Abstract P3-10-26: Predicting benefit from HER2-targeted therapies in patients with ER+/HER2+ breast cancer
Authors: Turnbull AK , Webber V , McStay D , Arthur L , Martinez-Perez C , Fernando A , Renshaw L , Keys J , Clarke R , Sims AH , Dixon JM 
Published: May 2019

Abstract
Background: ER+/HER2+ accounts for up to 10% of all breast cancers (BCs) and most are treated with endocrine therapy (ET) after surgery to reduce the recurrence risk. We developed and validated an immunohistochemistry (IHC) based test (EA2Clin) that incorporates baseline IL6ST, clinical variables and on-treatment measurement of MCM4. Responders (Rs) and non-responders (NRs) to ET are identified and it accurately estimates recurrence-free survival (RFS) and BC-specific overall survival (BCSS). The aim was to determine if EA2Clin could accurately predict ER+/HER2+ patients likely to benefit from ET and to determine if it can identify those for whom HER2-targeted therapies are required.
Methods: 3 cohorts were studied:
A: 32 post-menopausal women (PMW) with large ER+/HER2+ BC treated with neoadjuvant (3-6 months) then adjuvant letrozole. 5 also received adjuvant chemotherapy plus Herceptin. Neoadjuvant clinical response was assessed by changes in tumour volume. Tumour core biopsies were taken at 0, 14 days and 3 months. Gene expression analysis using Illumina HT12 whole-genome beadarrays was performed on a subset (n=17) where fresh tissue was available.
B: 13 PMW with ER+/HER2+ BC who were treated by surgery without neoadjuvant therapy. RNA was extracted from excision tissues and analysed using whole-genome Affymetrix U133A microarrays.
C: 15 PMW with ER+/HER2+ BC treated with 2-weeks of pre-operative letrozole (n=7) or anastrozole (n=8). All received adjuvant letrozole. Tissues were collected at pre-treatment and at surgery. None received Herceptin or chemotherapy.
All patients were followed-up after surgery (median follow-up = 6.4 years).
Results: In cohort A, half (16/32) of the patients responded to ET with tumour volume reductions of &gt;70% with neoadjuvant treatment. Innate resistance was apparent in 3 patients with continued tumour growth on ET, whereas 13 patients developed resistance after a period of response. EAClin2 predicted neoadjuvant response with a 92% accuracy. There was increased expression of phospho-AKT and phospho-ERK in NRs, not seen in Rs. Half (8/16) of the NR cancers expressed phospho-ER; but was not seen in any responsive cancer. Gene expression analysis in 17 patients showed increased MAPK and PI3K pathway activity in the 9 NR compared with the 8 R tumours. These results were recapitulated in cohort B where MAPK and PI3K activity were associated with low levels of IL6ST.
In the 16/32 patients who responded well to neoadjuvant ET the actuarial recurrence rate was 0% at 5 and 10 years. The rate of recurrence in the NR was 30% at both 5 and 10 years. Of the 5 patients who received chemotherapy plus Herceptin, none recurred despite a poor response to neoadjuvant letrozole (median length to last follow-up was 6.1 years). Initial data suggest that in cohort B EA2Clin identifies a group of ER+/HER2+ cancers that can be managed by ET alone.
Conclusions:
· The EA2Clin test identifies ER+/HER2+ BCs who respond well to ET alone and those with a poor clinical response who have higher risk of recurrence.
· NR to ET have increased expression of PI3K and MAPK pathways, consistent with active HER2 signalling.
· There is potential role for EA2Clin in selecting ER+/HER2+ patients that require and benefit from HER2-targeted therapies.
Citation Format: Turnbull AK, Webber V, McStay D, Arthur L, Martinez-Perez C, Fernando A, Renshaw L, Keys J, Clarke R, Sims AH, Dixon JM. Predicting benefit from HER2-targeted therapies in patients with ER+/HER2+ breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-10-26.