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Immune-related adverse events (irAEs) are the most common complication of immune checkpoint inhibitor (ICI) therapy. With the widespread use of ICIs in patients with solid tumors, up to 40% of the patients develop irAEs within five months of treatment, and 11% develop severe irAEs requiring interventions. A predictive test for irAEs would be a crucial tool for monitoring for complications during and after ICI therapy. We performed an extensive review of potential predictive biomarkers for irAEs in patients who received ICI therapy. Currently, only thyroid-stimulating hormone is utilized in common clinical practice. This is due to the unavailability of commercial tests and unclear predictive values from various studies. Given the lack of single strong predictive biomarkers, some novel approaches using composite scores using genomic, transcriptomics, cytokine levels, or clinical parameters appear appealing. Still, these have yet to be validated and incorporated into clinical practice. Further research conducted to validate the models before implementing them into real-world settings will be of the utmost importance for irAE prediction.

Tumor heterogeneity, especially intratumoral heterogeneity, is a primary reason for treatment failure. A single biopsy may not reflect the complete genomic architecture of the tumor needed to make therapeutic decisions. Circulating tumor DNA (ctDNA) is believed to overcome these limitations. We analyzed concordance between ctDNA and whole-exome sequencing/whole-genome sequencing (WES/WGS) of tumor samples from patients with breast (n = 12), gastrointestinal (n = 20), lung (n = 19), and other tumor types (n = 13). Correlation in the driver, hotspot, and actionable alterations was studied. Three cases in which more-in-depth genomic analysis was required have been presented. A total 58% (37/64) of patients had at least one concordant mutation. Patients who had received systemic therapy before tissue next-generation sequencing (NGS) and ctDNA analysis showed high concordance (78% (21/27) vs. 43% (12/28) p = 0.01, respectively). Obtaining both NGS and ctDNA increased actionable alterations from 28% (18/64) to 52% (33/64) in our patients. Twenty-one patients had mutually exclusive actionable alterations seen only in either tissue NGS or ctDNA samples. Somatic hotspot mutation analysis showed significant discordance between tissue NGS and ctDNA analysis, denoting significant tumor heterogeneity in these malignancies. Increased tissue tumor mutation burden (TMB) positively correlated with the number of ctDNA mutations in patients who had received systemic therapy, but not in treatment-naïve patients. Prior systemic therapy and TMB may affect concordance and should be taken into consideration in future studies. Incorporating driver, actionable, and hotspot analysis may help to further refine the correlation between these two platforms. Tissue NGS and ctDNA are complimentary, and if done in conjunction, may increase the detection rate of actionable alterations and potentially therapeutic targets.