Schettini, Francesco (2021) Improving the Management of Breast Cancer. [Tesi di dottorato]

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The clinical scenario for both early-stage breast cancer (EBC) and advanced breast cancer (ABC) is complex, multifaced and rapidly evolving. Overall, this work aimed at providing evidence to improve the management of EBC and ABC by: 1. Identifying or validating novel biomarkers predictive of response to treatments and novel pharmacological targets; 2. Improving treatment algorithms for hormone receptor positive/HER2-negative (HR+/HER2-neg.) ABC. With respect to the first objective, the focus was put on breast cancer molecular subtypes and the validation of their use in neoadjuvant setting in HER2-positive (+) tumors, so to predict pCR and support escalated or de-escalated therapeutic approaches. Furthermore, following the discovery of the efficacy of novel anti-HER2-directed ADC in HER2-neg. tumors presenting some level of expression of HER2 (i.e. HER2-low tumors), the first extensive molecular and clinicopathological characterization of this potentially novel subgroup of breast tumors was conducted. Finally, the mTOR inhibitor everolimus, in combination with exemestane is approved for pretreated HR+/HER2-neg. ABC. However, a number of very effective therapeutic alternatives has emerged during the last few years and the identification of biomarkers of response would be particularly useful to identify patients that might benefit most from this drug. With respect to the second aim, the focus was put on improving current treatment algorithms for advanced luminal tumors, due to the discrepancy observed between main international guidelines' recommendations and "real world" clinical practice. The studies conducted had the objective to provide a comprehensive assessment of the efficacy of current therapeutic options and novel pooled evidence to support current treatment guidelines and help clinician's with their therapeutic choices. All the thesis objectives were addressed in 5 different studies, now published in different peer-reviewed international journals. Overall, the articles that are part of this thesis provided evidence to: 1. Support the use of the PAM50 HER2-Enriched molecular subtype, if not in the clinical practice, at least in future clinical trials to assess neoadjuvant escalated or de-escalated therapeutic approaches in HER2+ tumors, irrespective of HR status; 2. Further explore circulating endothelial cells, neutrophil-to-lymphocyte ratio and lymphocytes subpopulations as biomarkers of response to select optimal candidates to everolimus in HR+ breast cancer patients; 3. Support main international treatment guidelines in recommending endocrine therapy + target therapy as the preferred 1st/2nd-line treatment of HR+/HER2-neg. postmenopausal metastatic breast tumors, especially CDK4/6-inhibitors-based regimens; 4. Support the use of CDK4/6-inhibitors-based regimens instead of single agent endocrine therapy, independently from age, menopausal status, endocrine sensitiveness and visceral involvement. Finally, we dissected for the first time the clinicopathological and molecular characteristics of HER2-low breast tumors and find out that this category do not show the features of an independent breast cancer subtype. However, the detection of HER2 low protein levels as well as the assessment of ERBB2 mRNA levels, might play an important role from a therapeutic perspective in the near future. Moreover, HR+/HER2-low showed distinct features from triple negative (TNBC)/HER2-low and HER2 0, as well as from HR+/HER2 0 tumors, while TNBC/HER2-low did not show substantial differences with TNBC/HER2 0.

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