Recent data suggest that the tumor suppressor gene ARID1A is associated with high antitumor immunity and may be a predictive biomarker of response to immunotherapy in CPNPC
Recent data examining ARID1A changes in circulating tumor DNA (ctDNA) from a large cohort of patients with advanced non-small cell lung cancer (NSCLC) was presented virtually during the ASCO 2020 Annual Meeting. In this study, a liquid biopsy assay was used to assess changes in ARID1A related to activating changes (drivers) in NSCLC and other biomarkers of immune coreceptor inhibitors.
Consecutive samples from patients with phase IIIB / IV NSCLC examined between March 2016 and August 2019 were evaluated using Guardant360, a study of cDNA NGS (next generation sequencing) evaluating 73 to 74 genes. The tests included analysis of single nucleotide variants, insertions or deletions, fusions and amplifications (KEAP1 was not tested). Mutation frequencies were compared using Fisher’s exact test, with variants of uncertain significance excluded.
Of the 27,776 patients with NSCLC with more than 1 ctDNA alteration detected, 1,094 (3.9%) had more than 1 functional mutation in ARID1A (fARID1A). Mutations in fARID1A were significantly more common in patients with squamous histology compared to adenocarcinomas (5.1% vs 3.8%, p = 0.0007). There were significantly less deletion mutations in EGFR exon 19 (4.9% vs 11.1%; p <0.0001) and EGFR L858R mutations (4.0% vs 7.0%; p <0.0001) and significantly more changes in BRAF V600E (2.2% vs 1.4%; p = 0.0338) in patients with fARID1A. There was no significant difference in the frequency of ALK and ROS1 fusions, nor in the mutations in STK11 between patients with and without fARID1A (8.0% vs 6.8%; p = 0.126). Activating mutations in KRAS were significantly more frequent in patients with fARID1A (31.1% vs 19.4%; p <0.0001), including KRAS G12C (10.9% vs 7.0%; p <0.0001).
These data provide more information regarding the mutations present in the NSCLC. Mutations in fARID1A have been associated with different frequencies in the different driver changes found in NSCLC, with particular interest in the EGFR mutated cohort, in which the effectiveness of immune coreceptor inhibitors is low. The frequency of mutations in STK11, a possible negative predictor of the effectiveness of immune coreceptor inhibitors, was not significantly different. KRAS mutations were significantly more frequent in patients with fARID1A, which is quite relevant given the recently released data that mutations in KRAS (particularly KRAS G12C) can be a positive predictor of response to biomarker immune coreceptor inhibitors in NSCLC. The determination of the effectiveness of biomarker immune coreceptor inhibitors in patients with fARID1A is in progress.
J Clin Oncol 38: 2020 (suppl; abstr 9523). DOI:10.1200/JCO.2020.38.15_suppl.9523