Impact of mutational profiles on response of primary oestrogen receptor-positive breast cancers to oestrogen deprivation.
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 ∼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.
Breast Cancer Now Research Centre at The Institute of Cancer Research, 237 Fulham Road, London SW7 3RP, UK.
Pascal
P
Gellert
Breast Cancer Now Research Centre at The Institute of Cancer Research, 237 Fulham Road, London SW7 3RP, UK.
Corrinne V
CV
Segal
Breast Cancer Now Research Centre at The Institute of Cancer Research, 237 Fulham Road, London SW7 3RP, UK.
Qiong
Q
Gao
Breast Cancer Now Research Centre at The Institute of Cancer Research, 237 Fulham Road, London SW7 3RP, UK.
Elena
E
López-Knowles
Breast Cancer Now Research Centre at The Institute of Cancer Research, 237 Fulham Road, London SW7 3RP, UK.
Lesley-Ann
LA
Martin
Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK.
Andrew
A
Dodson
McDonnell Genome Institute, Washington University School of Medicine, 4444 Forest Park Boulevard, St Louis, 63108 Missouri, USA.
Tiandao
0000-0003-1650-0555
T
Li
McDonnell Genome Institute, Washington University School of Medicine, 4444 Forest Park Boulevard, St Louis, 63108 Missouri, USA.
Christopher A
0000-0003-4266-6700
CA
Miller
McDonnell Genome Institute, Washington University School of Medicine, 4444 Forest Park Boulevard, St Louis, 63108 Missouri, USA.
Charles
C
Lu
McDonnell Genome Institute, Washington University School of Medicine, 4444 Forest Park Boulevard, St Louis, 63108 Missouri, USA.
Elaine R
ER
Mardis
Clinical Trials and Statistics Unit at The Institute of Cancer Research, 15 Cotswold Road, Sutton SM2 5NG, UK.
Alexa
A
Gillman
Clinical Trials and Statistics Unit at The Institute of Cancer Research, 15 Cotswold Road, Sutton SM2 5NG, UK.
James
J
Morden
Breast Cancer Now Research Centre at The Institute of Cancer Research, 237 Fulham Road, London SW7 3RP, UK.
Manuela
M
Graf
Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK.
Kally
K
Sidhu
Poole General Hospital, Longfleet Road, Dorset BH15 2JB, UK.
Abigail
A
Evans
Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, UK.
Michael
M
Shere
Royal Liverpool University Hospital, 200 London Road, Liverpool L3 9TA, UK.
Christopher
C
Holcombe
Queen's University Belfast, University Road, Belfast BT7 1NN, UK.
Stuart A
SA
McIntosh
University Hospital of South Manchester, Education and Research Centre, Southmoor Road, Manchester M23 9LT, UK.
Nigel
N
Bundred
Royal Bournemouth Hospital, Castle Ln E, Bournemouth BH7 7DW, UK.
Anthony
A
Skene
Withybush General Hospital, Fishguard Road, Haverfordwest SA61 2PZ, UK.
William
W
Maxwell
University of Nottingham, Derby Road, Nottingham NG7 2UH, UK.
John
J
Robertson
Clinical Trials and Statistics Unit at The Institute of Cancer Research, 15 Cotswold Road, Sutton SM2 5NG, UK.
Judith M
JM
Bliss
Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK.
Ian
I
Smith
Breast Cancer Now Research Centre at The Institute of Cancer Research, 237 Fulham Road, London SW7 3RP, UK.|Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK.
Mitch
M
Dowsett
D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D047072:Aromatase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D001706:Biopsy / Q000379:methods; D001940:Breast / Q000473:pathology; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004967:Estrogens / Q000378:metabolism; D005260:Female; D000091344:Filaggrin Proteins; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008875:Middle Aged; D009154:Mutation; D011960:Receptors, Estrogen / Q000378:metabolism; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D000073359:Exome Sequencing / Q000379:methods
D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D004967:Estrogens; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D019394:Ki-67 Antigen; D011960:Receptors, Estrogen; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53