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  • br Trastuzumab has radically changed the clinical scenario i


    Trastuzumab has radically changed the clinical scenario in the adjuvant treatment of eBC (leading to a durable 40% reduction of the relative risk of recurrence and to 34% fewer death).6,7 It is noteworthy that no clinical or preclinical evidences support the 12-months duration whose choice was based on data coming from clinical trials.8 Therefore, researchers are doing efforts to modify the treatment by either shortening Trastuzumab duration (de-escalation) or combining it with another HER2-inhibitors (dual blockade) or even extending treatment duration (escalation).9 These strategies, on one hand, might lead to reserve low-risk patients a less-toxic and less-resource demanding treatment, on the other hand, to improve high-risk patients’ prognosis.
    For this reason, a definitive and reliable risk stratification of patients assigned to adjuvant treatment with anti-HER2 agents represents a clinical unmet need. HER2+ eBC is a biologically heterogeneous disease. Both tumor biology and host factors may influence patients’ outcome, even acting together. Subgroups analysis from biggest trial in the adjuvant setting showed inconsistent data and were not pre-planned in the majority of cases.10
    Regarding retrospective analyses, whilst different timing and patterns of recurrence within HER2+ disease according to HR status have been already reported,11 the role of patient characteristics such us body mass index (BMI) and obesity is still Imatinib (STI571) of debate.
    Aim of our real-life multicentric study is to assess, in a population of HER2+ eBC patients receiving standard-of-care treatment, how different clinical-pathological features, such us staging, node status, BMI and HR status may affect the risk of recurrence. In particular, we focused on the interaction between BMI index and HR expression, looking at their role when taken together. This might allow to improve future trials design at a stratification level and to give an answer to many unmet needs evocated by recent trials in this setting.
    Patients and methods
    In this non-randomized retrospective study, we enrolled 279 women treated in two Italian University Hospitals (UniversitĂ  Politecnica delle Marche-Ospedali Riuni ti, Ancona and Azienda Ospedaliera Universitaria Pisana, Pisa) between 2006 and 2016. Eligibility criteria included histologically confirmed, early (stage I to III) invasive BC. HER2 positivity was defined as score 3+ by immunohistochemistry (scores range from 0 to 3+) in more than 10% of immunoreactive cells or amplification of ERBB2 by in situ hybridization.12 To avoid selection bias, only patients who completed adjuvant chemotherapy (taxane-based, anthracycline-based or both) and who concluded one year of trastuzumab administration (as per international guidelines)13 were included in the analysis.
    Recorded patients characteristics and clinical-pathological features were: age, menopausal state, BMI (calculated as weight(kg)/height(m)2), date of surgery, tumor characteristics (tumor size, lymph node status, pathological stage according to the version of the American Joint Committee on Cancer (AJCC) Staging Manual applicable at the time of diagnosis, histological type, grade, presence and amount of lymph vascular invasion, amount and type of a ductal carcinoma in situ component, presence of central necrosis, Ki-67, estrogen receptor (ER)/progesterone receptor (PgR) expression) and treatment modality (type of surgery, complementary radiotherapy, adjuvant chemotherapy and endocrine treatment).
    Follow up included history taking, physical examination and blood tests (including Carcinoembryonic Antigen (CEA) and Cancer Antigen 15-3 (CA 15-3) every 6 months, annual mammography (the first 6 months after the end of adjuvant radiotherapy) and breast ultrasound. Further evaluation was added in case of symptoms.
    As only few events of death were expected in our population (due to the adjuvant setting, the indolent course of eBC and the high probability of recurrence even after 15 or 20 years of follow up especially in HR+/HER2+ patients),14 we selected distant disease-free survival (DDFS) rather than overall survival (OS) as primary end-point. DDFS was defined as the time from surgery to first appearance of distant metastases or death from any causes, whichever occurred first. This particular endpoint was selected in order to exclude ipsilateral breast recurrence, locoregional invasive progression and appearance of a second primary cancer (including contralateral breast cancer) as events of progression and finally remove the bias represented by locoregional treatment (surgery and/or radiotherapy). According to
    APHINITY trial,10 we analyzed DDFS at 3 years (3yDDFS) as another end-point to look at risk of early recurrence. The cut-point of three years was modeled a priori based on previous observations11,15 showing that the peak hazard of