Predicting clinicAL outcoMes During First-line CDK4/6 Inhibitors Plus Endocrine Therapy in Patients With Advanced Hormone REceptor-poSitive HER2-negative Breast Cancer: the Retrospective-prospective Multicenter Italian PALMARES-2 Study

The PALMARES-2 study aims to collect data from different sources, i.e. real-world clinical data, medical images and biological data and samples, from patients treated with CDK4/6i as first-line therapy for patients with HR+/HER2- advanced breast cancer. Due to the complexity of the data collected and the different objectives of the study, this protocol includes several sub-studies, which include different methodologies for data collection, extraction and analysis:

• The first sub-study (RWD sub-study) will aim to collect real-world clinical data of patients who received ET+CDK4/6i in the first-line setting; the primary objective of this sub-study is to assess whether there is a difference in OS between the three CDK4/6i in the real-world population, while secondary objectives include comparisons in specific sub-groups;

• The second sub-study (Safety sub-study) includes the collection of comorbidities, concomitant medications and toxicities of patients enrolled in the study; the primary objective of this sub-study is to evaluate the difference in severe toxicity between the three CDK4/6i in the real-world population

• The third sub-study (medical imaging sub-study) consists of the collection of computed tomography (CT) and fluorodeoxyglucose positron emission tomography (FdG-PET) images at baseline and digitised haematoxylin-eosin (HE) slides to build a multi-omics predictive model;

• The fourth sub-study (translational sub-study) aims to collect tumour samples from a proportion of patients enrolled in the study to perform genomics and transcriptomics analyses; information from this data source will be integrated into the model built with the previous data to further improve the performance of the previous model

• The fifth sub-study (subsequent lines sub-study) focuses on the lines of treatment administered to patients enrolled in the study at the time of progression after first-line treatment with ET+CDK4/6i, with the aim of building predictive models of response to subsequent lines of treatment, capable of supporting oncologists' and patients' decisions in this context.