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Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. Here we develop a targeted gene expression biomarker that predicts meningioma outcomes and radiotherapy responses. Using a discovery cohort of 173 meningiomas, we developed a 34-gene expression risk score and performed clinical and analytical validation of this biomarker on independent meningiomas from 12 institutions across 3 continents (N = 1,856), including 103 meningiomas from a prospective clinical trial. The gene expression biomarker improved discrimination of outcomes compared with all other systems tested (N = 9) in the clinical validation cohort for local recurrence (5-year area under the curve (AUC) 0.81) and overall survival (5-year AUC 0.80). The increase in AUC compared with the standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval 0.07 to 0.17, P

Cancer biomarker discoveries typically involve using patient specimens. In practice, there is often strong desire to preserve high quality biospecimens for studies that are most likely to yield useful information. Previously, we proposed a two-stage adaptive design for binary endpoints which terminates the biomarker study in a futility interim if the model performance is unsatisfactory. In this work, we extend the two-stage design framework to accommodate time-to-event endpoints. The first stage of the procedure involves testing whether the measure of discrimination for survival models (C-index) exceeds a prespecified threshold. We describe the computation of cross-validated C-index and evaluation of the statistical significance using resampling techniques. The second stage involves an independent model validation. Our simulation studies show that under the null hypothesis, the proposed design maintains Type I error at the nominal level and has high probabilities of terminating the study early. Under the alternative hypothesis, power of the design is a function of the true event proportion, the sample size, and the targeted improvement in the discriminant measure. We apply the method to design of a prognostic biomarker study in patients with triple-negative breast cancer. Some practical aspects of the proposed method are discussed. [ABSTRACT FROM AUTHOR]

Purpose: Programmed death ligand 1 [PD-(L)1]-targeted therapies have shown modest survival benefit in triple-negative breast cancer (TNBC). PD-L1 + microenvironments in TNBC are not well characterized and may inform combinatorial immune therapies. Herein, we characterized clinicopathologic features, RNA-based immune signatures, and spatially defined protein-based tumor-immune microenvironments (TIME) in early-stage PD-L1 + and PD-L1 - TNBC., Experimental Design: From a large cohort of chemotherapy-naïve TNBC, clinicopathologic features, deconvoluted RNA immune signatures, and intraepithelial and stromal TIME (Nanostring GeoMX) were identified in subsets of PD-L1 + and PD-L1 - TNBC, as defined by FDA-approved PD-L1 companion assays., Results: 228 of 499 (46%) TNBC were PD-L1 + (SP142: ≥1% immune cells-positive). Using PD-L1 22C3, 46% had combined positive score (CPS) ≥ 1 and 16% had CPS ≥10. PD-L1 + TNBC were higher grade with higher tumor-infiltrating lymphocytes (TIL; P < 0.05). PD-L1 was not associated with improved survival following adjustment for TILs and other variables. RNA profiles of PD-L1 + TNBC had increased dendritic cell, macrophage, and T/B cell subset features; and decreased myeloid-derived suppressor cells. PD-L1+ stromal and intraepithelial TIMEs were highly enriched in IDO-1, HLA-DR, CD40, and CD163 compared with PD-L1-TIME, with spatially specific alterations in CTLA-4, Stimulator of Interferon Genes (STING), and fibronectin. Macrophage- and antigen presentation-related proteins correlated most strongly with PD-L1 protein., Conclusions: In this early-stage TNBC cohort, nearly 50% were PD-L1 + (SP142 companion assay) while 16% were PD-L1 + with the 22C3 companion assay. PD-L1 + TNBC had specific myeloid-derived and lymphoid features. Spatially defined PD-L1 + TIME were enriched in several clinically actionable immune proteins. These data may inform future studies on combinatorial immunotherapies for patients with PD-L1 + TNBC. See related commentary by Symmans, p. 5446 ., (©2021 The Authors; Published by the American Association for Cancer Research.)