Predictive value of ZFHX4 mutation for the efficacy of immune checkpoint inhibitors in non-small cell lung cancer and melanoma.

Studies have shown that the Zinc finger homeobox 4 (ZFHX4) might be a factor in the prognosis of malignancies. However, little is known about the association between the ZFHX4 mutation and the effectiveness of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) and melanoma. Three public ICIs-treated NSCLC cohorts were divided into discovery cohort (n=75) and validation cohort (n=62), which were used to evaluate the relationship between ZFHX4 mutation and ICIs effectiveness in NSCLC. Seven ICIs-treated melanoma cohorts (n = 418) were used to analyze the relationship between ZFHX4 mutation and immunotherapy efficacy in melanoma. NSCLC and skin cutaneous melanoma (SKCM) cohorts from The Cancer Genome Atlas (TCGA) were used to investigate underlying mechanism. Patients with ZFHX4 mutant-type (ZFHX4-Mut) showed a superior objective response rate (ORR) (P < 0.01) and longer progression-free survival (PFS) (P < 0.05) than patients with ZFHX4 wild-type (ZFHX4-WT) in NSCLC cohorts. In the melanoma cohorts, patients carrying ZFHX4-Mut had a higher ORR (P = 0.042) and longer overall survival (OS) (P = 0.011). Besides, patients with NSCLC and melanoma harboring ZFHX4-Mut had a higher tumor mutation burden (TMB) (P<0.001) and tumor neoantigen burden (TNB) (P<0.001) than those harboring ZFHX4-WT. ZFHX4 mutation was associated with higher levels of plasma B cells, activated CD4+ memory T cells, and CD8+ T cells. Seven DNA damage repair pathways were significantly enriched in the ZFHX4-Mut group. ZFHX4 mutation could serve as a predicter for the efficacy of ICIs therapy in NSCLC and melanoma.

Fu C ，Gu H ，Sun L ，Wang Z ，Zhang Q ，Luo N ，Chen D ，Zhou T ... -  《-》

PCDH11X mutation as a potential biomarker for immune checkpoint therapies in lung adenocarcinoma.

Immune checkpoint inhibitors (ICIs) have achieved impressive success in lung adenocarcinoma (LUAD). However, the response to ICIs varies among patients, and predictive biomarkers are urgently needed. PCDH11X is frequently mutated in LUAD, while its role in ICI treatment is unclear. In this study, we curated genomic and clinical data of 151 LUAD patients receiving ICIs from three independent cohorts. Relations between PCDH11X and treatment outcomes of ICIs were examined. A melanoma cohort collected from five published studies, a pan-cancer cohort, and non-ICI-treated TCGA-LUAD cohort were also examined to investigate whether PCDH11X mutation is a specific predictive biomarker for LUAD ICI treatment. Among the three ICI-treated LUAD cohorts, PCDH11X mutation (PCDH11X-MUT) was associated with better clinical response compared to wild-type PCDH11X (PCDH11X-WT). While in ICI-treated melanoma cohort, the pan-cancer cohort excluding LUAD, and the non-ICI-treated TCGA-LUAD cohort, no significant differences in overall survival (OS) were observed between the PCDH11X-MUT and PCDH11X-WT groups. PCDH11X mutation was associated with increased PD-L1 expression, tumor mutation burden (TMB), neoantigen load, DNA damage repair (DDR) mutations, and hot tumor microenvironment in TCGA-LUAD cohort. Our findings suggested that the PCDH11X mutation might serve as a specific biomarker to predict the efficacy of ICIs for LUAD patients. Considering the relatively small sample size of ICI-treated cohorts, future research with larger cohorts and prospective clinical trials will be essential for validating and further exploring the role of PCDH11X mutation in the context of immunotherapy outcomes in LUAD. KEY MESSAGES: PCDH11X mutation is associated with better clinical response compared to wild type PCDH11X in three ICIs-treated LUAD cohorts. In ICIs-treated melanoma cohort, the pan-cancer cohort excluding LUAD, and non-ICIs-treated TCGA-LUAD cohorts PCDH11X mutation is not associated with better clinical response, suggesting PCDH11X mutation might be a specific biomarker to predict the efficacy of ICIs treatment for LUAD patients. PCDH11X mutation is associated with increased PD-L1 expression, tumor mutation burden, and neoantigen load in TCGA-LUAD cohort. PCDH11X mutation is associated with hot tumor microenvironment in TCGA-LUAD cohort.

Liu M ，Yang M ，Zhang B ，Xia S ，Zhao J ，Yan L ，Ren Y ，Guo H ，Zhao J ... -  《-》

Influence of TP53 Comutation on the Tumor Immune Microenvironment and Clinical Outcomes With Immune Checkpoint Inhibitors in STK11-Mutant Non-Small-Cell Lung Cancer.

Naqash AR ，Floudas CS ，Aber E ，Maoz A ，Nassar AH ，Adib E ，Choucair K ，Xiu J ，Baca Y ，Ricciuti B ，Alessi JV ，Awad MM ，Kim C ，Judd J ，Raez LE ，Lopes G ，Nieva JJ ，Borghaei H ，Takebe N ，Ma PC ，Halmos B ，Kwiatkowski DJ ，Liu SV ，Mamdani H ... -  《JCO Precision Oncology》

Identification of gene signatures relevant to the efficacy of immune checkpoint inhibitors in non-small cell lung cancer.

Despite significant advancements in the treatment of non-small cell lung cancer (NSCLC) through immunotherapy, many patients still exhibit resistance to this approach. This study aims to identify the characteristics of individuals who can benefit from immunotherapy, especially immune checkpoint inhibitors (ICIs), and to investigate optimal strategies for patients who experience resistance to it. Data on gene expression patterns and clinical information from NSCLC patients who underwent immunotherapy were obtained from the Gene Expression Omnibus databases. A predictive signature for immunotherapy prognosis was developed using a training dataset and validated with validation datasets. Immune landscape and immunotherapy responsiveness analyses were conducted to assess the risk signature. Additionally, data from a study on immunotherapy were used to evaluate the correlation between MNX1 mutation and the effectiveness of ICIs, including clinical data and whole exome sequencing data. We identified 7 genes in NSCLC using RNA-seq data that were significantly associated with the efficacy of immunotherapy. Based on these genes, a risk signature was created to predict the efficacy of ICIs. Patients in the low-risk group had better outcomes compared to those in the high-risk group after receiving ICIs. Additionally, our analysis of the immune landscape revealed a significant association between the high-risk signature and an immunosuppressive state. We also discovered an unexpected role of tumor-specific MNX1 and HOXD1 in suppressing the immune response against cancer. Notably, NSCLC patients with MNX1 mutations experienced prolonged progression-free survival. Furthermore, we identified several medications that exhibited increased sensitivity in patients with high MNX1 expression, with topoisomerase inhibitors showing the highest level of sensitivity. This could be a potential strategy to improve the efficacy of ICIs. The risk signature has demonstrated its effectiveness in forecasting the prognosis of NSCLC treated with ICIs, enabling better patient stratification and more accurate prediction of immunotherapy response. Moreover, MNX1 and HOXD1 have been identified as key molecules related to immunotherapy resistance. Inhibition of these molecules, combined with current ICIs, offers novel strategies for the management of NSCLC patients.

Liu M ，Li Q ，Meng X ，Cui Y ，Sun W ，Wang H ，Gao Q ... -  《-》

Decoding KRAS mutation in non-small cell lung cancer patients receiving immunotherapy: A retrospective institutional comparison and literature review.

KRAS mutation the most common molecular alteration in advanced non-small cell lung cancer (NSCLC) and is associated with an unfavourable prognosis, largely due to the lack of targeted therapeutic options for the majority of the KRAS mutated isoforms. The landscape of NSCLC treatment has expanded with the introduction of immune checkpoint inhibitors (ICIs). Nonetheless, data regarding the efficacy of ICI in NSCLC patients harbouring KRAS mutations are conflicting. This study aimed to compare clinical outcomes of ICIs in advanced NSCLC with different isoforms of KRAS mutations. A retrospective study was conducted on 143 patients with advanced NSCLC harbouring different KRAS mutation and treated with immune checkpoint inhibitors (ICI) between December 2020 and July 2022 at "Fondazione IRCCS Istituto Nazionale dei Tumori" in Milan. Log-rank and Cox Hazard methods were used for survival analysis. We evaluated 143 patients with advanced non-small cell lung cancer (NSCLC) harboring KRAS mutations. The most common mutation was G12C (41 %), followed by G12V (23.7 %) and G12D (11.8 %). The G12C mutation was notably associated with a higher incidence of bone metastases (42 %). Immunotherapy was administered as monotherapy in 54.5 % of cases, while 69 % received it as part of a first-line combination with chemotherapy. Co-mutations were detected in 52 % of patients, with Q61 (63 %) and G12C (58 %) being the most prevalent. Among these, 24 % had STK11 co-mutations, and 29 % had TP53 co-mutations. No significant differences in overall survival (OS) or progression-free survival (PFS) were observed across different KRAS subtypes. The longest OS was seen in patients with Q61 (46.5 months), 13X (31.8 months), and G12C (28.7 months). The highest overall response rate (ORR) of 73 % was observed in the G12D group, particularly with the combination of chemoimmunotherapy, where stable disease was the most common outcome at 40 %. The median duration of response (DOR) was 7.4 months across both treatments. The longest DOR was seen in the G12V group at 10.2 months, with no significant difference between treatments. In contrast, the shortest DOR was in the G12A group, with 1.54 months in those treated with combination therapy compared to 2.57 months with single-agent therapy. Regarding co-mutations, patients with STK11 co-mutations had a higher median OS than those without (39.7 vs. 26.1 months), but this was not statistically significant (p = 1). Similarly, TP53 co-mutations were associated with a lower median OS (19.1 vs. 26.1 months, p = 0.7), though this too was not statistically significant. Importantly, bone metastases emerged as a significant adverse prognostic factor, nearly doubling the risk of mortality (HR: 2.81, p < 0.001), regardless of KRAS subtype or co-mutation status. KRAS mutation subtypes demonstrate varying clinical outcomes. Although no statistically significant differences were observed in overall survival (OS) or progression-free survival (PFS), bone metastases were identified as a significant adverse prognostic factor, nearly doubling the risk of mortality (HR: 2.72, p < 0.001) regardless of KRAS subtype or co-mutation status. These findings underscore the importance of personalized treatment approaches tailored to the genetic profiles of patients with advanced NSCLC.

Urtecho SB ，Provenzano L ，Spagnoletti A ，Bottiglieri A ，Pircher C ，Massa G ，Sposetti C ，Proto C ，Brambilla M ，Occhipinti M ，Mazzeo L ，Beninato T ，Leporati R ，Giani C ，Cavalli C ，Serino R ，Prina MM ，Bassetti A ，Nasca V ，di Mauro RM ，Abate A ，Manglaviti S ，Dumitrascu AD ，Liberti GD ，Cassano TS ，Ganzinelli M ，Wu S ，Garassino MC ，de Braud FGM ，Russo GL ，Prelaj A ... -  《-》