mutations predict survival benefit in advanced cancer patients treated with immune checkpoint inhibitors.

Background: Numerous biomarkers are being tested to enhance the ability of clinicians to predict responses and prognosis after treatment with immune checkpoint inhibitors (ICIs). Polycomb repressive complex 2 (PRC2) is a histone methyltransferase family that plays a major role in chromatin silencing. Preclinical evidence implicates PRC2 components such as enhancer of zeste homolog 2 (EZH2) in immune resistance. This study aimed to assess the clinical relevance of mutations in the clinical outcome of ICI-treated patients.

Materials And Methods: Next-generation sequencing (NGS) data from tumor samples of patients treated with ICIs (anti-PD-1/PD-L1, anti-CTLA-4 or both) were interrogated for alterations in PRC2-related genes. The Kaplan-Meier method was used to assess the association between altered and unaltered -related genes with overall survival.

Results: Somatic NGS data from 1662 advanced-stage, ICI-treated patients with various primaries (lung, melanoma, bladder, kidney, head neck, esophagogastric, glioma, colorectal, breast, unknown primary) were examined. Seventy patients (4%) harbored truncating or missense mutations or fusions in (2.4%), (1.2%), (0.9%) or (0.7%) genes. Patients carrying alterations in genes had significantly longer median overall survival (44 months) compared with those with unaltered tumors (18 months, log-rank =0.0174). These findings were validated in two additional cohorts of patients (=313) with various primaries (melanoma, lung, bladder, head neck, anal, sarcoma) who were treated with ICIs.

Conclusions: Inactivating mutations in the PRC2 chromatin silencing machinery, although rare, may predict favorable outcomes in ICI-treated patients with metastatic cancers. This warrants prospective confirmation, and suggests that epigenetic regulators could serve as surrogate markers to guide ICI treatment decisions.