Gellert, P., Segal, C. V., Gao, Q., Lopez-Knowles, E., Martin, L. A., Dodson, A., Li, T. D., Miller, C. A., Lu, C., Mardis, E. R., Gillman, A., Morden, J., Graf, M., Sidhu, K., Evans, A., Shere, M., Holcombe, C., McIntosh, S. A., Bundred, N., Skene, A., Maxwell, W., Robertson, J., Bliss, J. M., Smith, I., Dowsett, M., Triali, Poetic Trial Management Grp (2016) Impact of mutational profiles on response of primary oestrogen receptor-positive breast cancers to oestrogen deprivation. Nature Communications, 7. ISSN 2041-1723

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Abstract

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 similar to 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.

Item Type:	Article
Authors (ICR Faculty only):	Bliss, Judith and Dowsett, Mitch and Smith, Ian and Martin, Lesley-Ann
All Authors:	Gellert, P., Segal, C. V., Gao, Q., Lopez-Knowles, E., Martin, L. A., Dodson, A., Li, T. D., Miller, C. A., Lu, C., Mardis, E. R., Gillman, A., Morden, J., Graf, M., Sidhu, K., Evans, A., Shere, M., Holcombe, C., McIntosh, S. A., Bundred, N., Skene, A., Maxwell, W., Robertson, J., Bliss, J. M., Smith, I., Dowsett, M., Triali, Poetic Trial Management Grp
Additional Information:	ISI Document Delivery No.: EB3MC Times Cited: 0 Cited Reference Count: 38 Gellert, Pascal Segal, Corrinne V. Gao, Qiong Lopez-Knowles, Elena Martin, Lesley-Ann Dodson, Andrew Li, Tiandao Miller, Christopher A. Lu, Charles Mardis, Elaine R. Gillman, Alexa Morden, James Graf, Manuela Sidhu, Kally Evans, Abigail Shere, Michael Holcombe, Christopher McIntosh, Stuart A. Bundred, Nigel Skene, Anthony Maxwell, William Robertson, John Bliss, Judith M. Smith, Ian Dowsett, Mitch Mary-Jean Mitchell Green Foundation; Breast Cancer Now; NIHR RM/ICR Biomedical Research Centre; Cancer Research UK ICR-CTSU through core programme grant [CRUK/07/015] Lila Zabaglo, Elizabeth Folkerd, Margaret Hills, Simone Detre and Maria Afentakis provided excellent laboratory support. We thank all participating patients and staff at POETIC centres, and ICR-CTSU who contributed to trial management and data and sample collection, and the independent data-monitoring committee and trial-steering committee for their oversight of the trial. This work was supported by the Mary-Jean Mitchell Green Foundation, Breast Cancer Now and the NIHR RM/ICR Biomedical Research Centre. The POETIC trial (C1491/A8671/CRUK/07/015, C1491/A15955 and C406/A8962), from which samples were obtained for this study, was supported by Cancer Research UK (CRUK/07/015) as is ICR-CTSU through its core programme grant. POETIC was registered with ISRCTN registry (ISRCTN63882543). 0 NATURE PUBLISHING GROUP LONDON NAT COMMUN
Uncontrolled Keywords:	SEQUENCING DATA CLINICAL ONCOLOGY/COLLEGE AROMATASE INHIBITORS ENDOCRINE THERAPY AMERICAN SOCIETY KI67 EXPRESSION RECOMMENDATIONS IDENTIFICATION LANDSCAPE EVOLUTION
Research teams:	Clinical Units > Breast Unit ICR divisions > Clinical Studies > Clinical Trials & Statistics Unit ICR divisions > Breast Cancer Research > Endocrinology ICR divisions > Molecular Pathology > Endocrinology
Depositing User:	Barry Jenkins
Date Deposited:	07 Dec 2016 13:39
Last Modified:	07 Dec 2016 13:43
URI:	http://publications.icr.ac.uk/id/eprint/15498

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