Matthew I Ebia, Edik M Blais, Yujie Cui, Emanuel F Petricoin, Michael Pishvaian, Srinivas Gaddam, Jun Gong, Arsen Osipov, Andrew E Hendifar
{"title":"评估KRAS变异对胰腺癌生存结局和治疗反应的影响。","authors":"Matthew I Ebia, Edik M Blais, Yujie Cui, Emanuel F Petricoin, Michael Pishvaian, Srinivas Gaddam, Jun Gong, Arsen Osipov, Andrew E Hendifar","doi":"10.1200/PO-24-00684","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>Tumor molecular profiling is recommended in pancreatic ductal adenocarcinoma (PDAC). However, the predictive and prognostic value of <i>KRAS</i> variants on clinical outcomes including response to standard therapies remains unknown.</p><p><strong>Methods: </strong>In this retrospective analysis using real-world data from patients with early-stage (I to III) and metastatic PDAC who underwent molecular profiling via referrals to Perthera or the PanCAN Know Your Tumor program, patients included were 18 years and older, received standard chemotherapy in the first- and second-line setting, and had complete records. Main outcomes were overall survival (OS) and progression-free survival (PFS) measured from the date of diagnosis of metastatic/recurrent metastatic disease stratified by the <i>KRAS</i> variants and chemotherapy regimen. OS and PFS on first- or second-line therapies were analyzed using Cox regression. Outcomes from each subgroup were compared with reference cohort G12D/V using a Bonferroni-adjusted significance threshold of α = .00714 (0.05/7).</p><p><strong>Results: </strong>A total of 1359 patients (median [range] age, 64 [28-94] years; 689 [50.7%] male; 707 [52.0%] White) were included. <i>KRAS</i> wild type had significantly longer OS compared with G12D/V (2.1 <i>v</i> 1.4 years; hazard ratio [HR], 0.61 [95% CI, 0.48 to 0.77]; <i>P</i> < .0001). Q61 had shorter OS (1.1 <i>v</i> 1.5 years; HR, 2.28 [95% CI, 1.33 to 3.92]; <i>P</i> = .0027) and PFS (3.13 <i>v</i> 9.03 months; HR, 2.54 [95% CI, 1.43 to 4.52]; <i>P</i> = .0015) on first-line fluorouracil-based therapy compared with G12D/V. G12R had numerically longer OS (1.8 <i>v</i> 1.5 years; HR, 0.69 [95% CI, 0.48 to 0.98]; <i>P</i> = .0366) and PFS (12.17 <i>v</i> 9.03 months; HR, 0.6 [95% CI, 0.41 to 0.88]; <i>P</i> = .0091) on first-line fluorouracil-based therapy compared with G12D/V.</p><p><strong>Conclusion: </strong><i>KRAS</i> variants are associated with survival and may be predictive of response to standard therapies. A molecularly driven, variant-specific approach is recommended to guide PDAC treatment and better inform prognosis.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2400684"},"PeriodicalIF":5.6000,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12379785/pdf/","citationCount":"0","resultStr":"{\"title\":\"Evaluating the Effect of <i>KRAS</i> Variants on Survival Outcomes and Therapy Response in Pancreatic Cancer.\",\"authors\":\"Matthew I Ebia, Edik M Blais, Yujie Cui, Emanuel F Petricoin, Michael Pishvaian, Srinivas Gaddam, Jun Gong, Arsen Osipov, Andrew E Hendifar\",\"doi\":\"10.1200/PO-24-00684\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>Tumor molecular profiling is recommended in pancreatic ductal adenocarcinoma (PDAC). However, the predictive and prognostic value of <i>KRAS</i> variants on clinical outcomes including response to standard therapies remains unknown.</p><p><strong>Methods: </strong>In this retrospective analysis using real-world data from patients with early-stage (I to III) and metastatic PDAC who underwent molecular profiling via referrals to Perthera or the PanCAN Know Your Tumor program, patients included were 18 years and older, received standard chemotherapy in the first- and second-line setting, and had complete records. Main outcomes were overall survival (OS) and progression-free survival (PFS) measured from the date of diagnosis of metastatic/recurrent metastatic disease stratified by the <i>KRAS</i> variants and chemotherapy regimen. OS and PFS on first- or second-line therapies were analyzed using Cox regression. Outcomes from each subgroup were compared with reference cohort G12D/V using a Bonferroni-adjusted significance threshold of α = .00714 (0.05/7).</p><p><strong>Results: </strong>A total of 1359 patients (median [range] age, 64 [28-94] years; 689 [50.7%] male; 707 [52.0%] White) were included. <i>KRAS</i> wild type had significantly longer OS compared with G12D/V (2.1 <i>v</i> 1.4 years; hazard ratio [HR], 0.61 [95% CI, 0.48 to 0.77]; <i>P</i> < .0001). Q61 had shorter OS (1.1 <i>v</i> 1.5 years; HR, 2.28 [95% CI, 1.33 to 3.92]; <i>P</i> = .0027) and PFS (3.13 <i>v</i> 9.03 months; HR, 2.54 [95% CI, 1.43 to 4.52]; <i>P</i> = .0015) on first-line fluorouracil-based therapy compared with G12D/V. G12R had numerically longer OS (1.8 <i>v</i> 1.5 years; HR, 0.69 [95% CI, 0.48 to 0.98]; <i>P</i> = .0366) and PFS (12.17 <i>v</i> 9.03 months; HR, 0.6 [95% CI, 0.41 to 0.88]; <i>P</i> = .0091) on first-line fluorouracil-based therapy compared with G12D/V.</p><p><strong>Conclusion: </strong><i>KRAS</i> variants are associated with survival and may be predictive of response to standard therapies. A molecularly driven, variant-specific approach is recommended to guide PDAC treatment and better inform prognosis.</p>\",\"PeriodicalId\":14797,\"journal\":{\"name\":\"JCO precision oncology\",\"volume\":\"9 \",\"pages\":\"e2400684\"},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2025-08-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12379785/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"JCO precision oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1200/PO-24-00684\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/8/20 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"JCO precision oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1200/PO-24-00684","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/8/20 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
目的：在胰腺导管腺癌（PDAC）中推荐肿瘤分子谱分析。然而，KRAS变异对临床结果（包括对标准治疗的反应）的预测和预后价值仍然未知。方法：在这项回顾性分析中，使用来自早期（I至III）和转移性PDAC患者的真实数据，这些患者通过转介到Perthera或PanCAN Know Your Tumor项目进行了分子分析，纳入的患者年龄在18岁及以上，在一线和二线环境中接受了标准化疗，并且有完整的记录。主要结局是总生存期（OS）和无进展生存期（PFS），从转移性/复发性转移性疾病的诊断日期开始测量，按KRAS变异和化疗方案分层。采用Cox回归分析一线或二线治疗的OS和PFS。每个亚组的结果与参考队列G12D/V进行比较，采用bonferroni调整显著性阈值α = 0.00714（0.05/7）。结果：共纳入1359例患者（年龄中位数[范围]64岁[28-94]岁；男性689例[50.7%]；白人707例[52.0%]）。KRAS野生型与G12D/V相比，生存期明显更长（2.1 V 1.4年；风险比[HR]， 0.61 [95% CI, 0.48 ~ 0.77]; P < 0.0001）。与G12D/ v相比，Q61一线氟尿嘧啶治疗的OS （1.1 v 1.5年；HR, 2.28 [95% CI， 1.33至3.92];P = 0.0027）和PFS （3.13 v 9.03个月；HR, 2.54 [95% CI， 1.43至4.52];P = 0.0015）更短。与G12D/ v相比，G12R一线氟尿嘧啶治疗的OS （1.8 v 1.5年；HR, 0.69 [95% CI， 0.48至0.98];P = 0.066）和PFS （12.17 v 9.03个月；HR, 0.6 [95% CI， 0.41至0.88];P = 0.0091）数值上更长。结论：KRAS变异与生存相关，并可预测对标准治疗的反应。推荐一种分子驱动的、变异特异性的方法来指导PDAC的治疗，并更好地告知预后。
Evaluating the Effect of KRAS Variants on Survival Outcomes and Therapy Response in Pancreatic Cancer.
Purpose: Tumor molecular profiling is recommended in pancreatic ductal adenocarcinoma (PDAC). However, the predictive and prognostic value of KRAS variants on clinical outcomes including response to standard therapies remains unknown.
Methods: In this retrospective analysis using real-world data from patients with early-stage (I to III) and metastatic PDAC who underwent molecular profiling via referrals to Perthera or the PanCAN Know Your Tumor program, patients included were 18 years and older, received standard chemotherapy in the first- and second-line setting, and had complete records. Main outcomes were overall survival (OS) and progression-free survival (PFS) measured from the date of diagnosis of metastatic/recurrent metastatic disease stratified by the KRAS variants and chemotherapy regimen. OS and PFS on first- or second-line therapies were analyzed using Cox regression. Outcomes from each subgroup were compared with reference cohort G12D/V using a Bonferroni-adjusted significance threshold of α = .00714 (0.05/7).
Results: A total of 1359 patients (median [range] age, 64 [28-94] years; 689 [50.7%] male; 707 [52.0%] White) were included. KRAS wild type had significantly longer OS compared with G12D/V (2.1 v 1.4 years; hazard ratio [HR], 0.61 [95% CI, 0.48 to 0.77]; P < .0001). Q61 had shorter OS (1.1 v 1.5 years; HR, 2.28 [95% CI, 1.33 to 3.92]; P = .0027) and PFS (3.13 v 9.03 months; HR, 2.54 [95% CI, 1.43 to 4.52]; P = .0015) on first-line fluorouracil-based therapy compared with G12D/V. G12R had numerically longer OS (1.8 v 1.5 years; HR, 0.69 [95% CI, 0.48 to 0.98]; P = .0366) and PFS (12.17 v 9.03 months; HR, 0.6 [95% CI, 0.41 to 0.88]; P = .0091) on first-line fluorouracil-based therapy compared with G12D/V.
Conclusion: KRAS variants are associated with survival and may be predictive of response to standard therapies. A molecularly driven, variant-specific approach is recommended to guide PDAC treatment and better inform prognosis.
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