Liquid biopsies – A revolution in oncology

Article in leMag.sante

Assessing the response to treatment, adapting it in the event of resistance, early detection of residual disease predicting a relapse:

These are the major challenges of the innovation with which the Nice University Hospital has equipped itself.

The article is available below in French:

Article biopsies liquides

Fusion-positive non-small cell lung carcinoma: Biological principles, clinical practice, and diagnostic implications

Article in Wiley

From: Daniel Kazdal, Véronique Hofman, Petros Christopoulos, Marius Ilié, Albrecht Stenzinger, Paul Hofman

2021 October

Abstract

Based on superior efficacy and tolerability, targeted therapy is currently preferred over chemotherapy and/or immunotherapy for actionable gene fusions that occur in late-stage non-small cell lung carcinoma (NSCLC). Consequently, current clinical practice guidelines mandate testing for ALK, ROS1, NTRK, and RET gene fusions in all patients with newly diagnosed advanced non-squamous NSCLC (NS-NSCLC). Gene fusions can be detected using different approaches, but today RNA next-generation sequencing (NGS) or combined DNA/RNA NGS is the method of choice. The discovery of other gene fusions (involving, eg, NRG1, NUT, FGFR1, FGFR2, MET, BRAF, EGFR, SMARC fusions) and their partners has increased progressively in recent years, leading to the development of new and promising therapies and mandating the development and implementation of comprehensive detection methods. The purpose of this review is to focus on recent data concerning the main gene fusions identified in NSCLC, followed by the discussion of major challenges in this domain.

Full article

A small-molecule P2RX7 activator promotes antitumor immune responses and sensitizes lung tumor to immunotherapy

Article in Nature Communications

From: Laetitia Douguet, Serena Janho dit Hreich, Jonathan Benzaquen, Laetitia Seguin, Thierry Juhel, Xavier Dezitter, Christophe Duranton, Bernhard Ryffel, Jean Kanellopoulos, Cecile Delarasse, Nicolas Renault, Christophe Furman, Germain Homerin, Chloé Féral, Julien Cherfils-Vicini, Régis Millet, Sahil Adriouch, Alina Ghinet, Paul Hofman & Valérie Vouret-Craviari

2021 January

Abstract

Only a subpopulation of non-small cell lung cancer (NSCLC) patients responds to immunotherapies, highlighting the urgent need to develop therapeutic strategies to improve patient outcome. We develop a chemical positive modulator (HEI3090) of the purinergic P2RX7 receptor that potentiates αPD-1 treatment to effectively control the growth of lung tumors in transplantable and oncogene-induced mouse models and triggers long lasting antitumor immune responses. Mechanistically, the molecule stimulates dendritic P2RX7-expressing cells to generate IL-18 which leads to the production of IFN-γ by Natural Killer and CD4+ T cells within tumors. Combined with immune checkpoint inhibitor, the molecule induces a complete tumor regression in 80% of LLC tumor-bearing mice. Cured mice are also protected against tumor re-challenge due to a CD8-dependent protective response. Hence, combination treatment of small-molecule P2RX7 activator followed by immune checkpoint inhibitor represents a strategy that may be active against NSCLC.

Full article

Association of TRF2 expression and myeloid- derived suppressor cells infiltration with clinical outcome of patients with cutaneous melanoma

New article in OncoImmunology

From: Marius Ilié, Elisabeth Lantéri, Emmanuel Chamorey, Brice Thamphya, Marame Hamila, Henri Montaudié, Alexandra Picard-Gauci, Sophie Gardrat, Thierry Passeron, Sandra Lassalle, Elodie Long-Mira, Julien Cherfils-Vicini, Eric Gilson, Véronique Hofman & Paul Hofman

2021 March

Abstract

The outcome of patients with cutaneous melanoma has been strongly modified by recent advances obtained with Immune Checkpoint Inhibitors (ICIs). However, despite this breakthrough, durable response to ICIs is limited to a subset of patients. We investigated whether the expression of TRF2, which preserves telomere integrity, and have an effect on tumor immunosurveillance notably by directly recruiting and activating myeloid-derived suppressor cells (MDSCs), could be a prognostic biomarker in patients with relapsed or metastatic melanoma based on different treatment regimens. We evaluated retrospectively the association of TRF2 expressed in melanoma cells in combination with intratumoral CD33+ CD15+ CD14- MDSCs, as detected by immunohistochemistry and quantified by digital analysis, to clinicopathological features and overall survival (OS) among 48 patients treated with ICIs and 77 patients treated with other treatment options. The densities/mm2 of TRF2+ cells (P=.003) and CD33+ cells (P=.004) were individually significantly related to poor OS. In addition, only the combined expression of CD33+/CD15+/CD14- cells/mm2 was significantly correlated to poor OS (P=.017) in the whole study population as well as in patients treated by ICIs (P=.023). There was no significant difference in OS when analyzing the other markers individually or in combination according to the treatment regimen. The pre-treatment assessment of TRF2 expression and CD33+ cells/mm2 along with the density of CD33+/CD15+/CD14- cells/mm2 could assess OS and better predict clinical response of patients with melanoma treated by ICIs.

Full article

Prospective Multicenter Validation of the Detection of ALK Rearrangements of Circulating Tumor Cells for Noninvasive Longitudinal Management of Patients With Advanced NSCLC

New article in Journal of Thoracic Oncology

From: Marius Ilié, MD, PhD, Julien Mazières, MD, PhD, Emmanuel Chamorey, MD, PhD, Simon Heeke, PhD, Jonathan Benzaquen, MD, PhD, Brice Thamphya, MSc, Jacques Boutros, MD, Angélica Tiotiu, MD, PhD, Julien Fayada, MSc, Jacques Cadranel, MD, PhD, Michel Poudenx, MD, Denis Moro-Sibilot, MD, PhD, Fabrice Barlesi, MD, PhD, Juliette Thariat, MD, PhD, Christelle Clément-Duchêne, MD, PhD, Pascale Tomasini, MD, PhD, Véronique Hofman, MD, PhD, Charles-Hugo Marquette, MD, PhD, Paul Hofman, MD, PhD

2021 May

Abstract

Introduction: Patients with advanced-stage NSCLC whose tumors harbor an ALK gene rearrangement benefit from treatment with multiple ALK inhibitors (ALKi). Approximately 30% of tumor biopsy samples contain insufficient tissue for successful ALK molecular characterization. This study evaluated the added value of analyzing circulating tumor cells (CTCs) as a surrogate to ALK tissue analysis and as a function of the response to ALKi.

Methods: We conducted a multicenter, prospective observational study (NCT02372448) of 203 patients with stage IIIB/IV NSCLC across nine French centers, of whom 81 were ALK positive (immunohistochemistry or fluorescence in situ hybridization [FISH]) and 122 ALK negative on paraffinembedded tissue specimens. Blood samples were collected at baseline and at 6 and 12 weeks after ALKi initiation or at disease progression. ALK gene rearrangement was evaluated with CTCs using immunocytochemistry and FISH analysis after enrichment using a filtration method.

Results: At baseline, there was a high concordance between the detection of an ALK rearrangement in the tumor tissue and in CTCs as determined by immunocytochemistry (sensitivity, 94.4%; specificity 89.4%). The performance was lower for the FISH analysis (sensitivity, 35.6%; specificity, 56.9%). No significant association between the baseline levels or the dynamic change of CTCs and overall survival (hazard ratio ¼ 0.59, 95% confidence interval: 0.24–1.5, p ¼ 0.244) or progression-free survival (hazard ratio ¼ 0.84, 95% confidence interval: 0.44–1.6, p ¼ 0.591) was observed in the patients with ALK-positive NSCLC.

Conclusions: CTCs can be used as a complementary tool to a tissue biopsy for the detection of ALK rearrangements. Longitudinal analyses of CTCs revealed promise for realtime patient monitoring and improved delivery of molecularly guided therapy in this population

Full article

Recommendations for a practical implementation of circulating tumor DNA mutation testing in metastatic non-small-cell lung cancer

New article in ESMO Open

From: E. Heitzer, D. van den Broek, M. G. Denis, P. Hofman, M. Hubank, F. Mouliere, L. Paz-Ares, E. Schuuring, H. Sültmann, G. Vainer, E. Verstraaten, L. de Visser & D. Cortinovis

2022 April

Abstract

Background: Liquid biopsy (LB) is a rapidly evolving diagnostic tool for precision oncology that has recently found its
way into routine practice as an adjunct to tissue biopsy (TB). The concept of LB refers to any tumor-derived
material, such as circulating tumor DNA (ctDNA) or circulating tumor cells that are detectable in blood. An LB is not
limited to the blood and may include other fluids such as cerebrospinal fluid, pleural effusion, and urine, among others.

Patients and methods: The objective of this paper, devised by international experts from various disciplines, is to
review current challenges as well as state-of-the-art applications of ctDNA mutation testing in metastatic non-smallcell
lung cancer (NSCLC). We consider pragmatic scenarios for the use of ctDNA from blood plasma to identify
actionable targets for therapy selection in NSCLCs.

Results: Clinical scenarios where ctDNA mutation testing may be implemented in clinical practice include complementary
tissue and LB testing to provide the full picture of patients’ actual predictive profiles to identify resistance mechanism (i.e.
secondary mutations), and ctDNA mutation testing to assist when a patient has a discordant clinical history and is
suspected of showing intertumor or intratumor heterogeneity. ctDNA mutation testing may provide interesting
insights into possible targets that may have been missed on the TB. Complementary ctDNA LB testing also provides
an option if the tumor location is hard to biopsy or if an insufficient sample was taken. These clinical use cases
highlight practical scenarios where ctDNA LB may be considered as a complementary tool to TB analysis.

Conclusions: Proper implementation of ctDNA LB testing in routine clinical practice is envisioned in the near future. As
the clinical evidence of utility expands, the use of LB alongside tissue sample analysis may occur in the patient cases
detailed here.

Full article here

Salivary detection of COVID-19: clinical performance of oral sponge sampling for SARS-CoV-2 testing

New article in ERJ Open Research

From : Jacques Boutros, Jonathan Benzaquen, Charles Hugo Marquette, Marius Ilié, Mickelina Labaky, Didier Benchetrit, Thibaut Lavrut, Sylvie Leroy, Richard Chemla, Michel Carles, Virginie Tanga, Charlotte Maniel, Olivier Bordone, Maryline Allégra, Virginie Lespinet, Julien Fayada, Jennifer Griffonnet, Véronique Hofman, and Paul Hofman

Abstract

Background The current diagnostic standard for coronavirus disease 2019 (COVID-19) is reverse
transcriptase-polymerase chain reaction (RT-PCR) testing with nasopharyngeal (NP) swabs. The
invasiveness and need for trained personnel make the NP technique unsuited for repeated community-based
mass screening. We developed a technique to collect saliva in a simple and easy way with the sponges that
are usually used for tamponade of epistaxis. This study was carried out to validate the clinical performance
of oral sponge (OS) sampling for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing.

Methods Over a period of 22 weeks, we collected prospectively 409 paired NP and OS samples from
consecutive subjects presenting to a public community-based free screening centre. Subjects were referred
by their attending physician because of recent COVID-19 symptoms (n = 147) or by the contact tracing
staff of the French public health insurance because they were considered as close contacts of a laboratoryconfirmed
COVID-19 case (n = 262).

Results In symptomatic subjects, RT-PCR SARS-CoV-2 testing with OS showed a 96.5% (95% CI: 89.6–
94.8) concordance with NP testing, and a 93.2% (95% CI: 89.1–97.3) sensitivity when using the IdyllaTM
platform and a sensitivity of 76.3% (95% CI: 69.4–83.2) on the Synlab Barla laboratory platform. In close
contacts the NP-OS concordance (93.8%, 95% CI: 90.9–96.7) and OS sensitivity (71.9%, 95% CI: 66.5–77.3)
were slightly lower.

Conclusion These results strongly suggest that OS testing is a straightforward, low-cost and highthroughput
sampling method that can be used for frequent RT-PCR testing of COVID-19 patients and
mass screening of populations.

Full article

OncoAge participated in the Marathon Nice-Cannes 2021

We are very happy to announce that FHU OncoAge participated in the Marathon Nice-Cannes. The event took place on the 28th of November 2021.

This support was given to Aveni and it will contribute to the fight against Covid-19. It will contribute more particularly to the Mucovax project. Mucovax is a nasal spray vaccinaion against the SARS-COV-2 Virus.

You can find more information about Mucovax here.