistically significant improvement in EFS. In contrast, the benefit of atezolizumab was limited in patients with low or intermediate TIL levels.
Transcriptomic subtyping further refined response prediction, particularly in patients with intermediate TIL levels, a group characterized by marked heterogeneity. Within this subgroup, BLIA tumors exhibited strong immune activation, with a pCR rate of 68.9%, significantly higher than the 38.6% observed in BLIS tumors, along with superior survival outcomes.
The key finding was that the EFS benefit from atezolizumab was almost entirely confined to patients with BLIA tumors. Among patients with intermediate TIL levels, approximately 51% were classified as BLIA and 39% as BLIS. Atezolizumab significantly prolonged EFS only in the BLIA subgroup, whereas no benefit was observed in the BLIS subgroup compared with placebo.
Conclusions Atezolizumab significantly improves EFS in patients with immune-activated tumors, particularly those with TILs ≥30% or the BLIA subtype. Tumors with intermediate TIL levels are heterogeneous, comprising both immune-activated and immune-suppressed subtypes. Therefore, TNBC molecular subtyping should be more widely incorporated into clinical trials and diagnostic practice. Biomarker development for immunotherapy continues to evolve, and future efforts should focus on precisely identifying highly immune-active tumors and further characterizing BLIA tumors within the intermediate-TIL population. Additional validation in other clinical trial cohorts is also needed, including comparisons between PD-L1 and PD-1 inhibitors.
Expert Commentary This study represents a high-quality, in-depth analysis of a phase III trial with a negative primary endpoint, successfully uncovering clinically meaningful heterogeneity in immunotherapy benefit. It provides strong evidence supporting a transition toward precision immunotherapy in TNBC. The findings confirm that atezolizumab can significantly improve EFS in patients with immune-activated tumors, particularly those with high TIL levels or the BLIA subtype. In clinical practice, TIL assessment may help predict which patients are most likely to benefit from immunotherapy.
Importantly, the study highlights the biological complexity of tumors with intermediate TIL levels, which include both immune-activated and immune-exhausted phenotypes. This heterogeneity likely explains the inconsistent benefit observed with immunotherapy in this group. Future treatment decisions for these patients may need to integrate molecular subtyping and immune microenvironment profiling to avoid a one-size-fits-all approach. BLIA tumors demonstrate strong immune responsiveness, whereas BLIS tumors exhibit immunosuppressive characteristics and limited benefit from immunotherapy.
Overall, this report serves as a rigorous “post-trial analysis” that refines our understanding of immunotherapy efficacy in TNBC. It suggests that different TNBC subtypes should follow different therapeutic pathways and treatment intensities. Translating multi-gene expression profiling into clinically accessible tools will be critical for shifting decision-making from a binary choice of whether to use immunotherapy toward a more nuanced strategy of selecting the right immunotherapy combination for the right patient. Future integration of artificial intelligence, multi-omics data, and clinically practical predictive models may further optimize individualized treatment strategies for TNBC.
Professor Jin Feng
Second-Level Professor, Chief Physician, PhD Supervisor Department of Breast Surgery, The First Hospital of China Medical University
Professor Yu Xinmiao
Department of Breast Surgery, The First Hospital of China Medical University
Professor Zheng Ang
Associate Professor, PhD Supervisor Department of Breast Surgery, The First Hospital of China Medical University
