ICI have become key in the treatment armamentarium for pts with advanced cancer. Besides PD-L1, numerous biomarkers are being tested to enhance clinicians' ability to predict responses and prognosis. The polycomb repressive complex 2 (PKC2) is a histone methtyltransferase family that plays a major role in chromatin silencing. Preclinical evidence implicates PKC2 components such as EZH2 in immune resistance. This study aimed to assess the clinical relevance of PKC2 mutations (mts) in outcomes of ICI-treated pts.
NGS data from tumor samples of pts treated with ICI (anti-PD-1/PD-L1, anti-CTLA4 or both) were queried (cbioportal.org: MSKCC, Nat Genet 2019) for mts in PKC2-related genes, including EZH1, EZH2, EED, and SUZ12. The Kaplan Meier method was used to assess the association between mutated and unmutated PKC2 genes with OS (mos). All results were reported at the 0.05 significance level.
1662 pts were examined (350 NSCLC,321 melanoma,214 bladder, 151 RCC,138 head neck-HN,126 esoph/gastr-EG, 117 glioma,110 CRC,90 unknown primary-CUP, 45 breast). The majority received a PD-1 or PD-L1 inhibitor: nivo, pembro, atezo, ave or durva (n=1256), 146 were treated with anti-CTLA4 (ipi or treme) and rest with combinations (n=260). 70 pts (4%) harbored truncating or missense mts in EZH2 (2.4%), EZH1 (1.2%), SUZ12 (0.9%) or EED (0.7%). Presence of these mts was more frequent in CRC (8.2%), followed by bladder (6.2%), melanoma (5.6%), EG (4.8%), glioma (4.3%), HN (3.6%), CUP (3.4%), RCC (3.3%), and NSCLC (1.7%). No significant mt co-occurence or mutual exclusivity among PRC2 genes was found. Pts carrying mts in PRC2 genes had a significantly longer median OS (44 mos) compared to those without (18 mos, log-rank P=0.0174).
Inactivating mts in the PRC2 chromatin silencing machinery, although rare, may predict favorable outcomes in ICI-treated pts with metastatic cancers. This warrants prospective confirmation and suggests that epigenetic regulators could serve as surrogate markers to guide ICI treatment decisions. Additionally, it justifies the rational for combinations of ICI with epigenetic modulators (e.g. EZH2 inhibitors) for unmutated tumors representing the majority of cases.
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