Multiple PIK3CA mutation clonality correlates with outcomes in taselisib + fulvestrant-treated ER+/HER2-, PIK3CA-mutated breast cancers.
Breast cancer
Clonal
Double PIK3CA mutation
PI3K inhibitor
PI3K signaling
PIK3CA
Taselisib
ctDNA
Journal
Genome medicine
ISSN: 1756-994X
Titre abrégé: Genome Med
Pays: England
ID NLM: 101475844
Informations de publication
Date de publication:
26 04 2023
26 04 2023
Historique:
received:
24
09
2022
accepted:
14
04
2023
medline:
28
4
2023
pubmed:
27
4
2023
entrez:
26
4
2023
Statut:
epublish
Résumé
Mutations in the p110α 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 p110α inhibitors. To understand the role of multiple PIK3CAmut in predicting response to p110α 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. 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. Our study establishes clonal multiple PIK3CAmut as an important molecular determinant of response to p110α inhibition and provides rationale for further clinical investigation of p110α inhibitors alone or with rationally-selected therapies in breast cancer and potentially other solid tumor types.
Sections du résumé
BACKGROUND
Mutations in the p110α 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 p110α inhibitors.
METHODS
To understand the role of multiple PIK3CAmut in predicting response to p110α 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 p110α inhibition and provides rationale for further clinical investigation of p110α inhibitors alone or with rationally-selected therapies in breast cancer and potentially other solid tumor types.
Identifiants
pubmed: 37101291
doi: 10.1186/s13073-023-01181-8
pii: 10.1186/s13073-023-01181-8
pmc: PMC10131374
doi:
Substances chimiques
Fulvestrant
22X328QOC4
2-(3-(2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo(f)imidazo(1,2-d)(1,4)oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide
0
Phosphatidylinositol 3-Kinases
EC 2.7.1.-
Receptor, ErbB-2
EC 2.7.10.1
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
28Informations de copyright
© 2023. The Author(s).
Références
Ann Oncol. 2021 Feb;32(2):197-207
pubmed: 33186740
Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):802-7
pubmed: 15647370
PLoS Comput Biol. 2018 Feb 7;14(2):e1005965
pubmed: 29415044
J Clin Oncol. 2016 May 10;34(14):1660-8
pubmed: 26951309
J Clin Oncol. 2018 May 1;36(13):1291-1299
pubmed: 29401002
NPJ Precis Oncol. 2021 Jul 20;5(1):69
pubmed: 34285332
J Mol Diagn. 2018 Sep;20(5):686-702
pubmed: 29936259
Nucleic Acids Res. 2016 Sep 19;44(16):e131
pubmed: 27270079
Nat Biotechnol. 2013 Nov;31(11):1023-31
pubmed: 24142049
Cancer Cell. 2018 Sep 10;34(3):427-438.e6
pubmed: 30205045
N Engl J Med. 2019 May 16;380(20):1929-1940
pubmed: 31091374
PLoS One. 2020 Sep 25;15(9):e0237802
pubmed: 32976510
Ann Oncol. 2016 Nov;27(11):2059-2066
pubmed: 27573562
Cancer Res. 2005 Dec 1;65(23):10992-1000
pubmed: 16322248
Cancer Biol Ther. 2004 Aug;3(8):772-5
pubmed: 15254419
PLoS One. 2022 Mar 16;17(3):e0264138
pubmed: 35294956
Clin Cancer Res. 2023 Mar 14;29(6):1125-1136
pubmed: 36595567
Nat Med. 2017 Jun;23(6):703-713
pubmed: 28481359
Cell. 2017 Aug 10;170(4):605-635
pubmed: 28802037
Science. 2004 Apr 23;304(5670):554
pubmed: 15016963
Nature. 2015 Feb 12;518(7538):240-4
pubmed: 25409150
Science. 2019 Nov 8;366(6466):714-723
pubmed: 31699932
Lancet Oncol. 2017 Jul;18(7):904-916
pubmed: 28576675
Cancer Cell. 2017 Jun 12;31(6):820-832.e3
pubmed: 28528867
Clin Cancer Res. 2021 Jun 1;27(11):3094-3105
pubmed: 33558422
Lancet Oncol. 2018 Jan;19(1):87-100
pubmed: 29223745
Science. 2009 Jan 2;323(5910):133-8
pubmed: 19023044
JCO Precis Oncol. 2022 Oct;6:e2200261
pubmed: 36265119