Dataset Information

Exonuclease 1 genetic variant is associated with clinical outcomes of pemetrexed chemotherapy in lung adenocarcinoma.

ABSTRACT: Pemetrexed is an anti-folate agent which is one of the most frequently used chemotherapy agents for non-squamous non-small cell lung cancer (NSCLC) patients. However, clinical response to pemetrexed chemotherapy and survival outcome of patients varies significantly. We evaluated whether the genetic variants in miRNA target sites may affect the treatment outcome of pemetrexed chemotherapy in lung adenocarcinoma patients. One hundred SNPs in miRNA binding regions in cancer-related genes were obtained from the crosslinking, ligation, and sequencing of hybrids (CLASH) and CancerGenes database, and the associations with the response to pemetrexed chemotherapy and survival outcomes were investigated in 314 lung adenocarcinoma patients. Two polymorphisms, EXO1 rs1047840G>A and CAMKK2 rs1653586G>T, were significantly associated with worse chemotherapy response (adjusted odds ratio [aOR] = 0.41, 95% CI = 0.24-0.68, P = 0.001, under dominant model; and aOR = 0.33, 95% CI = 0.16-0.67, P = 0.002, under dominant model, respectively) and worse OS (adjusted hazard ratio [aHR] = 1.34, 95% CI = 1.01-1.77, P = 0.04, under dominant model; and aHR = 1.50, 95% CI = 1.06-2.13, P = 0.02, under dominant model, respectively) in multivariate analyses. Significantly increased luciferase activity was noted in EXO1 rs1047840 A allele compared to G allele. In conclusion, two SNPs in miRNA binding sites, especially EXO1 rs1047840G>A, were associated with the chemotherapy response and survival outcome in lung adenocarcinoma patients treated with pemetrexed.

SUBMITTER: Hong MJ

PROVIDER: S-EPMC9809306 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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<i>Exonuclease 1</i> genetic variant is associated with clinical outcomes of pemetrexed chemotherapy in lung adenocarcinoma.

Hong Mi Jeong MJ Park Ji Eun JE Lee Shin Yup SY Lee Jang Hyuck JH Choi Jin Eun JE Kang Hyo-Gyoung HG Do Sook Kyung SK Jeong Ji Yun JY Shin Kyung Min KM Lee Won Ki WK Seok Yangki Y Choi Sun Ha SH Lee Yong Hoon YH Seo Hyewon H Yoo Seung Soo SS Lee Jaehee J Cha Seung Ick SI Kim Chang Ho CH Park Jae Yong JY

Journal of Cancer 20221207 15

Pemetrexed is an anti-folate agent which is one of the most frequently used chemotherapy agents for non-squamous non-small cell lung cancer (NSCLC) patients. However, clinical response to pemetrexed chemotherapy and survival outcome of patients varies significantly. We evaluated whether the genetic variants in miRNA target sites may affect the treatment outcome of pemetrexed chemotherapy in lung adenocarcinoma patients. One hundred SNPs in miRNA binding regions in cancer-related genes were obtai ...[more]

PMID: 36606188

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Project description:Objective: This study investigated survival in selected Chinese patients with advanced lung adenocarcinoma who received initial chemotherapy with pemetrexed. We also explored the relationship between genetic biomarkers and pemetrexed efficacy. Methods: We retrospectively collected patients (n = 1,047) enrolled in the Chinese Patient Assistance Program from multiple centers who received pemetrexed alone or combined with platinum as initial chemotherapy and continued pemetrexed maintenance therapy for advanced lung adenocarcinoma from November 2014 to June 2017. The outcomes were duration of treatment (DOT) and overall survival (OS). Clinical features were analyzed for their influence on the treatment effect and prognosis. Next-generation sequencing (NGS) was performed to identify genetic biomarkers associated with the efficacy of pemetrexed. Results: The median DOT was 9.1 months (95% CI: 8.5-9.8), and the median OS was 26.2 months (95% CI: 24.2-28.1). OS was positively correlated with DOT (r = 0.403, P < 0.001). Multivariable analysis showed that smoking status and Eastern Cooperative Oncology Group (ECOG) performance status (PS) were independently associated with DOT; smoking status, ECOG PS, targeted therapy, and EGFR/ALK/ROS1 status were independently associated with OS. NGS in 22 patients with available samples showed genes with high mutation rates were: TP53 (54.5%), EGFR (50.0%), MYC (18.2%), and PIK3CA (13.6%). When grouped based on progression-free survival (PFS) reported in the PARAMOUNT study, the DOT > 6.9 months set was associated with PIK3CA, ALK, BRINP3, CDKN2A, CSMD3, EPHA3, KRAS, and RB1 mutations, while ERBB2 mutation was observed only in the DOT ≤ 6.9 months set. Conclusion: This study shows that initial chemotherapy with pemetrexed is an effective regimen for advanced lung adenocarcinoma in selected Chinese patients. There is no specific genetic profile predicting the benefit of pemetrexed found by NGS. Biomarkers predicting the efficacy of pemetrexed need further exploration.

Project description:BackgroundAlthough pemetrexed plus cis/carboplatin has become the most effective chemotherapy regimen for patients with advanced lung adenocarcinoma, predictive biomarkers are not yet available, and new tools to identify chemosensitive patients who would likely benefit from this treatment are desperately needed. In this study, we constructed and validated predictive peptide models using the serum peptidome profiles of two datasets.MethodsOne hundred eighty-three patients treated with first-line platinum-based pemetrexed treatment for advanced lung adenocarcinoma were retrospectively enrolled and randomized into the training (n = 92) or validation (n = 91) set, and pre-treatment serum samples were analyzed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and ClinProTools software. Serum peptidome profiles from the training set were used to identify potential predictive peptide biomarkers and construct a predictive peptide model for accurate group discrimination; which was then used to classify validation samples into "good" and "poor" outcome groups. The clinical outcomes of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were analyzed based on the classification result.ResultsEight potential peptide biomarkers were identified. A predictive peptide model based on four distinct m/z features (2,142.12, 3,316.19, 4,281.94, and 6,624.02 Da) was developed based on the clinical outcomes of training set patients after first-line pemetrexed plus platinum treatment. In the validation set, the good group had significantly higher ORR (49.1% vs. 8.3%, P <0.001) and DCR (96.4% vs. 47.2%, P <0.001), and longer PFS (7.3 months vs. 2.7 months, P <0.001) vs. the poor group. However, the model did not predict OS (13.6 months vs. 12.7 months, P = 0.0675).ConclusionOur predictive peptide model could predict pemetrexed plus platinum treatment outcomes in patients with advanced lung adenocarcinoma and might thus facilitate appropriate patient selection. Further studies are needed to confirm these findings.

Project description:BackgroundRET rearrangements are targetable, oncogenic lung cancer drivers. While previous series have shown durable clinical benefit with pemetrexed-based therapies in ALK- and ROS1-rearranged lung cancers, the benefits of pemetrexed-based treatments in patients with RET-rearranged lung cancers relative to other genomic subsets have not previously been explored.Patients and methodsA retrospective review of patients with pathologically confirmed stage IIIB/IV lung adenocarcinomas and evidence of a RET, ROS1, or ALK rearrangement, or a KRAS mutation was conducted. Patients were eligible if they received treatment with pemetrexed alone or in combination. The primary outcome of progression-free survival (PFS), and secondary outcomes of overall response rate (ORR, RECIST v1.1), time to progression (TTP), and time to treatment discontinuation were compared between RET-rearranged and groups of ROS1-rearranged, ALK-rearranged, and KRAS-mutant lung cancers.ResultsWe evaluated 104 patients. Patients with RET-rearranged lung cancers (n = 18) had a median PFS of 19 months [95% confidence interval (CI) 12-not reached (NR)] that was comparable with patients with ROS1- (23 months, 95% CI 14-NR, n = 10) and ALK-rearranged (19 months, 95% CI 15-36, n = 36) lung cancers, and significantly improved compared with patients with KRAS-mutant lung cancers (6 months, 95% CI 5-9, P < 0.001, n = 40). ORR (45%), median TTP (20 months, 95% CI 17-NR), and median time to treatment discontinuation (21 months, 95% CI 6-NR) in patients with RET-rearranged lung cancers were not significantly different compared with patients with ALK- and ROS1-rearranged lung cancers, and improved compared with patients with KRAS-mutant lung cancers.ConclusionDurable benefits with pemetrexed-based therapies in RET-rearranged lung cancers are comparable with ALK- and ROS1-rearranged lung cancers. When selecting therapies for patients with RET-rearranged lung cancers, pemetrexed-containing regimens should be considered.

Dataset Information

Exonuclease 1 genetic variant is associated with clinical outcomes of pemetrexed chemotherapy in lung adenocarcinoma.

Publications

<i>Exonuclease 1</i> genetic variant is associated with clinical outcomes of pemetrexed chemotherapy in lung adenocarcinoma.

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