High somatic mutations in circulating tumor DNA predict response of metastatic pancreatic ductal adenocarcinoma to first-line nab-paclitaxel plus S-1: prospective study
Abstract 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...
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| Format: | Article |
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BMC
2024-02-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-024-04989-z |
| _version_ | 1797273501952901120 |
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| author | Lei Huang Yao Lv Shasha Guan Huan Yan Lu Han Zhikuan Wang Quanli Han Guanghai Dai Yan Shi |
| author_facet | Lei Huang Yao Lv Shasha Guan Huan Yan Lu Han Zhikuan Wang Quanli Han Guanghai Dai Yan Shi |
| author_sort | Lei Huang |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-07T14:44:14Z |
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| id | doaj.art-fd0890b3b637439fae96a32c1777e114 |
| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-03-07T14:44:14Z |
| publishDate | 2024-02-01 |
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| spelling | doaj.art-fd0890b3b637439fae96a32c1777e1142024-03-05T20:06:49ZengBMCJournal of Translational Medicine1479-58762024-02-0122112310.1186/s12967-024-04989-zHigh somatic mutations in circulating tumor DNA predict response of metastatic pancreatic ductal adenocarcinoma to first-line nab-paclitaxel plus S-1: prospective studyLei Huang0Yao Lv1Shasha Guan2Huan Yan3Lu Han4Zhikuan Wang5Quanli Han6Guanghai Dai7Yan Shi8Medical Center on Aging of Ruijin Hospital, MCARJH, Shanghai Jiaotong University School of MedicineDepartment of Medical Oncology, Chinese PLA General HospitalDepartment of Medical Oncology, Chinese PLA General HospitalDepartment of Medical Oncology, Chinese PLA General HospitalDepartment of Medical Oncology, Chinese PLA General HospitalDepartment of Medical Oncology, Chinese PLA General HospitalDepartment of Medical Oncology, Chinese PLA General HospitalDepartment of Medical Oncology, Chinese PLA General HospitalDepartment of General Surgery, Shanghai Seventh People’s Hospital, Shanghai University of Traditional Chinese MedicineAbstract 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.https://doi.org/10.1186/s12967-024-04989-zMetastatic pancreatic ductal adenocarcinoma (mPDAC)Circulating tumor DNA (ctDNA)High mutation allelic frequency (MAF)Nab-paclitaxel plus S-1 (NPS)Efficacy predictionProspective longitudinal study |
| spellingShingle | Lei Huang Yao Lv Shasha Guan Huan Yan Lu Han Zhikuan Wang Quanli Han Guanghai Dai Yan Shi High somatic mutations in circulating tumor DNA predict response of metastatic pancreatic ductal adenocarcinoma to first-line nab-paclitaxel plus S-1: prospective study Journal of Translational Medicine Metastatic pancreatic ductal adenocarcinoma (mPDAC) Circulating tumor DNA (ctDNA) High mutation allelic frequency (MAF) Nab-paclitaxel plus S-1 (NPS) Efficacy prediction Prospective longitudinal study |
| title | High somatic mutations in circulating tumor DNA predict response of metastatic pancreatic ductal adenocarcinoma to first-line nab-paclitaxel plus S-1: prospective study |
| title_full | High somatic mutations in circulating tumor DNA predict response of metastatic pancreatic ductal adenocarcinoma to first-line nab-paclitaxel plus S-1: prospective study |
| title_fullStr | High somatic mutations in circulating tumor DNA predict response of metastatic pancreatic ductal adenocarcinoma to first-line nab-paclitaxel plus S-1: prospective study |
| title_full_unstemmed | High somatic mutations in circulating tumor DNA predict response of metastatic pancreatic ductal adenocarcinoma to first-line nab-paclitaxel plus S-1: prospective study |
| title_short | High somatic mutations in circulating tumor DNA predict response of metastatic pancreatic ductal adenocarcinoma to first-line nab-paclitaxel plus S-1: prospective study |
| title_sort | high somatic mutations in circulating tumor dna predict response of metastatic pancreatic ductal adenocarcinoma to first line nab paclitaxel plus s 1 prospective study |
| topic | Metastatic pancreatic ductal adenocarcinoma (mPDAC) Circulating tumor DNA (ctDNA) High mutation allelic frequency (MAF) Nab-paclitaxel plus S-1 (NPS) Efficacy prediction Prospective longitudinal study |
| url | https://doi.org/10.1186/s12967-024-04989-z |
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