A new biomarker analysis from the Phase III NeoTRIPaPDL1 trial demonstrates that tumor-specific major histocompatibility complex-II (tsMHC-II) expression can predict which triple-negative breast cancer (TNBC) patients will benefit from adding immunotherapy to neoadjuvant chemotherapy. The findings address a critical clinical need, as less than 10% of patients currently derive meaningful benefit from immune checkpoint inhibitors despite their approval as standard of care.
Biomarker Performance in Clinical Trial
The analysis included 220 patients from the NeoTRIPaPDL1 trial, which randomized 280 patients with high-risk early TNBC to receive eight cycles of carboplatin and nab-paclitaxel with or without the PD-L1 inhibitor atezolizumab. Using a predefined cutoff of 5% tumor cell positivity, researchers found that 41% of all breast cancers expressed tsMHC-II, with similar distribution between treatment arms (42.2% chemotherapy alone vs 40.5% chemo-immunotherapy, p=0.68).
The predictive capacity of tsMHC-II was demonstrated specifically in immunotherapy-treated patients, with an odds ratio of 2.58 for pathological complete response (pCR) and a p-value of 0.016. In contrast, the biomarker showed no predictive value in the chemotherapy-only arm (p=0.336, OR: 1.45).
Enhanced Sensitivity with Modified Cutoffs
Given that imaging mass cytometry (IMC) proved more sensitive than traditional immunohistochemistry methods, researchers conducted an exploratory analysis using the 80th percentile cutoff to identify approximately 20% of patients as positive. This stricter threshold strengthened the predictive association, yielding an odds ratio of 4.19 (p=0.006) in the immunotherapy arm while maintaining no predictive value in chemotherapy alone (p=0.956, OR: 1.03).
When tsMHC-II expression was evaluated as a continuous variable, a statistically significant interaction between biomarker status and treatment effect emerged (p=0.006). Receiver-operator characteristic analysis further confirmed improved predictive accuracy in the chemo-immunotherapy group compared to chemotherapy alone.
Clinical Significance and Mechanism
TsMHC-II represents a departure from traditional biomarkers in breast cancer immunotherapy. Unlike stromal tumor-infiltrating lymphocytes and PD-L1 expression, which have demonstrated prognostic value or predictive capacity for chemotherapy response, tsMHC-II specifically predicts immunotherapy benefit in randomized controlled trials.
MHC-II molecules, including HLA-DR, HLA-DP, and HLA-DQ, are typically expressed on antigen-presenting cells where they present exogenously derived peptides to CD4+ T-cells. However, these molecules can also be expressed on normal and cancer cells, including breast epithelial cells and tumors. The expression of MHC-II on tumor cells may signal an inflamed, immune-responsive tumor phenotype particularly relevant for PD-L1 blockade.
Validation Across Cancer Types
The predictive value of tsMHC-II has been independently validated across multiple cancer types, including melanoma, Hodgkin lymphoma, and bladder cancer. In breast cancer specifically, tsMHC-II was previously identified as a predictor of molecular response to single-agent anti-PD-1 in a small window trial and confirmed to predict both pCR and event-free survival in patients receiving PD-1/PD-L1 inhibitors plus neoadjuvant chemotherapy.
Ongoing Clinical Development
TsMHC-II is currently under evaluation as a planned integrated biomarker in multiple prospective Phase III clinical trials. These include studies evaluating pembrolizumab addition to chemotherapy in the adjuvant setting for TNBC patients (S1418; NCT02954874) and in neoadjuvant settings for high-risk ER-positive early breast cancer patients (S2206; NCT06058377).
Researchers are working to harmonize tsMHC-II assays to establish the most practical approach for prospective validation. The goal is to define a widely available assay that can be performed with technical rigor while demonstrating true clinical utility in pre-planned analyses.
Study Limitations and Future Directions
The current analysis has several limitations, including the use of atezolizumab and a chemotherapy regimen different from the currently approved pembrolizumab-based standard of care. Additionally, event-free survival data are not yet available for translational studies, and the analysis represents an exploratory correlative endpoint rather than a protocol-defined biomarker validation.
Despite these limitations, the consistency of results across different analytical approaches and previous validations supports tsMHC-II as a promising biomarker with potential clinical utility. If validated prospectively, tsMHC-II could enable personalized immunotherapy selection, potentially sparing non-responders from unnecessary immune-related adverse events while optimizing treatment for those most likely to benefit.
