Ottavia Amato, Laurence Buisseret, Geraldine Gebhart, Nicolas Plouznikoff, Denis Larsimont, Ahmad Awada, Martine Piccart, Philippe Aftimos
{"title":"<i>PIK3CA</i> copy-number gain and inhibitors of the PI3K/AKT/mTOR pathway in triple-negative breast cancer.","authors":"Ottavia Amato, Laurence Buisseret, Geraldine Gebhart, Nicolas Plouznikoff, Denis Larsimont, Ahmad Awada, Martine Piccart, Philippe Aftimos","doi":"10.1101/mcs.a006255","DOIUrl":null,"url":null,"abstract":"<p><p>As wider insights are gained on the molecular landscape of triple-negative breast cancer (TNBC), novel targeted therapeutic strategies might become an option in this setting as well. Activating mutations of <i>PIK3CA</i> represent the second most common alteration in TNBC after the <i>TP53</i> mutation, with a prevalence of ∼10%-15%. Considering the well-established predictive role of <i>PIK3CA</i> mutations for response to agents targeting the PI3K/AKT/mTOR pathway, several clinical trials are currently evaluating these drugs in patients with advanced TNBC. However, much less is known regarding the actionability of <i>PIK3CA</i> copy-number gains, which represent a thoroughly common molecular alteration in TNBC, with a prevalence estimated at 6%-20%, and are listed as \"likely gain-of-function\" alterations in the OncoKB database. In the present paper, we describe two clinical cases in which patients harboring <i>PIK3CA</i>-amplified TNBC received a targeted treatment with the mTOR-inhibitor everolimus and the PI3K-inhibitor alpelisib, respectively, with evidence of disease response on 18F-FDG positron-emission tomography (PET) imaging. Hence, we discuss the evidence presently available regarding a possible predictive value of <i>PIK3CA</i> amplification for response to targeted treatment strategies, suggesting that this molecular alteration might represent an intriguing biomarker in this sense. Considering that few of the currently active clinical trials assessing agents targeting the PI3K/AKT/mTOR pathway in TNBC select patients based on tumor molecular characterization, and none of these based on <i>PIK3CA</i> copy-number status, we urge for the introduction of <i>PIK3CA</i> amplification as a criterion for patient selection in future clinical trials in this setting.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":null,"pages":null},"PeriodicalIF":1.8000,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/25/fb/MCS006255Ama.PMC10240844.pdf","citationCount":"1","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cold Spring Harbor Molecular Case Studies","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/mcs.a006255","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 1
Abstract
As wider insights are gained on the molecular landscape of triple-negative breast cancer (TNBC), novel targeted therapeutic strategies might become an option in this setting as well. Activating mutations of PIK3CA represent the second most common alteration in TNBC after the TP53 mutation, with a prevalence of ∼10%-15%. Considering the well-established predictive role of PIK3CA mutations for response to agents targeting the PI3K/AKT/mTOR pathway, several clinical trials are currently evaluating these drugs in patients with advanced TNBC. However, much less is known regarding the actionability of PIK3CA copy-number gains, which represent a thoroughly common molecular alteration in TNBC, with a prevalence estimated at 6%-20%, and are listed as "likely gain-of-function" alterations in the OncoKB database. In the present paper, we describe two clinical cases in which patients harboring PIK3CA-amplified TNBC received a targeted treatment with the mTOR-inhibitor everolimus and the PI3K-inhibitor alpelisib, respectively, with evidence of disease response on 18F-FDG positron-emission tomography (PET) imaging. Hence, we discuss the evidence presently available regarding a possible predictive value of PIK3CA amplification for response to targeted treatment strategies, suggesting that this molecular alteration might represent an intriguing biomarker in this sense. Considering that few of the currently active clinical trials assessing agents targeting the PI3K/AKT/mTOR pathway in TNBC select patients based on tumor molecular characterization, and none of these based on PIK3CA copy-number status, we urge for the introduction of PIK3CA amplification as a criterion for patient selection in future clinical trials in this setting.
期刊介绍:
Cold Spring Harbor Molecular Case Studies is an open-access, peer-reviewed, international journal in the field of precision medicine. Articles in the journal present genomic and molecular analyses of individuals or cohorts alongside their clinical presentations and phenotypic information. The journal''s purpose is to rapidly share insights into disease development and treatment gained by application of genomics, proteomics, metabolomics, biomarker analysis, and other approaches. The journal covers the fields of cancer, complex diseases, monogenic disorders, neurological conditions, orphan diseases, infectious disease, gene therapy, and pharmacogenomics. It has a rapid peer-review process that is based on technical evaluation of the analyses performed, not the novelty of findings, and offers a swift, clear path to publication. The journal publishes: Research Reports presenting detailed case studies of individuals and small cohorts, Research Articles describing more extensive work using larger cohorts and/or functional analyses, Rapid Communications presenting the discovery of a novel variant and/or novel phenotype associated with a known disease gene, Rapid Cancer Communications presenting the discovery of a novel variant or combination of variants in a cancer type, Variant Discrepancy Resolution describing efforts to resolve differences or update variant interpretations in ClinVar through case-level data sharing, Follow-up Reports linked to previous observations, Plus Review Articles, Editorials, and Position Statements on best practices for research in precision medicine.