Impact d'un séquençage moléculaire systématique au diagnostic en oncologie digestive, expérience d'un centre

Introduction : les technologies de profilage moléculaire tumoral sont devenues de plus en plus importantes à l'ère de la médecine de précision, leur utilisation en routine est encore limitée par leur accessibilité, leur coût et la disponibilité du matériel tumoral.Matériels et méthodes : nous avons analysé rétrospectivement les traitements reçus et les données de survie des patients atteints d'un cancer digestif ayant bénéficié d’un test moléculaire de séquençage à haut débit (NGS) de manière systématique au diagnostic. L’objectif principal de cette étude monocentrique était de comparer la survie globale des patients qui ont été traités avec une thérapie ciblée sur une anomalie moléculaire à celle des patients qui ont bénéficié d’un traitement standard. La survie globale médiane a été calculée depuis le diagnostic initial de la maladie jusqu'au décès.Résultats : 528 patients ont été adressés dans le service d’Oncologie Digestive de l'hôpital de la Timone de Marseille entre janvier 2018, et novembre 2020 pour prise en charge d’un cancer digestif et ont bénéficié d’un séquençage moléculaire à haut débit. Parmi eux 461 patients avaient un carcinome digestif (75 ont été exclus du fait de la présence d’une GIST ou une Tumeur neuro endocrine, d’une localisation digestive de cancer extra digestif ou de l’absence de suivi dans notre centre) et 275 une maladie métastatique (synchrone ou métachrone). Pour les patients métastatiques, des altérations moléculaires actionnables ont été identifiées pour 95 patients (43,5%) et pour 13 patients (4,7%) un traitement ciblé a été administré sur les résultats du NGS initial. Il n’y avait pas de différence significative de médiane de survie globale entre les patients ayant reçu un traitement ciblé par les données du criblage moléculaire par rapport aux patients qui ont reçu le traitement standard recommandé (2,89 [95%CI 1,84 - 3,93] contre 2,86 [95%CI 1,52 - 4,19], p = 0,671). Discussion et conclusion : cette étude suggère que la génomique à haut débit peut améliorer la prise en charge des patients et bien que ces résultats n'aient pas montré un bénéfice chez les patients traités par une thérapie ciblée sur les données du NGS, ils sont prometteurs. Des essais randomisés sont nécessaires pour confirmer qu’il existe un bénéfice à traiter les patients par une thérapie ciblée sur les données d’un NGS même si les premiers résultats paraissent prometteurs

Adoptive Cell Therapy in Hepatocellular Carcinoma: Biological Rationale and First Results in Early Phase Clinical Trials

International audienceThe mortality of hepatocellular carcinoma (HCC) is quickly increasing worldwide. In unresectable HCC, the cornerstone of systemic treatments is switching from tyrosine kinase inhibitors to immune checkpoints inhibitors (ICI). Next to ICI, adoptive cell transfer represents another promising field of immunotherapy. Targeting tumor associated antigens such as alpha-fetoprotein (AFP), glypican-3 (GPC3), or New York esophageal squamous cell carcinoma-1 (NY-ESO-1), T cell receptor (TCR) engineered T cells and chimeric antigen receptors (CAR) engineered T cells are emerging as potentially effective therapies, with objective responses reported in early phase trials. In this review, we address the biological rationale of TCR/CAR engineered T cells in advanced HCC, their mechanisms of action, and results from recent clinical trials

Impact of a Molecular Sequencing Systematic at Diagnosis in Digestive Oncology: Experience of a French Center

International audienceIntroduction: Tumor-based molecular profiling has increased in the area of precision medicine. Their routine use is still limited by accessibility, cost and availability of tumor material. Materials and Methods: We retrospectively analysed the treatment received and the survival data of patients with digestive cancer who received molecular high-throughput sequencing (NGS) analyses at diagnosis. The primary objective of this single-center study was to compare the overall survival of patients who were treated with molecularly matched therapy with patients who received standard therapy. Median overall survival was calculated from initial disease diagnosis to death. Results: 528 patients were referred to the Digestive Oncology Department of the Timone Hospital in Marseille between January 2018, and November 2020 for management of digestive cancer and received high-throughput molecular sequencing. Among them, 461 patients had a digestive carcinoma (75 of them were excluded because of the presence of a GIST or a neuroendocrine tumor, a digestive localization of extra digestive cancer or the absence of follow-up in our center) and 275 had metastatic disease (synchronous or metachronous). For metastatic patients, actionable molecular alterations were identified in95 patients (43.5%) and for 13 patients (4.7%) a molecularly matched therapy was administered. There was no significant difference in median overall survival between patients who received matched therapy than patients who did not receive molecularly matched therapy (2.89 [95%CI 1.84-3.93] vs. 2.86 [95%CI 1.52-4.19], p=0.671). Conclusion: This study suggests that high-throughput genomics can improve management of patients. Although these results did not show a benefit in overall survival for tumors who harboured such actionable molecular alterations and who received molecularly matched therapy, than patients who did not receive molecularly matched therapy, they are promising. Randomized trials are needed to confirm that there is a benefit to treating patients with matched therapy based on NGS

PVRIG Expression Is an Independent Prognostic Factor and a New Potential Target for Immunotherapy in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a frequent and deadly cancer in need of new treatments. Immunotherapy has shown promising results in several solid tumors. The TIGIT/DNAM-1 axis gathers targets for new immune checkpoint inhibitors (ICIs). Here, we aimed at highlighting the potential of this axis as a new therapeutic option for HCC. For this, we built a large transcriptomic database of 683 HCC samples, clinically annotated, and 319 normal liver tissues. We interrogated this database for the transcriptomic expression of each member of the TIGIT/DNAM-1 axis and tested their prognostic value for survival. We then focused on the most discriminant one for these criteria, i.e., PVRIG, and analyzed the clinical characteristics, the disease-free and overall survivals, and biological pathways associated with PVRIG High tumors. Among all members of the TIGIT/DNAM-1 axis, PVRIG expression was higher in tumors than in normal liver, was heterogeneous across tumors, and was the only member with independent prognostic value for better survival. PVRIG High tumors were characterized by a higher lymphocytic infiltrate and enriched for signatures associated with tertiary lymphoid structures and better anti-tumor immune response. These results suggest that patients with PVRIG High tumors might be good candidates for immune therapy involving ICIs, notably ICIs targeting the TIGIT/DNAM-1 axis. Further functional and clinical validation is urgently required

Predictive value of vascular endothelial growth factor polymorphisms for maintenance bevacizumab efficacy in metastatic colorectal cancer: an ancillary study of the PRODIGE 9 phase III trial

Background: Several studies have reported the impact of single nucleotide polymorphisms (SNPs) in vascular endothelial growth factor ( VEGF ) pathway genes on the efficacy of bevacizumab in metastatic colorectal cancer (mCRC), but results are still inconsistent. The PRODIGE 9 phase III study compared bevacizumab maintenance versus observation alone after induction chemotherapy with FOLFIRI plus bevacizumab. Objective: We evaluated the impact of SNPs of VEGF-A , VEGF receptors ( VEGFR-1, VEGFR-2 ), and hypoxia inducible factor-1α ( HIF-1α ) on tumor control duration (TCD), overall survival (OS), progression-free survival (PFS), and duration of first chemotherapy free-intervals (CFI). Patients and methods: We included 314/491 patients from PRODIGE 9 with a DNA blood sample available. Nine SNPs were genotyped on germline DNA using real-time Polymerase Chain Reaction TaqMan TM (Thermo Fisher Scientific, Waltham, MA , USA 02451). Results: In the bevacizumab arm, patients with the VEGFR-1 rs9582036 CC genotype ( n  = 14) had significantly longer TCD [22.4 months (95% confidence interval (CI): 14.75-not reached)] than patients with the AA or CA genotype [14.4 months (95% CI: 11.7–17.1)] ( p  = 0.036), whereas there was no significant difference in the observation arm. In the bevacizumab arm, no significant difference was found between the CC, and AA or CA genotype for OS [28.2 (95% CI: 18.1–42.8) versus 22.5 (95% CI: 18.6–24.6) months, p  = 0.5], PFS [9.4 (95% CI: 7.2–11.3) versus 9.2 (95% CI: 8.71–10.1)], and duration of the first CFI [4.6 (95% CI: 1.6–13.3) versus 4.14 (95% CI: 0.5–29.0) months, p  = 0.3]. Conclusion: Among mCRC patients treated with bevacizumab maintenance, those with the VEGFR-1 rs9582036 CC genotype experienced longer TCD. The presence of this genotype may thus predict a benefit of bevacizumab maintenance in mCRC