Titolo progetto: PRIN2022 - Genomic, immune, and clinical characterization of estrogen receptor-positive, HER2-low breast cancer to improve treatment personalization in early breast cancer patients: a translational, multicenter trial

Programma di finanziamento: PRIN 2022

Responsabile scientifico: prof. Fabio Puglisi

Ruolo del DAME: partner

Descrizione generale:

Estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer (BC) is characterized by biological heterogeneity, which affects prognosis and response to treatments. For this reason, validated biomarkers are needed to improve personalization and cost-effectiveness of the treatment in patients with ER+/HER2- early disease. Although ER+/HER2- BC is defined as HER2-negative due to the lack of the HER2 gene amplification, about 47-65% of ER+/HER2- tumors express low levels of HER2 receptor (HER2-low breast cancer). Preliminary data indicate that novel HER2-directed antibody drug conjugates, namely trastuzumab deruxtecan and trastuzumab duocarmazine, have remarkable therapeutic activity in ER+/HER2-low BC. Moreover, several retrospective studies suggest that significant genomic, immune, and clinical differences exist between ER+/HER2-low tumors and ER+ tumors completely lacking HER expression (HER2-0 tumors). In this study, we aim to provide an in-depth characterization of HER-low and HER2-0 ER+ breast cancer, through the analysis of tumor samples obtained from BC patients enrolled in randomized clinical trials of the GIM (Gruppo Italiano Mammella) Investigator Group. By performing this large translational analysis we aim to validate the use of HER2-low expression as prognostic/predictive biomarker to guide treatment personalization in ER+/HER2- BC patients (short-term objective), and to identify novel potential therapeutic targets which could lead to new therapeutic options (long-term objective). Briefly, >300 primary BC tumor samples obtained from ER+/HER2- BC patients enrolled in the GIM2, GIM4 and GIM10 trials will be retrieved and reviewed for HER2 expression to be categorized as HER2-low and HER2-0. Samples will undergo RNA extraction for gene expression analysis of >700 gene involved in key processes in BC. Tumor infiltrating lymphocytes will be evaluated in each sample to study tumor immune microenvironment. In addition, in a subset of samples, an exploratory proteomic analysis on tissue will be conducted. Survival and clinical data of patients enrolled in the GIM2, GIM4 and GIM10 trials will be updated to investigate and validate the association between the explored biomarkers, prognosis and treatment resistance. This project will provide the largest collection of genomic and immunological data, combined with proteomic features, from ER+/HER2- early BC patients treated in the context of phase III clinical trials. This opportunity is likely to minimize the risk of selection biases which may impair the reliability of prognostic/predictive factors evaluated outside of clinical trials. This ambitious effort will give a great input to the field of biomarker research in BC. From a clinical point of view, the validation of novel prognostic and predictive biomarkers through this project may lead to a better treatment personalization of patients with ER+/HER2- BC, improving the cost-effectiveness of breast cancer care.

Partner del progetto:                                                                                

• Università degli Studi di Genova
• Università degli Studi di Udine
• Università degli Studi di Napoli Federico II

Date inizio e fine progetto: 18.10.2023 – 17.10.2025

Budget totale del progetto: 63.315,00€

Sito web: https://prin.mur.gov.it/ 

Finanziato dall’Unione europea – Next Generation EU