Search

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 = 32 from the IMfirst trial and n = 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 bothcohorts, 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., (©2024 American Association for Cancer Research.)

In the advanced renal cell carcinoma (RCC) scenario, there are no consistent biomarkers to predict the clinical benefit patients derived from immune checkpoint blockade (ICB). Taking this into consideration, herein, we conducted a retrospective study in order to develop and validate a gene expression score for predicting clinical benefit to the anti-PD-1 antibody nivolumab in the context of patients diagnosed with advanced clear cell RCC enrolled in the CheckMate-009, CheckMate-010, and CheckMate-025 clinical trials. First, a three-gene expression score (3GES) with prognostic value for overall survival integrating HMGA1, NUP62, and ARHGAP42 transcripts was developed in a cohort of patients treated with nivolumab. Its prognostic value was then validated in the TCGA-KIRC cohort. Second, the predictive value for nivolumab was confirmed in a set of patients from the CheckMate-025 phase 3 clinical trial. Lastly, we explored the correlation of our 3GES with different clinical, molecular, and immune tumor characteristics. If the results of this study are definitively validated in other retrospective and large-scale, prospective studies, the 3GES will represent a valuable tool for guiding the design of ICB-based clinical trials in the aRCC scenario in the near future., Competing Interests: UA-H—Travel, accommodations, expenses: Ipsen, Bayer, Merck, Pfizer, and Sanofi; honoraria for educational activities: Advanced Accelerator Applications - Novartis, Bayer, Ipsen, MSD, AstraZeneca, Merck, Eisai, Bristol-Myers Squibb, Kyowa Kirin, Rovi, GlaxoSmithKline, and LEO Pharma; honoraria for consultancies: Advanced Accelerator Applications - Novartis, Ipsen, AstraZeneca, Merck, Pfizer, Astellas, and Bayer. MF-L—Travel, accommodations, expenses: Seagen. VC-L—Travel, accommodations, expenses: AstraZeneca, Bristol-Myers Squibb, Eisai, Ipsen, Kyowa Kirin, Merck, Novartis, Pfizer, Pharmamar, Pierre-Fabre, Roche, and Sanofi; honoraria for educational activities: AstraZeneca and Pharmamar. LL-M—Travel, accommodations, expenses: Bristol-Myers Squibb, Lilly, MSD, and Roche; honoraria for educational activities: AstraZeneca, Boehringer Ingelheim, Novartis, Jansen, Astellas, and Sanofi; honoraria for consultancies: AstraZeneca, Boehringer Ingelheim, Novartis, Jansen, Astellas, and Sanofi. JG-G—Travel, accommodations, expenses: AstraZeneca, Bristol-Myers Squibb, MSD, Roche, Sanofi, and Takeda; honoraria for educational activities: AstraZeneca, Bristol-Myers Squibb, MSD, Novartis, Pierre-Fabre, Roche, Sanofi, and Takeda; honoraria for consultancies: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Novartis, Roche, Sanofi, and Takeda. NF-D—Travel, accommodations, expenses: GlaxoSmithKline, Lilly, Roche, and Sanofi. RL-L—Travel, accommodations, expenses: Lilly, Novartis, Pfizer, Merck, Roche, and Bristol-Myers Squibb; honoraria for educational activities: Lilly, Novartis, Pfizer, Merck, Roche, and Bristol-Myers Squibb; honoraria for consultancies: Pharmamar, Bayer, and Pierre Fabre. JR-B—Travel, accommodations, expenses: Merck, Pierre-Fabre, Sanofi, and Seagen; honoraria for educational activities: Ipsen; institutional research funding: Nouscom, Pfizer, and Roche. YZB, RL-L, and JR-B are inventors in one patent application over these results. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Betancor, Ferreiro-Pantín, Anido-Herranz, Fuentes-Losada, León-Mateos, García-Acuña, Vaamonde-Rodríguez, García-Pinel, Cebey-López, Villaverde-Viaño, Lombardía-Rodríguez, Kotrulev, Fernández-Díaz, Gomez-Tourino, Fernández-Baltar, García-González, Tubio, López-López and Ruiz-Bañobre.)

Background: In the advanced urothelial carcinoma (aUC) scenario there are no consistent immune checkpoint blockade predictive biomarkers. Recently a novel pan-tumor molecular tissue-based biomarker, the Immunotherapy Response Score (IRS), has been proposed. We conducted a retrospective study to validate the prognostic/predictive utility of the IRS in patients with aUC under atezolizumab monotherapy and to characterize its underlying molecular/immune features in the context of the IMvigor210 phase II trial., Patients and Methods: This is a post hoc pooled analysis of 261 patients with available clinical, molecular, and immune tumor data treated with atezolizumab monotherapy in the IMvigor210 phase II clinical trial. Efficacy endpoints were overall survival (OS), disease control rate (DCR), and overall response rate (ORR). Survival estimates were calculated by the Kaplan-Meier method, and groups were compared with the log-rank test. The Cox proportional hazards regression model was used to evaluate factors independently associated with OS. Factors associated with disease control (DC) and response were tested with logistic regression in univariable and multivariable analyses. Comparisons between patient and disease characteristics were carried out using chi-square or Fisher's exact tests. All P values were two-sided, and those <0.05 were considered statistically significant., Results: High IRS was significantly associated with a better OS in univariable [hazard ratio (HR) = 0.49, P < 0.001] and multivariable (HR = 0.60, P = 0.018) analyses. DCR and ORR were significantly higher among high IRS patients (DCR for high IRS versus low IRS patients: 57% versus 32%, P < 0.001; ORR: 42% versus 10%, P < 0.001). High IRS patients presented a higher probability of DC and response in univariable [DC: odds ratio (OR) = 2.72, P < 0.001; response: OR = 3.92, P < 0.001] and multivariable (DC: OR = 2.72, P < 0.001; response: OR = 3.92, P < 0.001) analyses., Conclusions: This study validates IRS as a strong independent prognostic and predictive biomarker for OS and DC/response in patients with aUC treated with atezolizumab monotherapy in the IMvigor210 phase II clinical trial., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Circulating tumor cell (CTC) enumeration has emerged as a powerful biomarker for the assessment of prognosis and the response to treatment in metastatic breast cancer (MBC). Moreover, clinical evidences show that CTC-cluster counts add prognostic information to CTC enumeration, however, their significance is not well understood, and more clinical evidences are needed. We aim to evaluate the prognostic value of longitudinally collected single CTCs and CTC-clusters in a heterogeneous real-world cohort of 54 MBC patients. Blood samples were longitudinally collected at baseline and follow up. CTC and CTC-cluster enumeration was performed using the CellSearch ® system. Associations with progression-free survival (PFS) and overall survival (OS) were evaluated using Cox proportional hazards modelling. Elevated CTC counts and CTC-clusters at baseline were significantly associated with a shorter survival time. In joint analysis, patients with high CTC counts and CTC-cluster at baseline were at a higher risk of progression and death, and longitudinal analysis showed that patients with CTC-clusters had significantly shorter survival compared to patients without clusters. Moreover, patients with CTC-cluster of a larger size were at a higher risk of death. A longitudinal analysis of a real-world cohort of MBC patients indicates that CTC-clusters analysis provides additional prognostic value to single CTC enumeration, and that CTC-cluster size correlates with patient outcome.