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.
The immune system is responsible for the maintenance of tissue homeostasis by initiating inflammatory reactions that involve the activation of innate and adaptive immune cells.• In cancer, immune responses that aim to eliminate the tumour are elicited. However, the neoplastic cells may escape the immune control through immune-editing which depends on both tumour and immune cell interactions. • New therapies have the potential to reactivate the immune response against cancer, e.g., in melanomas and lung cancer, and this is associated with improved outcomes. Novel Insights• Immune cell subpopulations, especially tumour-infiltrating lymphocytes (TILs) in the breast carcinoma microenvironment, can influence the tumour response to various neoadjuvant chemotherapy regimens, particularly in triple-negative and HER2-positive breast cancers. • Recognition of TIL subtypes and locations in relation to tumour cells in breast carcinoma are promising for the development of more effective options of targeted therapy. • The International TILs Working Group recommends the assessment of TILs on H&E sections. StromalTILs should be analysed excluding necrotic and crushed areas. Immunohistochemical and digital assessments of TILs are currently limited to the research setting. AbstractThe prognostic value of the immune cell infiltrate in the breast carcinoma microenvironment is still uncertain. We reviewed published articles analysing the infiltration of inflammatory cells in the microenvironment of breast carcinoma. Data revealed the importance of infiltration of these immune cells in the prognosis of breast carcinoma, particularly the triple-negative and HER2-positive phenotypes. Tumourinfiltrating lymphocytes and their subtypes play a fundamental role in predicting the pathological complete response (pCR) to neoadjuvant chemotherapy. More research aiming to dissect a complex network of communication between cancer cells and other cellular components of the tumour microenvironment is necessary to develop more effective therapeutic approaches.
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