Temozolomide-associated hypermutation and response to immunotherapy in advanced pulmonary neuroendocrine tumours

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Introduction: Temozolomide (TMZ) cytotoxicity depends on an intact DNA mismatch repair (MMR) pathway and low levels of O6-methylguanine DNA methyltransferase (MGMT). However, absence of MGMT-mediated repair coupled with defective MMR (dMMR) may lead to enrichment of C:G to A:T transitions throughout the genome, a marked increase in tumour mutational burden (TMB), and loss of TMZ-induced cytotoxicity. This resistance mechanism is called TMZ-associated hypermutation (TAH). Theoretically, this effect could lead to sensitivity to checkpoint inhibitor immunotherapy.

Aim(s): To investigate the frequency of TAH in pulmonary neuroendocrine tumours (PNET) patients after TMZ treatment. In addition, to evaluate the efficacy of checkpoint inhibition in the presence of TAH.

Materials and methods: From September 2022 on, whole genome sequencing (WGS) was performed in consecutive progressive PNET patients in a single centre. Their last treatment was CAP/TMZ, which initially resulted in a partial response.

Conference:

Presenting Author: Buikhuisen W

Authors: Buikhuisen W, Badrising S, Moonen L, Derks J, Monkhorst K,

Keywords: Pulmonary NET, whole genome sequencing, temozolomide signature, immunotherapy,