Assessing Clinical Features and Outcome of Breast Cancer in PALB2 Mutation Carriers: the Palbreast Study

This is a multicenter hospital-based retrospective cohort control study conducted across several Institutions with known expertise in managing hereditary breast cancer.

It is planned to enrol at least 300 PALB2-related BC diagnosed at the different Units and 300 BC as control group tested for multigene panel and resulted negative for mutations. It is expected to complete the accrual in one year; furthermore, a minimum follow-up of one more year is required for the final analysis of primary and secondary endpoints.

Since some delay in the Ethical committee approvals at different Centers can rising, the study could be extended for another year Subjects will be inserted in the registry after having identified a pathogenic or likely pathogenic germline PALB2 mutation. All BC stages at the diagnosis will be included in the analysis. The BC mutation negative control group will be consecutively selected from each center, as ratio 1:1 in respect with the number of gPALB2 mutated patients enrolled, matching those for age, stage and period of diagnosis. The following data for each patient will be collected

• Demographic and clinical characteristics: age at diagnosis, BMI.
• Tumor characteristics: breast imaging (US, mammogram, breast MRI), cito-histological examination from FNA/core biopsy, multifocality or bilaterality, clinical stage at diagnosis.
• Data about surgery and pathological features: date of surgery (the date of the primary tumor removal), type of surgery, tumor size and number of positive lymph nodes (pTN), biological features on surgical sample (histological type, ER, PR, HER2, Ki-67, grade, TILs, AR).
• Systemic treatment modalities (neoadjuvant, adjuvant, advanced therapies) with a detailed description of the treatment regimens: drugs administered, dosage of drugs and duration with start and end dates. In patients that underwent neoadjuvant treatment, data about pathological response (ypTN) and local regional treatment after NAC were collected. pCR is defined as documented CR to NAC and/or ypT0/is N0.
• Type of radiotherapy performed and duration.
• Type of first relapse (local/distant), location of lesions, date of detection and therapie
• Data concerning family history and other primary tumours
• Outcomes in terms of OS and DFS.
• Patient's participation in previous studies. Patients' characteristics and the distribution of each parameter across will be reported as absolute and percentage frequencies. For each group of patients registered at different Centers, the number of all tests performed will be reported, as denominator, in order to establish the frequencies of mutations in all the European countries.

Outcomes of interest will be DFS, DDFS and OS in the cohort and control groups. DFS, DDFS and OS curves will be conducted using Kaplan-Meier method and time time-to-event distributions will be compared with log-rank test (univariate regression). Log-rank test will be used to compare the difference between values over and under the selected cut-off on survival curves. Multivariate analysis will be conducted using Cox proportional hazard models to identify significant predictors of mortality. In case of documented PD, each participant will be contacted by telephone every 12 weeks (+-14 days) to assess for survival status until withdrawal of consent to participate in the study, becoming lost to follow up, death or end of the study, whichever occurs first. Statistical analysis will be conducted using SPSS Statistics for Windows Version 23.0 (IBM Corporation, Armonk, NY, USA).

In order to minimise bias on the subjects' selection, the analysts will not be informed about the origin of the patients, being the number attributed to each centre blinded for the cohort and control group.

For details on what is included in the efficacy and safety endpoints, see Section 3 Objectives and Endpoints.