Digital Profiling of Immune Biomarkers in Breast Cancer: Relation to Anthracycline Benefit
Bibliographic record
Abstract
Assessment of the tumor-immune microenvironment can be used as a prognostic tool for improved survival and as a predictive biomarker for treatment benefit, particularly from immune-modulating treatments including cytotoxic chemotherapy. Using digital spatial profiling (DSP), we studied the tumor-immune microenvironment of 522 breast cancer cases by quantifying 35 immune biomarkers on tissue microarrays from the MA.5 phase III clinical trial. In this trial, node-positive breast cancer patients were randomized to receive either non-anthracycline chemotherapy (cyclophosphamide, methotrexate, 5'-fluorouracil [CMF]) or anthracycline-containing cytotoxic chemotherapy (CEF). Donor block hematoxylin and eosin (H&E)-stained sections were scored for the level of stromal tumor-infiltrating lymphocytes (sTILs), according to the international guidelines. We hypothesized that patients with higher levels of tumor-immune infiltration, assessed by either DSP or H&E staining, would benefit from CEF (relative to CMF) more than patients with lower immune infiltration. Unsupervised hierarchical clustering of digitally scored biomarkers revealed 2 patient clusters: immune infiltrated versus ignored. Following a prespecified statistical plan crafted to meet REMARK (REporting recommendations for tumor MARKer prognostic studies) guidelines, we found that the DSP-derived Immune Cluster assignment did not predict an improved 10-year relapse-free survival for patients receiving CEF compared with CMF. However, a secondary hypothesis revealed a significant predictive value for H&E sTILs assessed on full-faced sections for CEF benefit over CMF in the entire cohort and the human epidermal growth factor receptor 2-enriched subset. As exploratory analyses, supervised clustering of DSP-scored biomarkers suggested that low levels of T-cell immunoglobulin and mucin domain 3 TIM-3 and high levels of human leukocyte antigen HLA-DR and programmed cell death protein ligand PD-L-1 are associated with sensitivity to CEF. Although novel high-plex techniques provide a detailed insight into the tumor microenvironment, conventional H&E staining remains a powerful tool that can be applied to full-faced sections to assess the value of the immune microenvironment, particularly sTILs, in predicting benefits from immunogenic chemotherapies.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".