Minimally Interventional Study on Prevalence of Emerging ESR1 Mutations in Liquid Biopsy in Three Cohorts of Patients With Breast Cancer in Comparison With Patient's Baseline ESR1 Mutation Status as Defined by Tissue Profiling.

Inclusion Criteria: Cohort 1: * BC patients, male and female, * 18 years old and older, * Pre or post menopausal, * With HR+ (ER and/or PR positive) and Her-2 negative (confirmed centrally), * Locally advanced irresectable and/or metastatic disease * Confirmation of HR and Her-2 status may be performed in the primary tumor or in the metastatic lesion (patients with discordant results may be included), * Patients must be candidates to CDK4/6i therapy in combination with endocrine therapy in the first line setting (with or without ovarian suppression) * Patients may have received one previous line of chemotherapy in the metastatic setting, but no endocrine therapy in the metastatic setting is allowed, * Patients may have received chemotherapy in the neo/adjuvant setting, * Patients may have received endocrine therapy (with or without ovarian suppression) in the neo/adjuvant setting, * Patients may have received a CDK4/6i in the adjuvant setting, provided they are still candidates for CDK4/6i therapy in the metastatic setting, * Patients must be able to undergo a liquid biopsy procedure before starting their first line treatment, * All patients must fill and sign an informed consent form. Cohort 2: * BC patients, * Male and female, * 18 years old and older, * pre or post menopausal, * With HR+ (ER and/or PR positive) and Her-2 negative (confirmed centrally), * Locally advanced irresectable and/or metastatic disease who have progressed on a CDK4/6i in combination with endocrine therapy (with or without ovarian suppression) in the first or second line setting, * All other non-conflicting inclusion criteria for cohort 1 apply. Cohort 3: * BC Patients, * Male and female, * 18 years or older, * pre- or post-menopausal, * With HR+ (ER and/or PR positive), HER2-negative (centrally confirmed) locally advanced unresectable and/or metastatic disease, * Confirmation of HR and HER2 status may be performed on the primary tumour or the metastatic lesion (patients with discordant results may be included), * Patients must be on first-line hormonal therapy with an aromatase inhibitor plus a CDK4/6 inhibitor (with or without ovarian suppression) for at least 6 months, * No clinical or radiological evidence of progressive disease, * Patients may have received a prior line of chemotherapy in the metastatic setting; however, prior endocrine therapy in the metastatic setting is not permitted, * Patients may have received chemotherapy in the neoadjuvant/adjuvant setting, * Patients may have received endocrine therapy (with or without ovarian suppression) in the neoadjuvant/adjuvant setting, * Patients may have received a CDK4/6 inhibitor in the adjuvant setting, provided they are still eligible for CDK4/6 inhibitor therapy in the metastatic setting, * Patients must be able to undergo a liquid biopsy procedure before starting their first-line treatment, * All patients must read and sign an Informed Consent Form. Exclusion Criteria: * Patients WITHOUT HR+ (ER- and/or PR-positive)/HER2-negative disease, * Patients without radiological and/or pathological confirmation of locally unresectable and/or metastatic breast cancer, * Patients who are NOT candidates for further systemic treatment following a diagnosis of metastatic disease or disease progression, * Patients who have already started a CDK4/6 inhibitor in combination with endocrine therapy (with or without ovarian suppression) for first-line metastatic disease (for Cohort 1); * Patients who have already started a new line of treatment for metastatic disease following progression on a CDK4/6 inhibitor in combination with endocrine therapy (with or without ovarian suppression) (for Cohort 2); * Patients with any suspicion of clinical or radiological disease progression at the time of the first liquid biopsy collection (for Cohort 3), * Patients who are NOT able to undergo a liquid biopsy procedure, * Patients who are NOT able to provide informed consent.