David Malka

Hypermutated tumours in the era of immunotherapy: The paradigm of personalised medicine

Immune checkpoint inhibitors have demonstrated unprecedented clinical activity in a wide range of cancers. Significant therapeutic responses have recently been observed in patients presenting mismatch repair-deficient (MMRD) tumours. MMRD cancers exhibit a remarkably high rate of mutations, which can result in the formation of neoantigens, hypothesised to enhance the antitumour immune response. In addition to MMRD tumours, cancers mutated in the exonuclease domain of the catalytic subunit of the DNA polymerase epsilon (POLE) also exhibit an ultramutated genome and are thus likely to benefit from immunotherapy. In this review, we provide an overview of recent data on hypermutated tumours, including MMRD and POLE-mutated cancers, with a focus on their distinctive clinicopathological and molecular characteristics as well as their immune environment. We also discuss the emergence of immune therapy to treat these hypermutated cancers, and we comment on the recent Food and Drug Administration approval of an immune checkpoint inhibitor, the programmed cell death 1 antibody (pembrolizumab, Keytruda), for the treatment of patients with metastatic MMRD cancers regardless of the tumour type. This breakthrough represents a turning point in the management of these hypermutated tumours and paves the way for broader strategies in immunoprecision medicine.

Angiogenesis inhibition in the second-line treatment of metastatic colorectal cancer: A systematic review and pooled analysis

The last two decades have seen intensive efforts devoted to the development of compounds that target angiogenesis for the treatment of metastatic colorectal cancer (mCRC). In this review, we describe supporting evidence and ongoing development of angiogenesis inhibitors in the second-line treatment of mCRC, and summarize relevant randomized trials to help therapeutic decision-making in daily practice.

Matching genomic molecular aberrations with molecular targeted agents: Are biliary tract cancers an ideal playground?

Biliary tract cancers (BTCs) are a heterogeneous group of tumours with geographical discrepancies in terms of incidence and risk factors. However, a convergent genomic and epigenetic mutational landscape emerges from the genome-wide screens of BTCs in South East Asia, Latin America and in the Western World. Specificities are observed for some alterations and anatomical subtypes: frequent fibroblast growth factor receptor 2 (FGFR2) and isocitrate dehydrogenase 1/2 (IDH1/2) alterations are specific to intrahepatic cholangiocarcinomas (ICCs), whereas frequent ERBB2 oncogene alterations are specific to extrahepatic cholangiocarcinomas (ECCs) and gallbladder carcinomas (GBCs). Until now, the outcome of patients with BTCs treated by molecular targeted agents (MTAs) alone or in combination with conventional chemotherapy in non-biology driven trials remains poor and does not exceed the outcome of patients treated with chemotherapy alone. Encouraging reports of biology-driven therapeutic approaches should accelerate the clinical development of MTAs in BTCs. Additionally, frequent epigenetic aberrations such as IDH1/2 mutations and switch/sucrose non-fermenting (SWI/SNF) complex dysfunctions suggest that epidrugs must also be considered. In this review, we expose the rationale and feasibility to biologically drive the treatment of BTC patients.

Essai OLIVIA : quadrithérapie avec bévacizumab

Il existe depuis 20 ans une escalade progressive dans l’intensite des traitements de premiere ligne du cancer colorectal metastatique (CCRm). En 2007, le groupe italien GONO a demontre pour la premiere fois dans un essai de phase 3 dans cette indication la superiorite, malgre une toxicite plus importante, d’une tri-chimiotherapie combinant 5-fluoro-uracile, oxaliplatine et irinotecan (schema FOLFOXIRI) comparativement a une bi-chimiotherapie standard (5-fluoro-uracile plus irinotecan, schema FOLFIRI) en termes de taux de reponse objective tumorale (66 % versus 41 %, p = 0,0002), de survie sans progression et de survie globale [1].