Abstract 53P
Background
POLE gene encodes DNA polymerase ε, which exhibits polymerase and exonuclease activities, including proofreading. Mutations in POLE's exonuclease domain lead to high tumor mutation burden (TMB) in various cancers, regardless of microsatellite stability. Mutations outside this domain are poorly understood.
Methods
We conducted an observational retrospective study in 1257 advanced solid tumor patients undergoing NGS testing of their disease between July 2019 and February 2024. We analyzed clinical data, treatment responses, TMB, and genetic alterations in POLE altered tumors.
Results
55 patients with POLE altered tumors were identified, mostly with lung cancer (13%), followed by endometrial (11%), ovarian (9%) and colorectal cancer (7%). Gender distribution was balanced, with 24 male (44%) and 31 female (56%) patients, the majority over 50 years old (72%). POLE alterations predominantly consisted of point mutations (96%) and two splicing events (4%); all non-hotspot alterations located outside the exonuclease domain. 35% of patients exhibited TMB high, and 15% showed an ultramutated phenotype with TMB>50 mut/Mb. Only two patients had MSI-H status. As expected, co-occurring genetic alterations were frequently observed, including genes of the cell growth pathway (TP53, 78%; PIK3CA, 31%; PTEN, 27.%; KRAS, 22%; MTOR, 22%; NF1, 22%; NOTCH1-3, 22%), the homologous recombination repair pathway (BRCA2, 26%; ATM, 20%), and the chromatin modulation pathway (MLL2, 55%; ARID1A, 27%; SPEN, 22%...). Immune checkpoint inhibitors were administered to 16 patients. None exhibited MSI-H or dMMR. Of those treated, 11 achieved disease control, including three with partial response, six with complete response, and three with stable disease. Six patients demonstrated prolonged responses to immunotherapy, exceeding 30 months.
Conclusions
In our cohort, patients with POLE mutated tumors showed a tendency towards high TMB and a favorable response to immunotherapy despite being non-hotspot mutations, outside the exonuclease domain. Insights from comprehensive genomic profiling reports hold significant promise in tailoring personalized treatment strategies.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.