Impact of mutational profiles on response of primary oestrogen receptor-positive breast cancers to oestrogen deprivation

Presurgical studies allow study of the relationship between mutations and response of estrogen receptor positive (ER+) breast cancer to aromatase inhibitors (AIs) but have been limited to small biopsies. Here in Phase I of this study, we perform exome sequencing on baseline, surgical core-cuts and blood from 60 patients (40 AI treated, 20 Controls). In poor responders (based on Ki67 change) we find significantly more somatic mutations than good responders. Subclones exclusive to baseline or surgical cores occur in approximately 30% of tumours. In Phase II we combine targeted sequencing on another 28 treated patients with Phase I. We find six genes frequently mutated: PIK3CA, TP53, CDH1, MLL3, ABCA13 and FLG with 71% concordance between paired cores. TP53 mutations are associated with poor response. We conclude that multiple biopsies are essential for confident mutational profiling of ER+ breast cancer and TP53 mutations are associated with resistance to oestrogen deprivation therapy.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

1 Dataset 2 Publications

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Dataset ID	Description	Technology	Samples
EGAD00001002651	Presurgical studies allow study of the relationship between mutations and response of estrogen receptor positive (ER+) breast cancer to aromatase inhibitors (AIs) but have been limited to small biopsies. Here in Phase I of this study, we perform exome sequencing on baseline, surgical core-cuts and blood from 60 patients (40 AI treated, 20 Controls). In poor responders (based on Ki67 change) we find significantly more somatic mutations than good responders. Subclones exclusive to baseline or surgical cores occur in approximately 30% of tumours. In Phase II we combine targeted sequencing on another 28 treated patients with Phase I. We find six genes frequently mutated: PIK3CA, TP53, CDH1, MLL3, ABCA13 and FLG with 71% concordance between paired cores. TP53 mutations are associated with poor response. We conclude that multiple biopsies are essential for confident mutational profiling of ER+ breast cancer and TP53 mutations are associated with resistance to oestrogen deprivation therapy.	Illumina HiSeq 2000	443

Publications	Citations
Impact of mutational profiles on response of primary oestrogen receptor-positive breast cancers to oestrogen deprivation. Gellert P, Segal CV, Gao Q, López-Knowles E, Martin LA, Dodson A, Li T, Miller CA, Lu C, Mardis ER, Gillman A, Morden J, Graf M, Sidhu K, Evans A, Shere M, Holcombe C, McIntosh SA, Bundred N, Skene A, Maxwell W, Robertson J, Bliss JM, Smith I, Dowsett M, POETIC Trial Management Group and Trialists. Nat Commun 7: 2016 13294	25
Genomic Instability and TP53 Genomic Alterations Associate With Poor Antiproliferative Response and Intrinsic Resistance to Aromatase Inhibitor Treatment. Schuster EF, Gellert P, Segal CV, López-Knowles E, Buus R, Cheang MCU, Morden J, Robertson J, Bliss JM, Smith I, Dowsett M, POETIC Trial Management Group and Trialists. JCO Precis Oncol 3: 2019 PO.18.00286	0

Publications

Citations

Impact of mutational profiles on response of primary oestrogen receptor-positive breast cancers to oestrogen deprivation.
Gellert P, Segal CV, Gao Q, López-Knowles E, Martin LA, Dodson A, Li T, Miller CA, Lu C, Mardis ER, Gillman A, Morden J, Graf M, Sidhu K, Evans A, Shere M, Holcombe C, McIntosh SA, Bundred N, Skene A, Maxwell W, Robertson J, Bliss JM, Smith I, Dowsett M, POETIC Trial Management Group and Trialists. Nat Commun 7: 2016 13294

Genomic Instability and TP53 Genomic Alterations Associate With Poor Antiproliferative Response and Intrinsic Resistance to Aromatase Inhibitor Treatment.
Schuster EF, Gellert P, Segal CV, López-Knowles E, Buus R, Cheang MCU, Morden J, Robertson J, Bliss JM, Smith I, Dowsett M, POETIC Trial Management Group and Trialists. JCO Precis Oncol 3: 2019 PO.18.00286