A. Boilève , A. Rousseau , M. Hilmi , A. Tarabay , J.R.R. Mathieu , J. Cartry , S. Bedja , N. Goudarzi , C. Nicotra , M. Ngo-Camus , V. Boige , M. Valéry , T. Pudlarz , M.-A. Bani , P. Dartigues , L. Tselikas , A. Italiano , S. Cosconea , M. Gelli , E. Fernandez-de-Sevilla , M. Ducreux
{"title":"密码子特异性 KRAS 突变可预测晚期胰腺癌患者的生存率","authors":"A. Boilève , A. Rousseau , M. Hilmi , A. Tarabay , J.R.R. Mathieu , J. Cartry , S. Bedja , N. Goudarzi , C. Nicotra , M. Ngo-Camus , V. Boige , M. Valéry , T. Pudlarz , M.-A. Bani , P. Dartigues , L. Tselikas , A. Italiano , S. Cosconea , M. Gelli , E. Fernandez-de-Sevilla , M. Ducreux","doi":"10.1016/j.esmogo.2023.100030","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p>How distinct <em>KRAS</em> alterations in pancreatic adenocarcinoma (PDAC) influence tumor initiation and outcomes remains unclear. Moreover, <em>KRAS</em> is now partly targetable with novel specific inhibitors targeting <em>KRAS</em><sub>G12</sub> (G12C or G12D), but specific outcomes of these subgroups of patients is poorly described. In this study, we compared clinical/genomic characteristics and outcomes of PDAC depending on codon-specific <em>KRAS</em> mutant (G12 versus others), as well as gene expression profiles and <em>in vitro</em> drug sensibility using organoids.</p></div><div><h3>Patients and methods</h3><p>All metastatic patients with PDAC and available molecular profile from 2015 to 2022 were eligible, and patients with <em>KRAS</em> mutation were included. Transcriptomic data from 69 <em>KRAS</em>-mutated tumors were also analyzed.</p></div><div><h3>Results</h3><p>Overall, 263 patients were included—239 <em>KRAS</em><sub>G12</sub> (91%) and 24 (9%) <em>KRAS</em><sub>other</sub>. There was no difference between <em>KRAS</em><sub>G12</sub> and <em>KRAS</em><sub>other</sub> regarding clinicopathological characteristics and potentially actionable alterations, except for <em>BRAF</em> that was found in 13% of <em>KRAS</em><sub>other</sub> (<em>P</em> = 0.01). <em>G protein subunit alpha S</em> (<em>GNAS</em>) was found more altered in <em>KRAS</em><sub>other</sub> tumors (<em>P</em> = 0.002) suggesting potential intraductal papillary mucinous neoplasm precursors. The median overall survival from metastatic diagnosis was 16.7 months [95% confidence interval (CI) 14.3-18.3 months] in <em>KRAS</em><sub>G12</sub> and 24.9 months (95% CI 17.4-43.4 months) in <em>KRAS</em><sub>other</sub> [hazard ratio (ref: <em>KRAS</em><sub>G12</sub>) = 0.56 (0.34-0.94), <em>P</em> = 0.04 adjusted]. The first-line treatment response was not different between groups (overall response rate and progression-free survival), as confirmed with a similar organoid <em>in vitro</em> sensibility. Transcriptomic analyses showed a significant and exclusive up-regulation of immune pathways in <em>KRAS</em><sub>G12</sub> tumors.</p></div><div><h3>Conclusions</h3><p>Codon-specific <em>KRAS</em> mutations are not equal and we report that <em>KRAS</em><sub>G12</sub> patients have a worst prognosis than <em>KRAS</em><sub>other</sub> patients in PDAC. These results warrant to be confirmed in larger-scale studies.</p></div>","PeriodicalId":100490,"journal":{"name":"ESMO Gastrointestinal Oncology","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2949819823000456/pdfft?md5=c2cf56bd7b06bdb14c542a5c496df425&pid=1-s2.0-S2949819823000456-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Codon-specific KRAS mutations predict survival in advanced pancreatic cancer\",\"authors\":\"A. Boilève , A. Rousseau , M. Hilmi , A. Tarabay , J.R.R. Mathieu , J. Cartry , S. Bedja , N. Goudarzi , C. Nicotra , M. Ngo-Camus , V. Boige , M. Valéry , T. Pudlarz , M.-A. Bani , P. Dartigues , L. Tselikas , A. Italiano , S. Cosconea , M. Gelli , E. Fernandez-de-Sevilla , M. Ducreux\",\"doi\":\"10.1016/j.esmogo.2023.100030\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><p>How distinct <em>KRAS</em> alterations in pancreatic adenocarcinoma (PDAC) influence tumor initiation and outcomes remains unclear. Moreover, <em>KRAS</em> is now partly targetable with novel specific inhibitors targeting <em>KRAS</em><sub>G12</sub> (G12C or G12D), but specific outcomes of these subgroups of patients is poorly described. In this study, we compared clinical/genomic characteristics and outcomes of PDAC depending on codon-specific <em>KRAS</em> mutant (G12 versus others), as well as gene expression profiles and <em>in vitro</em> drug sensibility using organoids.</p></div><div><h3>Patients and methods</h3><p>All metastatic patients with PDAC and available molecular profile from 2015 to 2022 were eligible, and patients with <em>KRAS</em> mutation were included. Transcriptomic data from 69 <em>KRAS</em>-mutated tumors were also analyzed.</p></div><div><h3>Results</h3><p>Overall, 263 patients were included—239 <em>KRAS</em><sub>G12</sub> (91%) and 24 (9%) <em>KRAS</em><sub>other</sub>. There was no difference between <em>KRAS</em><sub>G12</sub> and <em>KRAS</em><sub>other</sub> regarding clinicopathological characteristics and potentially actionable alterations, except for <em>BRAF</em> that was found in 13% of <em>KRAS</em><sub>other</sub> (<em>P</em> = 0.01). <em>G protein subunit alpha S</em> (<em>GNAS</em>) was found more altered in <em>KRAS</em><sub>other</sub> tumors (<em>P</em> = 0.002) suggesting potential intraductal papillary mucinous neoplasm precursors. The median overall survival from metastatic diagnosis was 16.7 months [95% confidence interval (CI) 14.3-18.3 months] in <em>KRAS</em><sub>G12</sub> and 24.9 months (95% CI 17.4-43.4 months) in <em>KRAS</em><sub>other</sub> [hazard ratio (ref: <em>KRAS</em><sub>G12</sub>) = 0.56 (0.34-0.94), <em>P</em> = 0.04 adjusted]. The first-line treatment response was not different between groups (overall response rate and progression-free survival), as confirmed with a similar organoid <em>in vitro</em> sensibility. Transcriptomic analyses showed a significant and exclusive up-regulation of immune pathways in <em>KRAS</em><sub>G12</sub> tumors.</p></div><div><h3>Conclusions</h3><p>Codon-specific <em>KRAS</em> mutations are not equal and we report that <em>KRAS</em><sub>G12</sub> patients have a worst prognosis than <em>KRAS</em><sub>other</sub> patients in PDAC. These results warrant to be confirmed in larger-scale studies.</p></div>\",\"PeriodicalId\":100490,\"journal\":{\"name\":\"ESMO Gastrointestinal Oncology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-01-24\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S2949819823000456/pdfft?md5=c2cf56bd7b06bdb14c542a5c496df425&pid=1-s2.0-S2949819823000456-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ESMO Gastrointestinal Oncology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2949819823000456\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ESMO Gastrointestinal Oncology","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2949819823000456","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Codon-specific KRAS mutations predict survival in advanced pancreatic cancer
Background
How distinct KRAS alterations in pancreatic adenocarcinoma (PDAC) influence tumor initiation and outcomes remains unclear. Moreover, KRAS is now partly targetable with novel specific inhibitors targeting KRASG12 (G12C or G12D), but specific outcomes of these subgroups of patients is poorly described. In this study, we compared clinical/genomic characteristics and outcomes of PDAC depending on codon-specific KRAS mutant (G12 versus others), as well as gene expression profiles and in vitro drug sensibility using organoids.
Patients and methods
All metastatic patients with PDAC and available molecular profile from 2015 to 2022 were eligible, and patients with KRAS mutation were included. Transcriptomic data from 69 KRAS-mutated tumors were also analyzed.
Results
Overall, 263 patients were included—239 KRASG12 (91%) and 24 (9%) KRASother. There was no difference between KRASG12 and KRASother regarding clinicopathological characteristics and potentially actionable alterations, except for BRAF that was found in 13% of KRASother (P = 0.01). G protein subunit alpha S (GNAS) was found more altered in KRASother tumors (P = 0.002) suggesting potential intraductal papillary mucinous neoplasm precursors. The median overall survival from metastatic diagnosis was 16.7 months [95% confidence interval (CI) 14.3-18.3 months] in KRASG12 and 24.9 months (95% CI 17.4-43.4 months) in KRASother [hazard ratio (ref: KRASG12) = 0.56 (0.34-0.94), P = 0.04 adjusted]. The first-line treatment response was not different between groups (overall response rate and progression-free survival), as confirmed with a similar organoid in vitro sensibility. Transcriptomic analyses showed a significant and exclusive up-regulation of immune pathways in KRASG12 tumors.
Conclusions
Codon-specific KRAS mutations are not equal and we report that KRASG12 patients have a worst prognosis than KRASother patients in PDAC. These results warrant to be confirmed in larger-scale studies.
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