Spatially Preserved Multi-Region Transcriptomic Subtyping and Biomarkers of Chemoimmunotherapy Outcome in Extensive-Stage Small Cell Lung Cancer

Melina Peressini, Rosario Garcia-Campelo, Bartomeu Massuti, Cristina Martí, Manuel Cobo, Vanesa Gutiérrez, Manuel Dómine, José Fuentes, Margarita Majem, Javier de Castro, Juan F. Córdoba, María P. Diz, Dolores Isla, Emilio Esteban, Enric Carcereny, Laia Vila, Alberto Moreno-Vega, Silverio Ros, Amaia Moreno, Francisco J. GarcíaGerardo Huidobro, Carlos Aguado, Victor Cebey-López, Javier Valdivia, Ramón Palmero, Pilar Lianes, Marta López-Brea, Oscar J. Vidal, Mariano Provencio, Edurne Arriola, Javier Baena, Mercedes Herrera, Helena Bote, Magdalena Molero, Vera Adradas, Santiago Ponce-Aix, Angel Nuñez-Buiza, Álvaro Ucero, Susana Hernandez, Fernando Lopez-Rios, Esther Conde, Luis Paz-Ares, Jon Zugazagoitia

Résultats de recherche: Contribution à un journalArticleRevue par des pairs

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Résumé

Purpose: Transcriptomic subtyping holds promise for personalized therapy in extensive-stage small cell lung cancer (ES-SCLC). In this study, we aimed to assess intratumoral transcriptomic subtype diversity and to identify biomarkers of long-term chemoimmunotherapy benefit in human ES-SCLC. Experimental Design: We analyzed tumor samples from 58 patients with ES-SCLC enrolled in two multicenter single-arm phase IIIb studies evaluating frontline chemoimmunotherapy in Spain: n ¼ 32 from the IMfirst trial and n ¼ 26 from the CANTABRICO trial. We used the GeoMx Digital Spatial Profiler system to perform multi-region transcriptomic analysis. For subtype classification, we performed hierarchical clustering using the relative expression of ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and YAP1 (SCLC-Y). Results: Subtype distribution was found to be similar between both cohorts, except for SCLC-P, which was not identified in the CANTABRICO_DSP cohort. A total of 44% of the patients in both cohorts had tumors with multiple coexisting transcriptional subtypes. Transcriptional subtypes or subtype heterogeneity was not associated with outcomes. Most potential targets did not show subtype-specific expression. Consistently in both cohorts, tumors from patients with long-term benefit (time to progression ≥12 months) contained an IFNγ-dominated mRNA profile, including enhanced capacity for antigen presentation. Hypoxia and glycolytic pathways were associated with resistance to chemoimmunotherapy. Conclusions: This work suggests that intratumoral heterogeneity, inconsistent association with outcome, and unclear subtype-specific target expression might be significant challenges for subtype-based precision oncology in SCLC. Preexisting IFNγ-driven immunity and mitochondrial metabolism seem to be correlates of long-term efficacy in this study, although the absence of a chemotherapy control arm precludes concluding that these are predictive features specific for immunotherapy.

langue originaleAnglais
Pages (de - à)3036-3049
Nombre de pages14
journalClinical Cancer Research
Volume30
Numéro de publication14
Les DOIs
étatPublié - 15 juil. 2024
Modification externeOui

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