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Temozolomide Treatment Alters Mismatch Repair and Boosts Mutational Burden in Tumor and Blood of Colorectal Cancer Patients.
Crisafulli, Giovanni; Sartore-Bianchi, Andrea; Lazzari, Luca; Pietrantonio, Filippo; Amatu, Alessio; Macagno, Marco; Barault, Ludovic; Cassingena, Andrea; Bartolini, Alice; Luraghi, Paolo; Mauri, Gianluca; Battuello, Paolo; Personeni, Nicola; Zampino, Maria Giulia; Pessei, Valeria; Vitiello, Pietro Paolo; Tosi, Federica; Idotta, Laura; Morano, Federica; Valtorta, Emanuele; Bonoldi, Emanuela; Germano, Giovanni; Di Nicolantonio, Federica; Marsoni, Silvia; Siena, Salvatore; Bardelli, Alberto.
Afiliação
  • Crisafulli G; Department of Oncology, University of Torino, Candiolo, Italy.
  • Sartore-Bianchi A; Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Italy.
  • Lazzari L; Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
  • Pietrantonio F; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy.
  • Amatu A; The FIRC Institute of Molecular Oncology, Milan, Italy.
  • Macagno M; Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
  • Barault L; Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
  • Cassingena A; Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Italy.
  • Bartolini A; Department of Oncology, University of Torino, Candiolo, Italy.
  • Luraghi P; Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Italy.
  • Mauri G; Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
  • Battuello P; Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Italy.
  • Personeni N; The FIRC Institute of Molecular Oncology, Milan, Italy.
  • Zampino MG; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy.
  • Pessei V; The FIRC Institute of Molecular Oncology, Milan, Italy.
  • Vitiello PP; Department of Oncology, University of Torino, Candiolo, Italy.
  • Tosi F; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.
  • Idotta L; Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
  • Morano F; Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IRCCS, Milan, Italy.
  • Valtorta E; Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Italy.
  • Bonoldi E; Department of Oncology, University of Torino, Candiolo, Italy.
  • Germano G; Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Italy.
  • Di Nicolantonio F; Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
  • Marsoni S; Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
  • Siena S; Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
  • Bardelli A; Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
Cancer Discov ; 12(7): 1656-1675, 2022 07 06.
Article em En | MEDLINE | ID: mdl-35522273
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Encefálicas / Neoplasias Colorretais Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Encefálicas / Neoplasias Colorretais Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article