| Added by | standudu |
|---|---|
| Group name | EquipeCTCS |
| Item Type | Journal Article |
| Title | Multiple PIK3CA mutation clonality correlates with outcomes in taselisib + fulvestrant-treated ER+/HER2-, PIK3CA-mutated breast cancers |
| Creator | Hutchinson et al. |
| Author | Katherine E. Hutchinson |
| Author | Jessica W. Chen |
| Author | Heidi M. Savage |
| Author | Thomas J. Stout |
| Author | Frauke Schimmoller |
| Author | Javier Cortés |
| Author | Susan Dent |
| Author | Nadia Harbeck |
| Author | William Jacot |
| Author | Ian Krop |
| Author | Sally E. Trabucco |
| Author | Smruthy Sivakumar |
| Author | Ethan S. Sokol |
| Author | Timothy R. Wilson |
| Abstract | BACKGROUND: Mutations in the p110? catalytic subunit of phosphatidylinositol 3-kinase (PI3K), encoded by the PIK3CA gene, cause dysregulation of the PI3K pathway in 35-40% of patients with HR+/HER2- breast cancer. Preclinically, cancer cells harboring double or multiple PIK3CA mutations (mut) elicit hyperactivation of the PI3K pathway leading to enhanced sensitivity to p110? inhibitors. METHODS: To understand the role of multiple PIK3CAmut in predicting response to p110? inhibition, we estimated the clonality of multiple PIK3CAmut in circulating tumor DNA (ctDNA) from patients with HR+/HER2- metastatic breast cancer enrolled to a prospectively registered clinical trial of fulvestrant?±?taselisib, and analyzed the subgroups against co-altered genes, pathways, and outcomes. RESULTS: ctDNA samples with clonal multiple PIK3CAmut had fewer co-alterations in receptor tyrosine kinase (RTK) or non-PIK3CA PI3K pathway genes compared to samples with subclonal multiple PIK3CAmut indicating a strong reliance on the PI3K pathway. This was validated in an independent cohort of breast cancer tumor specimens that underwent comprehensive genomic profiling. Furthermore, patients whose ctDNA harbored clonal multiple PIK3CAmut exhibited a significantly higher response rate and longer progression-free survival vs subclonal multiple PIK3CAmut. CONCLUSIONS: Our study establishes clonal multiple PIK3CAmut as an important molecular determinant of response to p110? inhibition and provides rationale for further clinical investigation of p110? inhibitors alone or with rationally-selected therapies in breast cancer and potentially other solid tumor types. |
| Publication | Genome Medicine |
| Volume | 15 |
| Issue | 1 |
| Pages | 28 |
| Date | 2023-04-26 |
| Journal Abbr | Genome Med |
| Language | eng |
| DOI | 10.1186/s13073-023-01181-8 |
| ISSN | 1756-994X |
| Library Catalog | PubMed |
| Extra | PMID: 37101291 PMCID: PMC10131374 |
| Tags | Breast Neoplasms, Class I Phosphatidylinositol 3-Kinases, clinic, Clonal, ctDNA, Double PIK3CA mutation, Female, Fulvestrant, Humans, Mutation, Phosphatidylinositol 3-Kinases, PI3K inhibitor, PI3K signaling, PIK3CA, Receptor, ErbB-2 |
| Date Added | 2023/10/16 - 16:50:50 |
| Date Modified | 2023/10/16 - 17:31:06 |
| Notes and Attachments | PubMed entry (Attachment) Texte intégral (Attachment) |
Institut de Recherche en Cancérologie de
