TY - JOUR
T1 - Impact of mutational profiles on response of primary oestrogen receptor-positive breast cancers to oestrogen deprivation
AU - Gellert, Pascal
AU - Segal, Corrinne V.
AU - Gao, Qiong
AU - López-Knowles, Elena
AU - Martin, Lesley Ann
AU - Dodson, Andrew
AU - Li, Tiandao
AU - Miller, Christopher A.
AU - Lu, Charles
AU - Mardis, Elaine R.
AU - Gillman, Alexa
AU - Morden, James
AU - Graf, Manuela
AU - Sidhu, Kally
AU - Evans, Abigail
AU - Shere, Michael
AU - Holcombe, Christopher
AU - McIntosh, Stuart A.
AU - Bundred, Nigel
AU - Skene, Anthony
AU - Maxwell, William
AU - Robertson, John
AU - Bliss, Judith M.
AU - Smith, Ian
AU - Dowsett, Mitch
N1 - Publisher Copyright:
© The Author(s) 2016.
PY - 2016/11/9
Y1 - 2016/11/9
N2 - Pre-surgical studies allow study of the relationship between mutations and response of oestrogen 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 1/430% 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.
AB - Pre-surgical studies allow study of the relationship between mutations and response of oestrogen 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 1/430% 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.
UR - https://www.scopus.com/pages/publications/84995436787
U2 - 10.1038/ncomms13294
DO - 10.1038/ncomms13294
M3 - Article
C2 - 27827358
AN - SCOPUS:84995436787
SN - 2041-1723
VL - 7
JO - Nature communications
JF - Nature communications
M1 - 13294
ER -