HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer
M.A. Bergamino, Elena López‐Knowles, Gabriele Morani, Holly Tovey, Lucy Kilburn, Eugene F. Schuster, Anastasia Alataki, Margaret Hills, Hui Xiao, Chris Holcombe, Anthony Skene, J.F.R. Robertson, Ian E. Smith, Judith M. Bliss, Mitch Dowsett, Maggie C.U. Cheang, Abigail Evans, Adrian Ball, A. Johri, Ali Nejim, Alison Jones, A P Corder, Amanda Thorne, Ambika Anand, Amitabha Chakrabarti, A. Robinson, Anthony Skene, Anupam Modi, Ashraf Patel, Ashutosh Kothari, Brendan McFall, Caroline Mortimer, Caroline Lee, Charlie Chan, Charlotte Abson, Christopher Holcombe, Christopher Hinton, Ciaran Hollywood, Claire Murphy, Clare Crowley, Claudia Harding-Mackean, C.D.M. Griffith, C. Lewanski, Daniel Rea, David Hwang, Derek Crawford, Dinesh Thekkinkattil, Douglas Ferguson, Douglas Adamson, Duncan Wheatley, Duraisamy Ravichandran, ED Babu, Elaine Hyett, Fawzia Ashkanani, Fiona Hoar, F.S. Kenny, Gary Dyke, Geoffrey Sparrow, Gilbert, Giles Cunnick, Hafiz Algurafi, Helen Sweetland, Highes-Davies Prof, Hisham Hamed, Ian Smith, Ian Laidlaw, Ilyas Khattak, Jacqueline C. Newby, Jacqueline Rees-Lee, Jalal Kokan, Jane Barrett, Jay Naik, Jayant S. Vaidya, Jennifer Forrest, Jitendra Parmar, Jocelyn Adams, John Fox, Jonathan Roberts, Jonathan I. Dawson, Julie Doughty, Jull Donnelly, Kathleen Dunn, Kian Chin, Kieran Horgan, Kislaya Thakur, Ludger Barthelmes, Lynda Wyld, Madhumita Bhattacharyya, Maher Hadaki, Makam Kishore, Marcus Ornstein, Maria Bramley, Maria Bews-Hair, Marina Parton, Mark Sibbering, Mark Kissin, Mark Churn, Martin Hogg, Mary Quigley, M. Hatton
Abstract
BACKGROUND: Oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks' presurgical AI treatment in ER+/HER2+ BCs. METHODS: ). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. FINDINGS: . Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14-5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. INTERPRETATION: Our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse. FUNDING: Cancer Research UK (CRUK/07/015).