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

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.

Clinicopathological response to neoadjuvant therapies and pathological complete response as a biomarker of survival in human epidermal growth factor receptor-2 enriched breast cancer – A retrospective cohort study

“…In the current analysis, it is unsurprising that histopathological and immunohistochemical characteristics such as PgR status, tumour grade and disease burden independently predict breast and axillary pCR, as described in several recent studies [ 15 , [41] , [42] , [43] ]. In their analysis of 2366 breast cancer patients in the Netherlands Cancer Registry treated with NAT, Goorts et al.…”

“…Such results prove promising, moreover while pCR rates of up to 70% have been described in HER2þ disease following NAT prescription [13,14]. In clinical practice, deciphering those likely to achieve such responses proves challenging to the oncologist, although recent evidence from Katayama et al suggests HER2 3þ on immunohistochemistry (IHC) and grade 3 disease accurately predict pCR to anti-HER2 therapies [15]. In spite of these promising data, patient and tumour heterogeneity may limit such conclusions until validated in independent analyses, and the prognostic value of pCR remains uncertain in certain circles.…”

Temporal and spatial topography of cell proliferation in cancer.

“…We applied coherence metrics to cell cycle dynamics in breast cancer tissues overexpressing the HER2 growth factor receptor 69 . HER2 expression de nes one of the major subclasses of breast cancer and is routinely assessed using immunohistochemistry 70 as both the magnitude and heterogeneity of HER2 protein expression predict response to HER2-directed therapy 71,69,72,73 . We performed CyCIF on a cohort of 26 breast cancer specimens (TMA1, TMA2), identi ed MPI +1 epithelial cells and used the ccD-CMD algorithm to quantify IOV and CFD for individual patients (Fig.…”

Neoadjuvant Pertuzumab plus Trastuzumab in Combination with Docetaxel and Carboplatin in Patients with HER2 Positive Breast Cancer: Real-World Data from a National Institute of Oncology in Poland.

“…Response to neoadjuvant treatment is a source of important information about tumor biology and is one of well evaluated prognostic factors. [7,12]. Based on the evaluation of the surgical specimens for pathologic complete response (pCR), decisions are made to continue the current therapy (trastuzumab +/-pertuzumab) following the surgery or, if the minimal residual disease is found, to switch to trastuzumab-emtansine to optimize long-term outcomes [13][14][15].…”