Prediction of response to immune checkpoint blockade in patients with metastatic colorectal cancer with microsatellite instability

T Ratovomanana; R Nicolle; R Cohen; A Diehl; A Siret; Q Letourneur; O Buhard; A Perrier; E Guillerm; F Coulet; P Cervera; P Benusiglio; K Labrèche; R Colle; A Collura; E Despras; P Le Rouzic; F Renaud; J Cros; A Alentorn; M Touat; M Ayadi; P Bourgoin; C Prunier; C Tournigand; C de la Fouchardière; D Tougeron; V Jonchère; J Bennouna; A de Reynies; J-F Fléjou; M Svrcek; T André; A Duval

doi:10.1016/j.annonc.2023.05.010

Prediction of response to immune checkpoint blockade in patients with metastatic colorectal cancer with microsatellite instability

Ann Oncol. 2023 Aug;34(8):703-713. doi: 10.1016/j.annonc.2023.05.010. Epub 2023 Jun 1.

Authors

T Ratovomanana¹, R Nicolle², R Cohen³, A Diehl¹, A Siret¹, Q Letourneur¹, O Buhard¹, A Perrier⁴, E Guillerm⁴, F Coulet⁴, P Cervera¹, P Benusiglio⁴, K Labrèche⁵, R Colle³, A Collura¹, E Despras¹, P Le Rouzic¹, F Renaud¹, J Cros⁶, A Alentorn⁷, M Touat⁷, M Ayadi⁸, P Bourgoin⁹, C Prunier¹⁰, C Tournigand¹¹, C de la Fouchardière¹², D Tougeron¹³, V Jonchère¹, J Bennouna¹⁴, A de Reynies¹⁵, J-F Fléjou⁹, M Svrcek⁹, T André³, A Duval¹⁶

Affiliations

¹ Sorbonne Université, INSERM, Unité Mixte de Recherche Scientifique 938 and SIRIC CURAMUS, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, Paris.
² Université Paris Cité, Centre de Recherche sur l'Inflammation (CRI), INSERM, U1149, CNRS, ERL 8252, Paris; GERCOR, Groupe Coopérateur Multidisciplinaire en Oncologie, Paris.
³ Sorbonne Université, INSERM, Unité Mixte de Recherche Scientifique 938 and SIRIC CURAMUS, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, Paris; GERCOR, Groupe Coopérateur Multidisciplinaire en Oncologie, Paris; Departments of Medical Oncology.
⁴ Sorbonne Université, INSERM, Unité Mixte de Recherche Scientifique 938 and SIRIC CURAMUS, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, Paris; Molecular Biology and Medical Genetics, Sorbonne Université, AP-HP, Hospital Pitié-Salpêtrière, Paris.
⁵ CinBioS, MS 37 PASS Production de données en Sciences de la vie et de la Santé, INSERM, Sorbonne Université et SIRIC CURAMUS, Paris.
⁶ Department of Pathology, Beaujon Hospital, AP-HP, Clichy.
⁷ Service de Neurologie 2-Mazarin, Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, 47-83 boulevard de l'Hôpital, Paris.
⁸ Programme "Cartes d'Identité des Tumeurs", Ligue Nationale Contre le Cancer, Paris.
⁹ Sorbonne Université, INSERM, Unité Mixte de Recherche Scientifique 938 and SIRIC CURAMUS, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, Paris; Department of Pathology, Sorbonne Université, AP-HP, Hôpital Saint-Antoine, Paris.
¹⁰ Sorbonne Université, INSERM, Unité Mixte de Recherche Scientifique 938 and SIRIC CURAMUS, Centre de Recherche Saint-Antoine, Equipe Signalisation TGFB, plasticité cellulaire et Cancer, Paris.
¹¹ Department of Medical Oncology, Hôpital Henri-Mondor, APHP, Université Paris Est Creteil, INSERM U955, Créteil.
¹² Department of Medical Oncology, Centre Léon Bérard, Lyon.
¹³ ProDicET, UR 24144, University of Poitiers and Hepato-Gastroenterology Department, Poitiers University Hospital, Poitiers.
¹⁴ Centre De Recherche En Cancérologie Et Immunologie Nantes-Angers (CRCINA), INSERM, Université d'Angers, Université De Nantes, Nantes.
¹⁵ Cartes d'Identité des Tumeurs Program, Ligue Nationale Contre Cancer, Paris, France.
¹⁶ Sorbonne Université, INSERM, Unité Mixte de Recherche Scientifique 938 and SIRIC CURAMUS, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, Paris; Molecular Biology and Medical Genetics, Sorbonne Université, AP-HP, Hospital Pitié-Salpêtrière, Paris. Electronic address: alex.duval@inserm.fr.

PMID: 37269904
DOI: 10.1016/j.annonc.2023.05.010

Abstract

Background: Mismatch repair-deficient (dMMR) tumors displaying microsatellite instability (MSI) represent a paradigm for the success of immune checkpoint inhibitor (ICI)-based immunotherapy, particularly in patients with metastatic colorectal cancer (mCRC). However, a proportion of patients with dMMR/MSI mCRC exhibit resistance to ICI. Identification of tools predicting MSI mCRC patient response to ICI is required for the design of future strategies further improving this therapy.

Patients and methods: We combined high-throughput DNA and RNA sequencing of tumors from 116 patients with MSI mCRC treated with anti-programmed cell death protein 1 ± anti-cytotoxic T-lymphocyte-associated protein 4 of the NIPICOL phase II trial (C1, NCT03350126, discovery set) and the ImmunoMSI prospective cohort (C2, validation set). The DNA/RNA predictors whose status was significantly associated with ICI status of response in C1 were subsequently validated in C2. Primary endpoint was progression-free survival by immune RECIST (iRECIST) (iPFS).

Results: Analyses showed no impact of previously suggested DNA/RNA indicators of resistance to ICI, e.g. MSIsensor score, tumor mutational burden, or specific cellular and molecular tumoral contingents. By contrast, iPFS under ICI was shown in C1 and C2 to depend both on a multiplex MSI signature involving the mutations of 19 microsatellites hazard ratio cohort C2 (HR_C2) = 3.63; 95% confidence interval (CI) 1.65-7.99; P = 1.4 × 10^-3] and the expression of a set of 182 RNA markers with a non-epithelial transforming growth factor beta (TGFB)-related desmoplastic orientation (HR_C2 = 1.75; 95% CI 1.03-2.98; P = 0.035). Both DNA and RNA signatures were independently predictive of iPFS.

Conclusions: iPFS in patients with MSI mCRC can be predicted by simply analyzing the mutational status of DNA microsatellite-containing genes in epithelial tumor cells together with non-epithelial TGFB-related desmoplastic RNA markers.

Keywords: DNA and RNA sequencing; immune checkpoint inhibitors (ICIs); metastatic colorectal cancer; microsatellite instability; prediction of MSI mCRC patient response to ICI; progression-free survival by iRECIST.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Colonic Neoplasms*
Colorectal Neoplasms* / drug therapy
Colorectal Neoplasms* / genetics
Colorectal Neoplasms* / pathology
DNA Mismatch Repair / genetics
Humans
Immune Checkpoint Inhibitors / pharmacology
Immune Checkpoint Inhibitors / therapeutic use
Microsatellite Instability
Prospective Studies
Rectal Neoplasms*

Substances

Immune Checkpoint Inhibitors

Supplementary concepts

Turcot syndrome

Associated data

ClinicalTrials.gov/NCT03350126