The Cancer Immunotherapy Biomarker Testing Landscape

Abstract

Context.— Cancer immunotherapy provides unprecedented rates of durable clinical benefit to late-stage cancer patients across many tumor types, but there remains a critical need for biomarkers to accurately predict clinical response. Although some cancer immunotherapy tests are associated with approved therapies and considered validated, other biomarkers are still emerging and at various states of clinical and translational exploration. Objective.— To provide pathologists with a current and practical update on the evolving field of cancer immunotherapy testing. The scientific background, clinical data, and testing methodology for the following cancer immunotherapy biomarkers are reviewed: programmed death ligand-1 (PD-L1), mismatch repair, microsatellite instability, tumor mutational burden, polymerase δ and ε mutations, cancer neoantigens, tumor-infiltrating lymphocytes, transcriptional signatures of immune responsiveness, cancer immunotherapy resistance biomarkers, and the microbiome. Data Sources.— Selected scientific publications and clinical trial data representing the current field of cancer immunotherapy. Conclusions.— The cancer immunotherapy field, including the use of biomarker testing to predict patient response, is still in evolution. PD-L1, mismatch repair, and microsatellite instability testing are helping to guide the use of US Food and Drug Administration–approved therapies, but there remains a need for better predictors of response and resistance. Several categories of tumor and patient characteristics underlying immune responsiveness are emerging and may represent the next generation of cancer immunotherapy predictive biomarkers. Pathologists have important roles and responsibilities as the field of cancer immunotherapy continues to develop, including leadership of translational studies, exploration of novel biomarkers, and the accurate and timely implementation of newly approved and validated companion diagnostics.

Spatial and Temporal Heterogeneity of PD-L1 Expression and Tumor Mutational Burden in Gastroesophageal Adenocarcinoma at Baseline Diagnosis and after Chemotherapy

“…However, measurement and thresholds for TMB were not yet standardized at the time we conducted this study (5,12). We stratified TMB using an assay and thresholds that are readily available in clinical practice, but this stratification led to very few samples being classified as TMB-H, which limited statistical power.…”

“…In recent years, immune checkpoint inhibitors (ICIs) have emerged as promising treatments for locally advanced or metastatic GEA, and the anti-programmed cell death protein 1 (anti-PD-1) antibody pembrolizumab was conditionally approved by the Food and Drug Administration (FDA) for use in a subset of patients with GEA after progression on initial systemic treatments (1,3,4). Biomarkers including programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB) might help define which patients are most likely to benefit from ICI therapy (5). Tumor cell PD-L1 expression ('TPS') is associated with response to anti-PD-1/anti-PD-L1 therapy in some cancers (6,7).…”

The Therapeutic Potential of DNA Damage Repair Pathways and Genomic Stability in Lung Cancer

“…Similarly, microsatellite instability, also associated with genome instability, is also linked with a better response to immunotherapy. Many commercial laboratories now offer a comprehensive gene sequencing report comprising of the PD-L1 expression, tumor mutation burden, and microsatellite instability status of tumors (124).…”

Evaluation of circulating tumor cell clusters for pan‐cancer noninvasive diagnostic triaging

“…Apart from the logistical aspects, there are other factors that affect tumor tissue procurement, such as inaccessibility of the tumor, proximity of the tumor to vital organs or vasculature, patients' comorbidities, and even patients' reluctance because of procedural risks. Repeat biopsies often may be desirable, such as 1) if the prior tissue sample was insufficient 2 or poorly representative, 3 2) to determine the status of therapeutically relevant biomarkers, 4 3) to characterize recurrent lesions, or 4) to identify a new lesion as a second primary or metastasis 5 . However, repeat biopsies are associated with increased procedural risks.…”