Tibor A Zwimpfer, Martin Heidinger, Ricardo Coelho, Nadja Stiegeler, Fabienne D Schwab, Céline Montavon, Ruth S Eller, Nadia Maggi, Julie M Loesch, Marcus Vetter, Matteo Lambertini, Walter P Weber, Christian Kurzeder, Viola Heinzelmann-Schwarz
{"title":"TP53突变和磷脂酰肌醇3-激酶/AKT通路改变是乳腺癌预后的关键决定因素，与亚型和分期无关。","authors":"Tibor A Zwimpfer, Martin Heidinger, Ricardo Coelho, Nadja Stiegeler, Fabienne D Schwab, Céline Montavon, Ruth S Eller, Nadia Maggi, Julie M Loesch, Marcus Vetter, Matteo Lambertini, Walter P Weber, Christian Kurzeder, Viola Heinzelmann-Schwarz","doi":"10.1200/PO-24-00767","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>Breast cancer (BC) is a heterogeneous disease with genetic alterations influencing prognosis and treatment response. <i>TP53</i> mutations (<i>TP53</i>muts) are present in approximately 30% of BC, but their prognostic impact remains controversial. In addition, the phosphatidylinositol 3-kinase (PI3K)/Ak strain transforming (AKT) pathway is frequently altered and represents a promising therapeutic target for BC. Understanding the combined prognostic impact of <i>TP53</i>mut and PI3K/AKT pathway alterations across BC subtypes remains underexplored.</p><p><strong>Methods: </strong>This retrospective cohort study integrated clinical and genomic data from 4,265 patients with BC from the Molecular Taxonomy of Breast Cancer International Consortium (n = 2,509) and the Memorial Sloan Kettering Cancer Center (n = 1,756). Genetic profiling identified <i>TP53</i>mut and PI3K/AKT pathway alterations (<i>AKT1</i>, <i>AKT2</i>, <i>AKT3</i>, <i>PIK3CA</i>, <i>PTEN</i>, <i>RICTOR</i>). Survival outcomes were assessed using Kaplan-Meier survival analysis and multivariable Cox proportional hazards models.</p><p><strong>Results: </strong>In 3,807 patients with available gene alteration status, <i>TP53</i>mut was associated with younger age, higher tumor grade, advanced stage, and aggressive subtypes (<i>P</i> < .001). <i>TP53</i>mut was associated with worse survival independent of subtype, stage, age, and grade (hazard ratio [HR], 1.43 [95% CI, 1.24 to 1.66]; <i>P</i> < .0001). The type of <i>TP53</i>mut has also been found to be prognostic in BC. PI3K/AKT pathway alterations were more frequent in <i>TP53</i>mut tumors and independently associated with worse survival (HR, 1.18 [95% CI, 1.03 to 1.35]; <i>P</i> = .0173). The combined presence of <i>TP53</i>mut and PI3K/AKT alterations resulted in the worst survival outcomes (HR, 1.61 [95% CI, 1.32 to 1.97]; <i>P</i> < .0001).</p><p><strong>Conclusion: </strong><i>TP53</i>mut status is a critical prognostic factor in BC, independent of subtypes and stage, and its adverse impact is amplified by PI3K/AKT pathway alterations. These findings emphasize the integration of genetic profiling into routine clinical practice to refine treatment strategies and identify potential therapeutic targets for this high-risk population.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2400767"},"PeriodicalIF":5.3000,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12122097/pdf/","citationCount":"0","resultStr":"{\"title\":\"<i>TP53</i> Mutations and Phosphatidylinositol 3-Kinase/AKT Pathway Alterations Are Key Determinants of Breast Cancer Outcome Independent of Subtype and Stage.\",\"authors\":\"Tibor A Zwimpfer, Martin Heidinger, Ricardo Coelho, Nadja Stiegeler, Fabienne D Schwab, Céline Montavon, Ruth S Eller, Nadia Maggi, Julie M Loesch, Marcus Vetter, Matteo Lambertini, Walter P Weber, Christian Kurzeder, Viola Heinzelmann-Schwarz\",\"doi\":\"10.1200/PO-24-00767\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>Breast cancer (BC) is a heterogeneous disease with genetic alterations influencing prognosis and treatment response. <i>TP53</i> mutations (<i>TP53</i>muts) are present in approximately 30% of BC, but their prognostic impact remains controversial. In addition, the phosphatidylinositol 3-kinase (PI3K)/Ak strain transforming (AKT) pathway is frequently altered and represents a promising therapeutic target for BC. Understanding the combined prognostic impact of <i>TP53</i>mut and PI3K/AKT pathway alterations across BC subtypes remains underexplored.</p><p><strong>Methods: </strong>This retrospective cohort study integrated clinical and genomic data from 4,265 patients with BC from the Molecular Taxonomy of Breast Cancer International Consortium (n = 2,509) and the Memorial Sloan Kettering Cancer Center (n = 1,756). Genetic profiling identified <i>TP53</i>mut and PI3K/AKT pathway alterations (<i>AKT1</i>, <i>AKT2</i>, <i>AKT3</i>, <i>PIK3CA</i>, <i>PTEN</i>, <i>RICTOR</i>). Survival outcomes were assessed using Kaplan-Meier survival analysis and multivariable Cox proportional hazards models.</p><p><strong>Results: </strong>In 3,807 patients with available gene alteration status, <i>TP53</i>mut was associated with younger age, higher tumor grade, advanced stage, and aggressive subtypes (<i>P</i> < .001). <i>TP53</i>mut was associated with worse survival independent of subtype, stage, age, and grade (hazard ratio [HR], 1.43 [95% CI, 1.24 to 1.66]; <i>P</i> < .0001). The type of <i>TP53</i>mut has also been found to be prognostic in BC. PI3K/AKT pathway alterations were more frequent in <i>TP53</i>mut tumors and independently associated with worse survival (HR, 1.18 [95% CI, 1.03 to 1.35]; <i>P</i> = .0173). The combined presence of <i>TP53</i>mut and PI3K/AKT alterations resulted in the worst survival outcomes (HR, 1.61 [95% CI, 1.32 to 1.97]; <i>P</i> < .0001).</p><p><strong>Conclusion: </strong><i>TP53</i>mut status is a critical prognostic factor in BC, independent of subtypes and stage, and its adverse impact is amplified by PI3K/AKT pathway alterations. These findings emphasize the integration of genetic profiling into routine clinical practice to refine treatment strategies and identify potential therapeutic targets for this high-risk population.</p>\",\"PeriodicalId\":14797,\"journal\":{\"name\":\"JCO precision oncology\",\"volume\":\"9 \",\"pages\":\"e2400767\"},\"PeriodicalIF\":5.3000,\"publicationDate\":\"2025-05-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12122097/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"JCO precision oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1200/PO-24-00767\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/5/22 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-24-00767","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/5/22 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
TP53 Mutations and Phosphatidylinositol 3-Kinase/AKT Pathway Alterations Are Key Determinants of Breast Cancer Outcome Independent of Subtype and Stage.
Purpose: Breast cancer (BC) is a heterogeneous disease with genetic alterations influencing prognosis and treatment response. TP53 mutations (TP53muts) are present in approximately 30% of BC, but their prognostic impact remains controversial. In addition, the phosphatidylinositol 3-kinase (PI3K)/Ak strain transforming (AKT) pathway is frequently altered and represents a promising therapeutic target for BC. Understanding the combined prognostic impact of TP53mut and PI3K/AKT pathway alterations across BC subtypes remains underexplored.
Methods: This retrospective cohort study integrated clinical and genomic data from 4,265 patients with BC from the Molecular Taxonomy of Breast Cancer International Consortium (n = 2,509) and the Memorial Sloan Kettering Cancer Center (n = 1,756). Genetic profiling identified TP53mut and PI3K/AKT pathway alterations (AKT1, AKT2, AKT3, PIK3CA, PTEN, RICTOR). Survival outcomes were assessed using Kaplan-Meier survival analysis and multivariable Cox proportional hazards models.
Results: In 3,807 patients with available gene alteration status, TP53mut was associated with younger age, higher tumor grade, advanced stage, and aggressive subtypes (P < .001). TP53mut was associated with worse survival independent of subtype, stage, age, and grade (hazard ratio [HR], 1.43 [95% CI, 1.24 to 1.66]; P < .0001). The type of TP53mut has also been found to be prognostic in BC. PI3K/AKT pathway alterations were more frequent in TP53mut tumors and independently associated with worse survival (HR, 1.18 [95% CI, 1.03 to 1.35]; P = .0173). The combined presence of TP53mut and PI3K/AKT alterations resulted in the worst survival outcomes (HR, 1.61 [95% CI, 1.32 to 1.97]; P < .0001).
Conclusion: TP53mut status is a critical prognostic factor in BC, independent of subtypes and stage, and its adverse impact is amplified by PI3K/AKT pathway alterations. These findings emphasize the integration of genetic profiling into routine clinical practice to refine treatment strategies and identify potential therapeutic targets for this high-risk population.
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