Journal Article

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

Mardis, Elaine R., Gillman, Alexa, Dowsett, Mitch, López-Knowles, Elena, Lu, Charles, Miller, Christopher A., Martin, Lesley-Ann, McIntosh, Stuart A., Graf, Manuela, Morden, James, Robertson, John, Bundred, Nigel, Bliss, Judith M., Gao, Qiong, Skene, Anthony, Dodson, Andrew, Holcombe, Christopher, Smith, Ian, Li, Tiandao, Evans, Abigail, Shere, Michael, Gellert, Pascal, Maxwell, William, Sidhu, Kally, Segal, Corrinne V.

2016

Overview

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. Aromatase inhibitors are used to treat oestrogen receptor positive breast cancers but the molecular basis for the response of patients is unclear. Here, the authors use samples from an aromatase inhibitor clinical trial and show that tumours from poor responders have more mutations than good responders and also more frequently harbour p53 mutations.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/208/69 / 631/67/1059/2326 / 692/4028/67/1347 / 82/51 / Aged / Aged, 80 and over / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Aromatase Inhibitors - pharmacology / Aromatase Inhibitors - therapeutic use / Biopsy / Biopsy - methods / Breast - pathology / Breast cancer / Breast Neoplasms - blood / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Breast Neoplasms - pathology / Cancer research / Cores / DNA Mutational Analysis - methods / Drug Resistance, Neoplasm - genetics / Estrogens - metabolism / Exome Sequencing - methods / Female / Filaggrin Proteins / Humanities and Social Sciences / Humans / Ki-67 Antigen - analysis / Medical research / Middle Aged / multidisciplinary / Mutation / Patients / Receptors, Estrogen - metabolism / Science / Science (multidisciplinary) / Treatment Outcome / Tumor Suppressor Protein p53 - genetics / Tumors