S-1 Maintenance Therapy After First-Line Treatment With Nab-Paclitaxel Plus S-1 for Advanced Pancreatic Adenocarcinoma: A Real-World Study

Shi, Yan; Han, Qi; Yan, Huan; Lv, Yao; Yuan, Jing; Li, Jie; Guan, Shasha; Wang, Zhikuan; Huang, Lei; Dai, Guanghai

doi:10.3389/fonc.2022.865404

Cited by 5 publications

(11 citation statements)

References 33 publications

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“…The progression of PDAC is the result of the evolving crosstalk between cancer cells and stroma cells. A main reason for the refractoriness of local primary PDAC to systemic therapy is that PDAC cells are surrounded by abundant tumour-stroma cells with an intense desmoplastic reaction, which may create a barrier to the drugs penetrating into the tumour, and the stroma has been considered as a potential therapeutic target; the role of the stroma proportion may explain the resistance of majorly local primary PDAC to chemotherapy 18 , 64 , 65 . In this study, patients receiving resection only without any non-surgical treatment were included, so the results would also be less probably influenced by the above concerns.…”

Section: Discussionmentioning

confidence: 99%

Gene signature developed for predicting early relapse and survival in early-stage pancreatic cancer

et al. 2023

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Background The aim of this study was to construct a predictive signature integrating tumour-mutation- and copy-number-variation-associated features using machine learning to precisely predict early relapse and survival in patients with resected stage I–II pancreatic ductal adenocarcinoma. Methods Patients with microscopically confirmed stage I–II pancreatic ductal adenocarcinoma undergoing R0 resection at the Chinese PLA General Hospital between March 2015 and December 2016 were enrolled. Whole exosome sequencing was performed, and genes with different mutation or copy number variation statuses between patients with and without relapse within 1 year were identified using bioinformatics analysis. A support vector machine was used to evaluate the importance of the differential gene features and to develop a signature. Signature validation was performed in an independent cohort. The associations of the support vector machine signature and single gene features with disease-free survival and overall survival were assessed. Biological functions of integrated genes were further analysed. Results Overall, 30 and 40 patients were included in the training and validation cohorts, respectively. Some 11 genes with differential patterns were first identified; using a support vector machine, four features (mutations of DNAH9, TP53, and TUBGCP6, and copy number variation of TMEM132E) were further selected and integrated to construct a predictive signature (the support vector machine classifier). In the training cohort, the 1-year disease-free survival rates were 88 per cent (95 per cent c.i. 73 to 100) and 7 per cent (95 per cent c.i. 1 to 47) in the low-support vector machine subgroup and the high-support vector machine subgroup respectively (P < 0.001). Multivariable analyses showed that high support vector machine was significantly and independently associated with both worse overall survival (HR 29.20 (95 per cent c.i. 4.48 to 190.21); P < 0.001) and disease-free survival (HR 72.04 (95 per cent c.i. 6.74 to 769.96); P < 0.001). The area under the curve of the support vector machine signature for 1-year disease-free survival (0.900) was significantly larger than the area under the curve values of the mutations of DNAH9 (0.733; P = 0.039), TP53 (0.767; P = 0.024), and TUBGCP6 (0.733; P = 0.023), the copy number variation of TMEM132E (0.700; P = 0.014), TNM stage (0.567; P = 0.002), and differentiation grade (0.633; P = 0.005), suggesting higher predictive accuracy for prognosis. The value of the signature was further validated in the validation cohort. The four genes included in the support vector machine signature (DNAH9, TUBGCP6, and TMEM132E were novel in pancreatic ductal adenocarcinoma) were significantly associated with the tumour immune microenvironment, G protein-coupled receptor binding and signalling, cell–cell adhesion, etc. Conclusion The newly constructed support vector machine signature precisely and powerfully predicted relapse and survival in patients with stage I–II pancreatic ductal adenocarcinoma after R0 resection.

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Section: Discussionmentioning

confidence: 99%

Gene signature developed for predicting early relapse and survival in early-stage pancreatic cancer

et al. 2023

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“…In our previous phase II NPSPAC trial [ 10 ], nab-paclitaxel plus S-1 (NPS) in the first-line setting showed encouraging activity and efficacy with promising objective response and survival for advanced PDAC under meticulous toxicological surveillance. We further showed that S-1 maintenance after non-progressive disease induced by first-line NPS therapy was effective and well-tolerated for patients with advanced PDAC, with encouraging survival [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

High somatic mutations in circulating tumor DNA predict response of metastatic pancreatic ductal adenocarcinoma to first-line nab-paclitaxel plus S-1: prospective study

Huang,

Lv,

Guan

et al. 2024

J Transl Med

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Aims We previously showed that the nab-paclitaxel plus S-1 (NPS) regimen had promising effects against metastatic pancreatic ducal adenocarcinoma (mPDAC), whose efficacy however could not be precisely predicted by routine biomarkers. This prospective study aimed to investigate the values of mutations in circulating tumor DNA (ctDNA) and their dynamic changes in predicting response of mPDAC to NPS chemotherapy. Methods Paired tumor tissue and blood samples were prospectively collected from patients with mPDAC receiving first-line NPS chemotherapy, and underwent next-generation sequencing with genomic profiling of 425 genes for ctDNA. High mutation allelic frequency (MAF) was defined as ≥ 30% and ≥ 5% in tumor tissue and blood, respectively. Kappa statistics were used to assess agreement between mutant genes in tumor and ctDNA. Associations of mutations in ctDNA and their dynamic changes with tumor response, overall survival (OS), and progression-free survival (PFS) were assessed using the Kaplan–Meier method, multivariable-adjusted Cox proportional hazards regression, and longitudinal data analysis. Results 147 blood samples and 43 paired tumor specimens from 43 patients with mPDAC were sequenced. The most common driver genes with high MAF were KRAS (tumor, 35%; ctDNA, 37%) and TP53 (tumor, 37%; ctDNA, 33%). Mutation rates of KRAS and TP53 in ctDNA were significantly higher in patients with liver metastasis, with baseline CA19-9 ≥ 2000 U/mL, and/or without an early CA19-9 response. κ values for the 5 most commonly mutated genes between tumor and ctDNA ranged from 0.48 to 0.76. MAFs of the genes mostly decreased sequentially during subsequent measurements, which significantly correlated with objective response, with an increase indicating cancer progression. High mutations of KRAS and ARID1A in both tumor and ctDNA, and of TP53, CDKN2A, and SMAD4 in ctDNA but not in tumor were significantly associated with shorter survival. When predicting 6-month OS, AUCs for the 5 most commonly mutated genes in ctDNA ranged from 0.59 to 0.84, larger than for genes in tumor (0.56 to 0.71) and for clinicopathologic characteristics (0.51 to 0.68). Repeated measurements of mutations in ctDNA significantly differentiated survival and tumor response. Among the 31 patients with ≥ 2 ctDNA tests, longitudinal analysis of changes in gene MAF showed that ctDNA progression was 60 and 58 days ahead of radiologic and CA19-9 progression for 48% and 42% of the patients, respectively. Conclusions High mutations of multiple driving genes in ctDNA and their dynamic changes could effectively predict response of mPDAC to NPS chemotherapy, with promising reliable predictive performance superior to routine clinicopathologic parameters. Inspiringly, longitudinal ctDNA tracking could predict disease progression about 2 months ahead of radiologic or CA19-9 evaluations, with the potential to precisely devise individualized therapeutic strategies for mPDAC.

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“…This underscores the urgent need for novel effective and precise treatment options based on novel targets. 4,5 Targeted transcriptome regulation presents a promising avenue for PDAC treatment. Aberrant, sustained gene transcription activated by super-enhancers (SEs) significantly correlates with cancer growth, progression and metastasis.…”

Section: Introductionmentioning

confidence: 99%

“…Although chemotherapy is the primary and major nonsurgical treatment for PDACs with definitive efficacy in prolonging survival, a significant proportion of such patients may experience rapid progression even with chemotherapy and/or molecular‐targeted therapies. This underscores the urgent need for novel effective and precise treatment options based on novel targets 4,5 …”

Section: Introductionmentioning

confidence: 99%

The suppressive efficacy of THZ1 depends on KRAS mutation subtype and is associated with super‐enhancer activity and the PI3K/AKT/mTOR signalling in pancreatic ductal adenocarcinoma: A hypothesis‐generating study

Huang,

Yang,

Chen

et al. 2023

Clinical & Translational Med

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BackgroundInhibition of CDK7, a potent transcription regulator, may bring new hope for treating pancreatic ductal adenocarcinoma (PDAC), which is featured by large genetic heterogeneity and abundant KRAS mutations. This investigation aimed at exploring the discrepant efficacies of THZ1, a small‐molecule covalent CDK7 inhibitor, on PDACs with different KRAS mutations and the underlying mechanisms.MethodsAssociations of CDK7 expression with survival by KRAS mutations were first assessed. Effects of THZ1 on PDAC by different KRAS mutations were then investigated in vitro and in vivo. Moreover, the effects of THZ1 on gene transcription and phosphorylation of RNA polymerase II (RNAPOLII) in different KRAS mutant PDACs were assessed, and the effect of THZ1 on super‐enhancer activity was evaluated using chromatin immunoprecipitation sequencing. Lastly, the effects of THZ1 on the binding of H3K27ac to PIK3CA and on the PI3K/AKT/mTOR signalling were analysed.ResultsHigh CDK7 expression was significantly linked to worse survival within PDAC patients carrying KRAS‐G12V mutation but not in those with KRAS‐G12D mutation. The apoptosis‐inducing effect of THZ1 was markedly stronger in KRAS‐G12V PDAC than KRAS‐G12D cancer. THZ1 significantly inhibited the growth of xenograft tumour with KRAS‐G12V mutation, and the inhibition was markedly stronger than for KRAS‐G12D tumour. In mini‐cell‐derived xenograft (CDX) models, THZ1 significantly suppressed KRAS‐G12V PDAC but not KRAS‐G12D cancer. THZ1 significantly suppressed the phosphorylation of RNAPOLII, and this effect was stronger in KRAS‐G12V PDAC (especially at ser5). KRAS‐G12V PDAC had more H3K27ac‐binding super‐enhancers, and the inhibition of THZ1 on super‐enhancer activity was also stronger in KRAS‐G12V PDAC. Furthermore, THZ1 significantly weakened the binding of H3K27ac to PIK3CA in KRAS‐G12V PDAC. THZ1 significantly suppressed the PI3K/AKT/mTOR pathway and its downstream markers, and this effect was stronger in KRAS‐G12V cells.ConclusionsIn this hypothesis‐generating study, THZ1 might selectively inhibit certain PDACs with KRAS‐G12V mutation more potently compared with some other PDACs with KRAS‐G12D mutation, which might be associated with its effect on super‐enhancer activity and the PI3K/AKT/mTOR signalling. Our findings might offer novel key clues for the precise management of PDAC and important evidence for future targeted trial design.Highlights THZ1 had a stronger effect on PDAC‐bearing KRAS‐G12V mutation than G12D mutation. Suppressive effect of THZ1 on phosphorylation of RNAPOLII was stronger in KRAS‐G12V than KRAS‐G12D PDAC. Inhibition of THZ1 on super‐enhancer activity and H3K27ac binding to PIK3CA was stronger in KRAS‐G12V PDAC. Suppressive effect of THZ1 on PI3K/AKT/mTOR pathway was stronger in KRAS‐G12V PDAC.

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S-1 Maintenance Therapy After First-Line Treatment With Nab-Paclitaxel Plus S-1 for Advanced Pancreatic Adenocarcinoma: A Real-World Study

Cited by 5 publications

References 33 publications

Gene signature developed for predicting early relapse and survival in early-stage pancreatic cancer

Gene signature developed for predicting early relapse and survival in early-stage pancreatic cancer

High somatic mutations in circulating tumor DNA predict response of metastatic pancreatic ductal adenocarcinoma to first-line nab-paclitaxel plus S-1: prospective study

The suppressive efficacy of THZ1 depends on KRAS mutation subtype and is associated with super‐enhancer activity and the PI3K/AKT/mTOR signalling in pancreatic ductal adenocarcinoma: A hypothesis‐generating study

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