Titolo progetto: Diagnostic role of ctDNA for disease monitoring during first-line endocrine treatment in patients with hormone receptor positive metastatic breast cancer

Programma di finanziamento: Fondazione AstraZeneca

Responsabile scientifico: prof. Fabio Puglisi

Collaboratori: Dott. Lorenzo Gerratana, prof. Gianluca Tell, prof. Giuseppe Damante, prof.ssa Carla Di Loreto, Prof. Chiara Zuiani, prof.ssa Miriam Isola

Ruolo del DAME: coordinatore

Descrizione generale:

Breast cancer can be classified into three major categories according to the expression levels of estrogen and progesterone receptors and human epidermal growth factor receptor 2 (HER2) amplification. Approximately 10% of newly diagnosed BC cases are metastatic, whereas 20%-50% of patients with early BC will eventually develop metastatic disease. Patients with hormone receptor-positive MBC are eligible for endocrine therapy as first line treatment which is based on strategies aimed to either block signaling pathways depending on the estrogen receptor (ESR1) or using ESR1 antagonists. Only a few accepted predictive factors are associated with treatment benefit for MBC. Frequent exams are associated with high risk of overestimation of median progression free survival, therefore, from a methodological point of view, if surveillance intervals are heterogeneous within a disease group, comparisons of median PFS across studies may not be meaningful. As demonstrated by analyzing a real world cohort treated at our Institution, outcome of women with MBC varied according to BC subtypes, both in terms of Overall Survival and PFS. The median OS of patients with ER-positive range from 29.7 to 45.3 months. The median PFS was 9.5 month among patients which received ET as first line treatment. A disproportionately high percentage of health care services is widely documented. Total health care costs are approximately 50% higher in patients who have more frequent disease-monitoring testing, even after accounting for the individual costs of the tests. Additionally, extreme users of disease-monitoring testing are more likely to have increased health care service utilization near the end of life. As demonstrated in our previous work, in absence of robust predictive factors of treatment benefit, decisions about treatment are usually based on rough estimation of the expected benefit. Interestingly, the ability to predict therapeutic benefit on the basis of previous treatment performance does not seem to apply equally to the different subgroups or to different treatments (chemotherapy or ET). Fribbens et al conducted a retrospective-prospective study assessing ESR1 mutations in plasma from the SoFEA trial and PALOMA3 trial. They observe that ctDNA analysis using digital polymerase chain reaction is a robust technique for ESR1 mutation detection. Methylation of promoter consists on silencing of gene expression in peripheral blood, it correlates with the non-expression of ER in tumor as highlighted in a cohort of 110 patients with early BC. Enhancers are more frequent than promoters in the mammalian genome. Methylation of enhancers consists on silencing of gene expression and allows stratification of ER-positive BC patients as responders to endocrine therapy in vitro on ER-positive hormone sensitive MCF7 cells. Furthermore, a standardized assessment evaluation for MBC is still lacking. Because of these unmet needs, ET is continued until disease progression, or if toxicity requiring discontinuation occurs. Resistance is frequent in the treatment of early BC and unavoidable in MBC. Recently, mutations in ESR1 have been described in MBC that had been previously exposed to aromatase inhibitors and are rarely detectable in primary BC. ER is a ligand- activated nuclear receptor and a major regulator of cell growth, survival, and metastasis. Besides that, resistance phenomena have been also linked to ESR1 cis-regulatory elements hypermethylation, both related to ESR1 silencing.

Partner:

• Università degli Studi di Udine
• National Cancer Institute IRCCS A.O.U. San Martino
• National Cancer Institute Centro di Riferimento Oncologico
• IRCCS A.O.U. San Martino - National Cancer Institute

Date inizio e fine progetto: 19.06.2018 – 31.03.2023

Budget totale del progetto: 110.500,00€