Real wOrld studY in the Adjuvant Setting for High Risk earLy Breast Cancer Patients

The treatment of high-risk hormone receptor (HR) positive, Her2 negative, early breast cancer (EBC) patients has recently changed following the results of practice changing phase III trials. The hormone therapy (HT) with tamoxifene (T) or Aromatase Inhibitors (AIs), in association with ovarian function failure suppression (OFS) in the premenopausal patients, represented the standard options available until 2022. The role of OFS, usually reached through the use of LhRh analogues in the premenopausal patients, was addressed and defined in the SOFT/TEXT trials. The association of LhRh analogues (LhRha) with exemestane (E) or T with LhRha in the premenopausal setting showed an improved disease free survival (DFS) if compared to T alone. Moreover, at 12 years of follow up, the E-LhRha increases the DFS if compared to T-LhRha3. In the SOFT study, premenopausal patients did not benefit from the addition of OFS, but for whose women at sufficient risk of recurrence to deserve adjuvant chemotherapy (CHT) and who maintained pre-menopausal estradiol, the addition of LhRha to T reduced the risk of recurrence. Moreover, the TEXT trial, adjuvant endocrine therapy with exemestane (E) plus LhRha, as compared with tamoxifen plus LhRha, significantly improved disease-free survival (DFS), breast cancer-free interval (BCFI) and distant disease-free survival (dDFS), thus representing a new treatment option for high-risk patients. The investigators of the SOFT and TEXT trials performed a combined secondary analysis to estimate the magnitude of absolute improvements in freedom from any recurrence (BCFI=breast cancer-free interval) according to quantitative composite measure of recurrence risk (hereafter referred to as "composite risk") defined by seven clinicopathologic characteristics.

Based on the results of MonarchE study, with the adjunct of Abemaciclib to the standard HT, the European Medicine Agency (EMA) recently approved Abemaciclib for the adjuvant treatment of high-risk EBC in combination with AI or T in the adjuvant setting. Moreover the results of OlympiA study highlights the role of Olaparib in the high-risk HR positive, Her2 negative, BRCA mutated, EBC patients. Based on the results of Olympia trial, Olaparib was approved for HR positive, HER2-negative patients who must have ≥4 pathologically confirmed positive lymph nodes or must have a CPS&EG score of ≥3 based on pre-treatment clinical and post-treatment pathologic stage (CPS), estrogen receptor (ER) status and histologic grade 8,9. Moreover Ribociclib recently has demonstrated activity in the phase III trial but a longer follow up will be needed to confirm the early results.

In this retrospective/prospective observational trial, we would like to assess the pattern of size in the high-risk HR positive, Her2 negative early breast cancer patients including BRCA mutated patients. Patients already taking intervention as part of their regular medical care for EBC must signed an informed consent in order to be recruited. After the patient has signed the informed consent for the participation in the study, data on the demographic and clinic-pathological characteristics obtained from the patients' computerized medical records will be collected and entered into an anonymized database. Questionnaires will also be administered to prospectively enrolled patients in order to evaluate quality of life and patient reported outcomes.

The recruitment phase will last about 2 years, each patient will be followed up for 5 years.

Inclusion criteria

• Patients will be enrolled in the study if they meet all of the following inclusion criteria:
• Age ≥ 18 years
• Endocrine sensitivity defined as estrogen and or progesterone receptors expression as per local pathological standards
• Her 2 negativity determined as ASCO/CAP guidelines
• Patients receiving abemaciclib, olaparib and endocrine therapy, as per Italian drugs agency rules (AIFA)
• Written informed consent, signed and dated by the patients
• High-risk HR positive, Her2 negative early breast cancer patients with one of the following characteristics:

• Anatomical stage IIA N0 with:

• Grade 2 and evidence of high risk:
• Ki-67 ≥ 20%
• Oncotype DX Breast Recurrence Score ≥ 26 or High risk via genomic risk profiling
• Grade 3
• Anatomical stage IIB.
• Pathological tumour involvement in ≥4 ipsilateral axillary lymph nodes.
• Pathological tumour involvement in 1 to 3 ipsilateral axillary lymph node(s) (for patients who received neoadjuvant therapy also cytological tumour involvement at time of initial diagnosis is allowed) and meet at least 1 of the following criteria:

• Grade 3 as defined by a combined score of at least 8 points per the modified Bloom-Richardson grading system (Elston and Ellis 1991),
• Pathological primary invasive tumour size ≥5 cm (for patients who received neoadjuvant therapy primary tumour size ≥5 cm on breast imaging is allowed). Note: if tumour size is needed to meet eligibility criteria, patients with multifocal/multicentric tumours may be eligible based on the addition of diameters of the individual lesions.

BRCA mutated populations

Patients must be node positive and fulfil one of the following criteria:

• HR positive, HER2-negative patients must have had ≥4 pathologically confirmed positive lymph nodes
• patients who received prior neoadjuvant chemotherapy: must have had a CPS&EG score of ≥3 based on pre-treatment clinical and post-treatment pathologic stage (CPS), estrogen receptor (ER) status and histologic grade

Exclusion criteria

• Patients unable to understand the reason for their participation in the study, lack of informed written consent,
• patients who do not meet the high risk criteria as specified in the inclusion criteria,
• patients suffering from other neoplasms for which they receive active treatment, or being diagnosed with other neoplasms (except for: Carcinoma in situ (CIS) of the cervix, CIS of the colon, basal cell and squamous cell carcinomas of the skin) in the five years before adjuvant treatment.