Florence T H Wu, James T Topham, Chris J O'Callaghan, Harriet Feilotter, Hagen F Kennecke, Leylah Drusbosky, Daniel J Renouf, Derek J Jonker, Dongsheng Tu, Eric X Chen, Jonathan M Loree
{"title":"加拿大癌症试验小组 CO.26 试验中利用循环肿瘤 DNA 对 RAS 基因突变进行的动力学分析表明，新 RAS 野生型转移性结直肠癌中 RAS 基因突变的缺失是短暂的。","authors":"Florence T H Wu, James T Topham, Chris J O'Callaghan, Harriet Feilotter, Hagen F Kennecke, Leylah Drusbosky, Daniel J Renouf, Derek J Jonker, Dongsheng Tu, Eric X Chen, Jonathan M Loree","doi":"10.1200/PO.24.00031","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>In metastatic colorectal cancer (mCRC), <i>RAS</i> mutations drive resistance to anti-epidermal growth factor receptor antibodies. It is unclear whether <i>RAS</i> mutations ever become clonally undetectable.</p><p><strong>Methods: </strong>CO.26 was a phase II clinical trial that assessed durvalumab + tremelimumab in heavily pretreated mCRC. <i>RAS</i> mutation status was tracked over time using circulating tumor DNA (ctDNA) sequencing at baseline, week 8, and on progression.</p><p><strong>Results: </strong>Among the 95 patients with <i>KRAS/NRAS</i> mutations in their archival tumor tissue, 6.3% (6/95) had undetectable <i>RAS</i> mutations in ctDNA collected at baseline or week 8 of the CO.26 study. Of these, 67% (4/6) of disappearances were transient, with the same mutation reappearing with progressive disease. In three cases, the simultaneous persistence of other preexisting CRC-associated truncal mutations could not be demonstrated, suggestive of low tumor shedding of ctDNA, leaving the incidence of true clonal reversion to <i>RAS</i>-wildtype (WT) possibly as low as 3.2% (3/95). Fewer patients in the neo-<i>RAS</i>-WT group (33%) had greater than four lesions at trial baseline compared with patients with persistent <i>RAS</i> mutations (75%), <i>P</i> = .046. The likelihood of synchronous metastases at cancer diagnosis (33% <i>v</i> 63%; <i>P</i> = .15) or liver metastases at trial baseline (50% <i>v</i> 68.5%; <i>P</i> = .17) was not significantly different between patients with disappearing versus persistent <i>RAS</i> mutations. Overall survival from stage IV diagnosis (hazard ratio, 0.77 [95% CI, 0.35 to 1.72]; <i>P</i> = .52) was not significantly different between those with disappearing versus persistent <i>RAS</i> mutations. The disappearance of <i>RAS</i> mutations was not associated with primary tumor sidedness (<i>P</i> = .41), archival <i>BRAF/MEK/ERK</i>-mutant status (<i>P</i> = .16/1.00/.09), nor baseline ctDNA <i>HER2</i> amplifications (<i>P</i> = 1.00).</p><p><strong>Conclusion: </strong>We identified a 3.2%-6.3% prevalence of the neo-<i>RAS</i>-WT phenomenon in the CO.26 trial. However, 67% of apparent cases were transient with subsequent re-emergence.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400031"},"PeriodicalIF":5.3000,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11371075/pdf/","citationCount":"0","resultStr":"{\"title\":\"Kinetic Profiling of <i>RAS</i> Mutations With Circulating Tumor DNA in the Canadian Cancer Trials Group CO.26 Trial Suggests the Loss of <i>RAS</i> Mutations in Neo-<i>RAS</i>-Wildtype Metastatic Colorectal Cancer Is Transient.\",\"authors\":\"Florence T H Wu, James T Topham, Chris J O'Callaghan, Harriet Feilotter, Hagen F Kennecke, Leylah Drusbosky, Daniel J Renouf, Derek J Jonker, Dongsheng Tu, Eric X Chen, Jonathan M Loree\",\"doi\":\"10.1200/PO.24.00031\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>In metastatic colorectal cancer (mCRC), <i>RAS</i> mutations drive resistance to anti-epidermal growth factor receptor antibodies. It is unclear whether <i>RAS</i> mutations ever become clonally undetectable.</p><p><strong>Methods: </strong>CO.26 was a phase II clinical trial that assessed durvalumab + tremelimumab in heavily pretreated mCRC. <i>RAS</i> mutation status was tracked over time using circulating tumor DNA (ctDNA) sequencing at baseline, week 8, and on progression.</p><p><strong>Results: </strong>Among the 95 patients with <i>KRAS/NRAS</i> mutations in their archival tumor tissue, 6.3% (6/95) had undetectable <i>RAS</i> mutations in ctDNA collected at baseline or week 8 of the CO.26 study. Of these, 67% (4/6) of disappearances were transient, with the same mutation reappearing with progressive disease. In three cases, the simultaneous persistence of other preexisting CRC-associated truncal mutations could not be demonstrated, suggestive of low tumor shedding of ctDNA, leaving the incidence of true clonal reversion to <i>RAS</i>-wildtype (WT) possibly as low as 3.2% (3/95). Fewer patients in the neo-<i>RAS</i>-WT group (33%) had greater than four lesions at trial baseline compared with patients with persistent <i>RAS</i> mutations (75%), <i>P</i> = .046. The likelihood of synchronous metastases at cancer diagnosis (33% <i>v</i> 63%; <i>P</i> = .15) or liver metastases at trial baseline (50% <i>v</i> 68.5%; <i>P</i> = .17) was not significantly different between patients with disappearing versus persistent <i>RAS</i> mutations. Overall survival from stage IV diagnosis (hazard ratio, 0.77 [95% CI, 0.35 to 1.72]; <i>P</i> = .52) was not significantly different between those with disappearing versus persistent <i>RAS</i> mutations. The disappearance of <i>RAS</i> mutations was not associated with primary tumor sidedness (<i>P</i> = .41), archival <i>BRAF/MEK/ERK</i>-mutant status (<i>P</i> = .16/1.00/.09), nor baseline ctDNA <i>HER2</i> amplifications (<i>P</i> = 1.00).</p><p><strong>Conclusion: </strong>We identified a 3.2%-6.3% prevalence of the neo-<i>RAS</i>-WT phenomenon in the CO.26 trial. However, 67% of apparent cases were transient with subsequent re-emergence.</p>\",\"PeriodicalId\":14797,\"journal\":{\"name\":\"JCO precision oncology\",\"volume\":\"8 \",\"pages\":\"e2400031\"},\"PeriodicalIF\":5.3000,\"publicationDate\":\"2024-08-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11371075/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"JCO precision oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1200/PO.24.00031\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"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.24.00031","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
Kinetic Profiling of RAS Mutations With Circulating Tumor DNA in the Canadian Cancer Trials Group CO.26 Trial Suggests the Loss of RAS Mutations in Neo-RAS-Wildtype Metastatic Colorectal Cancer Is Transient.
Purpose: In metastatic colorectal cancer (mCRC), RAS mutations drive resistance to anti-epidermal growth factor receptor antibodies. It is unclear whether RAS mutations ever become clonally undetectable.
Methods: CO.26 was a phase II clinical trial that assessed durvalumab + tremelimumab in heavily pretreated mCRC. RAS mutation status was tracked over time using circulating tumor DNA (ctDNA) sequencing at baseline, week 8, and on progression.
Results: Among the 95 patients with KRAS/NRAS mutations in their archival tumor tissue, 6.3% (6/95) had undetectable RAS mutations in ctDNA collected at baseline or week 8 of the CO.26 study. Of these, 67% (4/6) of disappearances were transient, with the same mutation reappearing with progressive disease. In three cases, the simultaneous persistence of other preexisting CRC-associated truncal mutations could not be demonstrated, suggestive of low tumor shedding of ctDNA, leaving the incidence of true clonal reversion to RAS-wildtype (WT) possibly as low as 3.2% (3/95). Fewer patients in the neo-RAS-WT group (33%) had greater than four lesions at trial baseline compared with patients with persistent RAS mutations (75%), P = .046. The likelihood of synchronous metastases at cancer diagnosis (33% v 63%; P = .15) or liver metastases at trial baseline (50% v 68.5%; P = .17) was not significantly different between patients with disappearing versus persistent RAS mutations. Overall survival from stage IV diagnosis (hazard ratio, 0.77 [95% CI, 0.35 to 1.72]; P = .52) was not significantly different between those with disappearing versus persistent RAS mutations. The disappearance of RAS mutations was not associated with primary tumor sidedness (P = .41), archival BRAF/MEK/ERK-mutant status (P = .16/1.00/.09), nor baseline ctDNA HER2 amplifications (P = 1.00).
Conclusion: We identified a 3.2%-6.3% prevalence of the neo-RAS-WT phenomenon in the CO.26 trial. However, 67% of apparent cases were transient with subsequent re-emergence.
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