Trial reportCancer discovery2022
Temozolomide Treatment Alters Mismatch Repair and Boosts Mutational Burden in Tumor and Blood of Colorectal Cancer Patients.
Trial report in Cancer discovery, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03519412 (Pembrolizumab in MMR-Proficient Metastatic Colorectal Cancer Pharmacologically Primed to Trigger Dynamic Hypermutation Status), which is not on this map. Cited by 81 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Pembrolizumab in MMR-Proficient Metastatic Colorectal Cancer Pharmacologically Primed to Trigger Dynamic Hypermutation Status
Who cites it
81 citing papers in PubMed, 1 synthesis or guideline pooled it, 108 citations in OpenAlex.
- A Comprehensive Evaluation of the Effectiveness and Safety of Pembrolizumab for the Treatment of Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis.Current cancer drug targets · 2026Pooled it
- A Phase Ib/II Study of Atezolizumab in Combination with Thiopurine Therapy in Patients with Metastatic Solid Tumors and Intermediate Tumor Mutational Burden.Cancer research communications · 2026Trial
- Mismatch Repair-Proficient Colorectal Cancer Can Evade Immune Surveillance through an Intrinsic Suppressive Program.Cancer discovery · 2026Article
- Targeting O6-methylguanine-DNA Methyltransferase Deficiency in Preclinical Models of Extracranial Human Cancers with a Tumor-Selective DNA-Modifying Agent.Molecular cancer therapeutics · 2026Article
- Review
- Pharmacologic Inhibition of PMS2 Induces MMR Deficiency and Response to Immune Checkpoint Blockade.Cancer discovery · 2026Article
- Whole genome and exome sequencing of pancreatic neuroendocrine tumour to investigate PRRT response.Endocrine-related cancer · 2026Article
- Tumor evolution: signaling pathways, molecular mechanisms and therapeutic targets.Signal transduction and targeted therapy · 2026Review
- Neural cues differentially modulate colorectal cancer cell behavior depending on patients' genomic background.iScience · 2026Article
- Review
- Dihydrotanshinone I as a novel signal transducer and activator of transcription 3 inhibitor for glioblastoma treatment.Journal of translational medicine · 2026Article
- Spatial predictors of response to chemo-immunotherapy in microsatellite stable metastatic colorectal cancer.Nature communications · 2026Article
- Combination immunotherapy for colorectal cancer: Clinical applications, rationale, challenges, and future perspectives.Cell reports. Medicine · 2026Review
- Review
- Acquired High Tumor Mutational Burden and Activity of Immunotherapy after Targeted Therapy in Microsatellite Stable Colorectal Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- Germline Predisposition to Oncogenic Alkylating Damage in Colorectal Cancer.Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2026Article
- Advances in immunotherapy for colorectal cancer: overcoming resistance in mismatch repair-proficient tumors.Cancer cell international · 2026Review
- Toward identification of common DNA repair process in mutational signatures.bioRxiv : the preprint server for biology · 2026Article
- Review
- Mismatch Repair as a Dynamic and Clinically Actionable Vulnerability in Cancer.Cancer research · 2025Review
21 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
Authors and funding
26 authors at 7 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The majority of metastatic colorectal cancers (mCRC) are mismatch repair (MMR) proficient and unresponsive to immunotherapy, whereas MMR-deficient (MMRd) tumors often respond to immune-checkpoint blockade. We previously reported that the treatment of colorectal cancer preclinical models with temozolomide (TMZ) leads to MMR deficiency, increased tumor mutational burden (TMB), and sensitization to immunotherapy. To clinically translate these findings, we designed the ARETHUSA clinical trial whereby O6-methylguanine-DNA-methyltransferase (MGMT)-deficient, MMR-proficient, RAS-mutant mCRC patients received priming therapy with TMZ. Analysis of tissue biopsies and circulating tumor DNA (ctDNA) revealed the emergence of a distinct mutational signature and increased TMB after TMZ treatment. Multiple alterations in the nucleotide context favored by the TMZ signature emerged in MMR genes, and the p.T1219I MSH6 variant was detected in ctDNA and tissue of 94% (16/17) of the cases. A subset of patients whose tumors displayed the MSH6 mutation, the TMZ mutational signature, and increased TMB achieved disease stabilization upon pembrolizumab treatment. SIGNIFICANCE: MMR-proficient mCRCs are unresponsive to immunotherapy. We provide the proof of concept that inactivation of MMR genes can be achieved pharmacologically with TMZ and molecularly monitored in the tissue and blood of patients with mCRC. This strategy deserves additional evaluation in mCRC patients whose tumors are no longer responsive to standard-of-care treatments. See related commentary by Willis and Overman, p. 1612. This article is highlighted in the In This Issue feature, p. 1599.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.