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Identification of 15 lncRNAs Signature for Predicting Survival Benefit of Advanced Melanoma Patients Treated with Anti-PD-1 Monotherapy.

ABSTRACT: The blockade of programmed cell death protein 1 (PD-1) as monotherapy has been widely used in melanoma, but to identify melanoma patients with survival benefit from anti-PD-1 monotherapy is still a big challenge. There is an urgent need for prognostic signatures improving the prediction of immunotherapy responses of these patients. We analyzed transcriptomic data of pre-treatment tumor biopsies and clinical profiles in advanced melanoma patients receiving only anti-PD-1 monotherapy (nivolumab or pembrolizumab) from the PRJNA356761 and PRJEB23709 data sets as the training and validation cohort, respectively. Weighted gene co-expression network analysis was used to identify the key module, then least absolute shrinkage and selection operator was conducted to determine prognostic-related long noncoding RNAs (lncRNAs). Subsequently, the differentially expressed genes between different clusters were identified, and their function and pathway annotation were performed. In this investigation, 92 melanoma patients with complete survival information (51 from training cohort and 41 from validation cohort) were included in our analyses. We initiallyidentified the key module (skyblue) by weighted gene co-expression network analysis, and then identified a 15 predictive lncRNAs (AC010904.2, LINC01126, AC012360.1, AC024933.1, AL442128.2, AC022211.4, AC022211.2, AC127496.5, NARF-AS1, AP000919.3, AP005329.2, AC023983.1, AC023983.2, AC139100.1, and AC012615.4) signature in melanoma patients treated with anti-PD-1 monotherapy by least absolute shrinkage and selection operator in the training cohort. These results were then validated in the validation cohort. Finally, enrichment analysis showed that the functions of differentially expressed genes between two consensus clusters were mainly related to the immune process and treatment. In summary, the 15 lncRNAs signature is a novel effective predictor for prognosis in advanced melanoma patients treated with anti-PD-1 monotherapy.

SUBMITTER: Zhou JG

PROVIDER: S-EPMC8143567 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Anti-programmed cell death 1 antibody is a standard therapy for advanced non-small cell lung cancer (NSCLC). However, immune-related adverse events (irAEs), such as skin reactions, are frequently observed. Although skin reactions are associated with clinical efficacy in melanoma, this association in advanced NSCLC and predictors of irAEs remain unclear. Accordingly, this study identified potential correlations of skin reactions with clinical efficacy and clinical predictors of development of skin reactions. SUBJECTS, MATERIALS, AND METHODS:We retrospectively surveyed patients with advanced NSCLC who received nivolumab or pembrolizumab monotherapy at Sendai Kousei Hospital (n =?155) during January 2016 to April 2018. Treatment efficacy was evaluated in patients with and without skin reactions, and associated predictive markers were determined. A 6-week landmark analysis was conducted to assess the clinical benefit of early skin reactions. RESULTS:Skin reactions were observed in 51 patients with a median time to onset of 6.4?weeks. The overall response rate (ORR) was significantly higher in patients with skin reactions (57% vs. 19%, p < .001). Median progression-free survival (PFS) durations of 12.9 and 3.5 months and overall survival durations of not reached and 11.4 months were observed in patients with and without skin reactions, respectively. In the 6-week landmark analysis, the ORR was significantly higher in patients with skin reactions, and skin reactions were significantly associated with increased PFS. A multivariate analysis identified pre-existing rheumatoid factor (RF) as an independent predictor of skin reactions. CONCLUSION:Skin reactions appeared beneficial in patients treated with nivolumab/pembrolizumab for advanced NSCLC and could be predicted by pre-existing RF. Further large-scale validations studies are warranted. IMPLICATIONS FOR PRACTICE:This single-institutional medical record review that included 155 patients with advanced non-small cell lung cancer who were treated with nivolumab or pembrolizumab monotherapy revealed that overall response rate and progression-free survival were significantly better in patients with skin reactions. Pre-existing rheumatoid factor was an independent predictor of skin reactions.

Project description:Background: The best response and survival outcomes between advanced melanoma patients treated with the anti-PD-1 monotherapy vary greatly, rendering a risk model in need to optimally stratify patients based on their likelihood to benefit from the said treatment. Methods: We performed an ad hoc analysis of 89 advanced melanoma patients treated with the anti-PD-1 monotherapy from two prospective clinical trials at the Peking University Cancer Hospital from April 2016 to May 2018. Clinicodemographical characteristics, baseline and early-on-treatment (median 0.6 months after anti-PD-1 monotherapy initiation) routine laboratory variables, including complete blood count and general chemistry, and best response/survival data were extracted and analyzed in both univariate and multivariate logistic and Cox proportional hazard models. Results: After three rounds of screening, risk factors associated with a poorer PFS included a high pre-treatment neutrophil, derived neutrophil-lymphocyte ratio (dNLR), low pre-treatment hemoglobin, and low early-on-/pre-treatment fold change of eosinophil; those with a poorer OS included a high pre-treatment neutrophil, eosinophil, PLT, early-on/pre-treatment fold change of LDH and neutrophil; and those with a poorer best response included a high pre-treatment NLR and early-on-/pre-treatment LDH fold change. Risk models (scale: low, median-low, median high, and high risk) were established based on these risk factors as dichotomous variables and M stage (with vs. without distant metastasis) for PFS (HR 1.976, 95% CI, 1.507-2.592, P < 0.001), OS (HR 2.348, 95% CI, 1.688-3.266), and non-responder (OR 3.586, 95% CI, 1.668-7.713, P = 0.001), respectively. For patients with low, median-low, median-high, and high risks of developing disease progression (PD), six-month PFS rates were 64.3% (95% CI, 43.5-95.0%), 37.5% (95% CI, 22.4-62.9%), 9.1% (95% CI, 3.1-26.7%), and 0%, respectively. For patients with OS risks of low, median-low, median-high, and high, OS rates at 12 months were 82.5% (95% CI, 63.1-100%), 76.6% (95% CI, 58.4-100%), 42.1% (95% CI, 26.3-67.3%), and 23.9% (95% CI, 11.1-51.3%), respectively. For patients with risks of low, median-low, median-high, and high of being a non-responder, objective response rates were 50.0% (95% CI, 15.7-84.3%), 27.8% (95% CI, 9.7-53.5%), 10.3% (95% CI, 2.9-24.2%), and 0%, respectively. Conclusion: A risk scoring model based on the clinicodemographical characteristics and easily obtainable routinely tested laboratory biomarkers may facilitate the best response and survival outcome prediction and personalized therapeutic decision making for the anti-PD-1 monotherapy treated advanced melanoma patients in Asia.

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Identification of 15 lncRNAs Signature for Predicting Survival Benefit of Advanced Melanoma Patients Treated with Anti-PD-1 Monotherapy.

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