Predictors of pathological complete response to neoadjuvant treatment and changes to post-neoadjuvant HER2 status in HER2-positive invasive breast cancer

Ayaka Katayama,Nahla Badr,Andrew H.S Lee,Abeer M Shaaban,Dave Purnell,Grace Callagy,Carol Murray ,Cecily Quinn ,Elena Provenzano,Karim Eldib,Michael S Toss,Colin A Purdie ,Sarah Pinder ,Rebecca Millican-Slater,Cian Martyn,Sho Shiino,Ian O Ellis ,Islam M Miligy,Sasagu Kurozumi,Tetsunari Oyama,Emad A Rakha

doi:10.1038/s41379-021-00738-5

Abstract

The response of human epidermal growth factor receptor2 (HER2)- positive breast cancer (BC) patients to anti-HER2 targeted therapy is significant. However, the response is not uniform and a proportion of HER2-positive patients do not respond. This study aims to identify predictors of response in the neoadjuvant treatment and to assess the discordance rate of HER2 status between pre- and post-treatment specimens in HER2-positive BC patients. The study group comprised 500 BC patients treated with neoadjuvant chemotherapy (NACT) and/or neoadjuvant anti-HER2 therapy and surgery who had tumours that were 3+ or 2+ with HER2 immunohistochemistry (IHC). HER2 IHC 2+ tumours were classified into five groups by fluorescence in situ hybridisation (FISH) according to the 2018 ASCO/CAP guidelines of which Groups 1, 2 and 3 were considered HER2 amplified. Pathological complete response (pCR) was more frequent in HER2 IHC 3+ tumours than in HER2 IHC 2+/HER2 amplified tumours, when either in receipt of NACT alone (38% versus 13%; p = 0.22) or neoadjuvant anti-HER2 therapy (52% versus 20%; p < 0.001). Multivariate logistic regression analysis showed that HER2 IHC 3+ and histological grade 3 were independent predictors of pCR following neoadjuvant anti-HER2 therapy. In the HER2 IHC 2+/HER2 amplified tumours or ASCO/CAP FISH Group 1 alone, ER-negativity was an independent predictor of pCR following NACT and/or neoadjuvant anti-HER2 therapy. In the current study, 22% of HER2-positive tumours became HER2-negative by IHC and FISH following neoadjuvant treatment, the majority (74%) HER2 IHC 2+/HER2 amplified tumours. Repeat HER2 testing after neoadjuvant treatment should therefore be considered.

Highlights

15% of invasive breast cancers (BCs) are human epidermal growth factor receptor2 (HER2) positive, defined as showing HER2 gene amplification or protein overexpression, and such tumours have been shown to be sensitive to anti-HER2 targeted therapy [1,2,3]
We aimed to identify predictive factors for Pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) across different HER2-positive categories
We showed that HER2 IHC 3+ invasive BC had a higher pCR rate than IHC 2+/HER2 amplified tumours when anti-HER2 therapy was received, consistent with earlier analyses [9]

Summary

Introduction

15% of invasive breast cancers (BCs) are human epidermal growth factor receptor (HER2) positive, defined as showing HER2 gene amplification or protein overexpression, and such tumours have been shown to be sensitive to anti-HER2 targeted therapy [1,2,3]. Immunohistochemistry (IHC) and/or in situ hybridisation (ISH) is routinely used to evaluate the HER2 status for treatment selection. The current American Society of Clinical Oncology/ College of American Pathologists (ASCO/CAP) guidelines regard HER2 IHC score 3+ as positive, score 2+ as equivocal and scores 0 and 1+ as negative [5]. If the IHC result is score 2+, such patients are tested for HER2 amplification by ISH; most commonly fluorescence in situ hybridisation (FISH), to assess the average HER2 gene and chromosome enumeration probe 17 (CEP17) copy numbers (CNs) per carcinoma cell and the ratio of these [5]. The 2018 ASCO/ CAP guidelines divide HER2 FISH status into five groups (Table 1) [5]

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