RESUMO
BACKGROUND: Cancer-testis antigens (CTAs) are tumor antigens that are normally expressed in the testes but are aberrantly expressed in several cancers. CTA overexpression drives the metastasis and progression of lung cancer, and is associated with poor prognosis. To improve lung cancer diagnosis, prognostic prediction, and drug discovery, robust CTA identification and quantitation is needed. In this study, we examined and quantified the co-expression of CTAs in lung cancer to derive cancer testis antigen burden (CTAB), a novel biomarker of immunotherapy response. METHODS: Formalin fixed paraffin embedded (FFPE) tumor samples in discovery cohort (n = 5250) and immunotherapy and combination therapy treated non-small cell lung cancer (NSCLC) retrospective (n = 250) cohorts were tested by comprehensive genomic and immune profiling (CGIP), including tumor mutational burden (TMB) and the mRNA expression of 17 CTAs. PD-L1 expression was evaluated by IHC. CTA expression was summed to derive the CTAB score. The median CTAB score for the discovery cohort of 170 was applied to the retrospective cohort as cutoff for CTAB "high" and "low". Biomarker and gene expression correlation was measured by Spearman correlation. Kaplan-Meier survival analyses were used to detect overall survival (OS) differences, and objective response rate (ORR) based on RECIST criteria was compared using Fisher's exact test. RESULTS: The CTAs were highly co-expressed (p < 0.05) in the discovery cohort. There was no correlation between CTAB and PD-L1 expression (R = 0.011, p = 0.45) but some correlation with TMB (R = 0.11, p = 9.2 × 10-14). Kaplan-Meier survival analysis of the immunotherapy-treated NSCLC cohort revealed better OS for the pembrolizumab monotherapy treated patients with high CTAB (p = 0.027). The combination group demonstrated improved OS compared to pembrolizumab monotherapy group (p = 0.04). The pembrolizumab monotherapy patients with high CTAB had a greater ORR than the combination therapy group (p = 0.02). CONCLUSIONS: CTA co-expression can be reliably measured using CGIP in solid tumors. As a biomarker, CTAB appears to be independent from PD-L1 expression, suggesting that CTAB represents aspects of tumor immunogenicity not measured by current standard of care testing. Improved OS and ORR for high CTAB NSCLC patients treated with pembrolizumab monotherapy suggests a unique underlying aspect of immune response to these tumor antigens that needs further investigation.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Masculino , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Antígeno B7-H1/metabolismo , Cetrimônio/uso terapêutico , Estudos Retrospectivos , Testículo/química , Testículo/metabolismo , Testículo/patologia , Antígenos de Neoplasias , Biomarcadores Tumorais/genéticaRESUMO
Genomic profiling is critical for precision oncology to guide treatment decisions. Liquid biopsy testing is a complementary approach to tissue testing, particularly when tissue is not readily available. The Labcorp Plasma Focus test is a circulating cell-free DNA genomic profiling test that identifies actionable variants in solid cancers, including non-small-cell lung, colorectal, melanoma, breast, esophageal, gastroesophageal junction, and gastric cancers. This study highlights the analytical validation of the test, including accuracy compared with orthogonal methods, as well as sensitivity, specificity, precision, reproducibility, and repeatability. Concordance with orthogonal methods showed percent positive agreement of 98.7%, 89.3%, and 96.2% for single nucleotide variants (SNVs), insertion/deletions (indels), and copy number amplifications (CNAs), respectively, and 100.0% for translocations and microsatellite instability (MSI). Analytical sensitivity revealed a median limit of detection of 0.7% and 0.6% for SNVs and indels, 1.4-fold for CNAs, 0.5% variant allele frequency for translocations, and 0.6% for MSI. Specificity was >99% for SNVs/indels and 100% for CNAs, translocations, and MSI. Average positive agreement from precision, reproducibility, and repeatability experiments was 97.5% and 88.9% for SNVs/indels and CNAs, and 100% for translocations and MSI. Taken together, these data show that the Labcorp Plasma Focus test is a highly accurate, sensitive, and specific approach for cell-free DNA genomic profiling to supplement tissue testing and inform treatment decisions.