Data documento
18/10/2024

Título
Gene expression profiles (GEPs) of immuno-oncologic pathways as predictors of response to checkpoint inhibitors in advanced NSCLC

Autor(es)
Pedro De Marchi - Leticia Ferro Leal - Luciane Sussuchi da Silva - Rodrigo de Oliveira Cavagna - Flavio Augusto Ferreira da Silva - Vinicius Duval da Silva - Eduardo Ca da Silva - Augusto O Saito - Vladmir C Cordeiro de Lima - Rui Manuel Reis.

Palavras chave
GEP; Gama interferon; Immunotherapy; Lung-tumor signature; NSCLC; Non-small cell lung cancer; PD-L1; TIS; anti-CTLA-4; anti-PD-(L)1; gene expression profile.

Resumo
Background: Immune checkpoint inhibitors (ICIs) revolutionized non-small-cell lung cancer (NSCLC) treatment. However, improving patients selection for this therapy is needed. Gene expression profile (GEP) is a promising biomarker tool. We assessed the predictive value of 48 onco-immune GEPs in an NSCLC real-world scenario. Methods: Retrospective cohort of Brazilian NSCLC patients treated with ICIs in any line. GEP was assessed in FFPE tumor tissue using the nCounter PanCancer IO360 panel, comprising 770 cancer immune genes. Results: The median age of the 135 patients was 61 years old, most male (57.8 %), history of smoking (83.6 %), ECOG-PS 0-1 (88.7 %), clinical stage IV (91.9 %) and adenocarcinoma (65.1 %). First-line ICI in 40 % of cases, alone or in combination with chemotherapy. The median follow-up was 28 months, overall survival after starting immunotherapy (post-immunotherapy survival - PIS) was 17.8 months, and real-world progression-free survival was 5.5 months. The GEP analysis was possible in 66 patients. We found that 14 different GEPs associated with PIS, namely IDO1, PD-L2, Cytotoxicity, Cytotoxic Cells, IFN Downstream, CTLA4, PD-L1, TIGIT, Lymphoid, Immunoproteasome, Exhausted CD8, IFN Gamma, TIS and APM. TIS and IFN-γ were the most significant GEPs associated with favorable outcomes. The median PIS for patients with high TIS expression was 29.2 versus 15.5 months (HR 0.42; 95 %CI; 0.17-0.67; p<0.05) for those with low expression. Similar results were observed for IFN-γ. Conclusions: The TIS (tumor inflammation signature) and IFN-γ signatures constitute predictive biomarkers to identify patients with NSCLC patients who would possibly benefit from ICI therapies.

Citação
Gene expression profiles (GEPs) of immuno-oncologic pathways as predictors of response to checkpoint inhibitors in advanced NSCLC. De Marchi P, Leal LF, da Silva LS, Cavagna RO, da Silva FAF, da Silva VD, da Silva EC, Saito AO, de Lima VCC, Reis RM.Transl Oncol. 2024 Jan;39:101818. doi: 10.1016/j.tranon.2023.101818. Epub 2023 Oct 31.PMID: 37918166

Data documento
19/03/2025

Título
PD-L1 expression and microsatellite instability (MSI) in cancer of unknown primary site

Autor(es)
João Neif Antonio Junior - Daniel D Almeida Preto - Maria Eduarda Zanatta Neder Lazarini - Marcos Alves de Lima - Murilo Bonatelli - Gustavo Noriz Berardinelli - Vinicius Duval da Silva - Céline Pinheiro - Rui Manuel Reis - Flavio Mavignier Cárcano.

Palavras chave
Immune checkpoint proteins; Immunotherapy; Microsatellite instability; Neoplasms; Unknown primary.

Resumo
Background: Cancer of unknown primary site (CUP) is a heterogeneous group of tumors for which the origin remains unknown. Clinical outcomes might be influenced by regulatory processes in its microenvironment. Microsatellite instability (MSI) is a predictive biomarker for cancer immunotherapy and its status, as well as co-occurrence with PD-L1 expression, is poorly evaluated. We aim to evaluate the expression of PD-L1 and the status of MSI in CUP and their possible associations with clinical-pathological features. Methods: The combined positive score (CPS) PD-L1 expression was evaluated by immunohistochemistry. MSI status was assessed using a hexa-plex marker panel by polymerase chain reaction followed by fragment analysis. Results: Among the 166 cases, MSI analysis was conclusive in 120, with two cases being MSI positive (1.6%). PD-L1 expression was positive in 18.3% of 109 feasible cases. PD-L1 expression was significantly associated with non-visceral metastasis and a dominance of nodal metastasis. The median overall survival (mOS) was 3.7 (95% CI 1.6-5.8) months and patients who expressed PD-L1 achieved a better mOS compared to those who did not express PD-L1 (18.7 versus 3.0 months, p-value: < .001). ECOG-PS equal to or more than two and PD-L1 expression were independent prognostic factors in multivariate analysis (2.37 and 0.42, respectively). Conclusion: PD-L1 is expressed in a subset (1/5) of patients with CUP and associated with improved overall survival, while MSI is a rare event. There is a need to explore better the tumor microenvironment as well as the role of immunotherapy to change such a bad clinical outcome.

Citação
unior JNA, Preto DD, Lazarini MEZN, de Lima MA, Bonatelli M, Berardinelli GN, da Silva VD, Pinheiro C, Reis RM, Cárcano FM.Int J Clin Oncol. 2024 Jun;29(6):726-734. doi: 10.1007/s10147-024-02494-3.Epub 2024 Mar 25. PMID: 38528294