Predictive Value of Combined Criteria to Tailor Breast Cancer Screening and New Opportunities From Circulating Markers. The Andromeda Study.

Breast cancer (BC) represents the most frequent neoplasm in women worldwide. In Italy about 1 out of 3 malignant cancers in women (29%) is a BC (leaving out cutaneous tumours) as reported by the Italian cancer registries between 2006 and 2009. Results from randomized trials, summarized in an updated review and meta-analysis for the U.S. Preventive Task Force by Nelson et al., showed that participating to a mammography screening program reduces BC mortality of 14-32%, depending on the age range. In Italy, mammography screening for early diagnosis has been implemented on a regional basis in several Italian areas. In compliance to national and international guidelines, most programmes invite women aged 50 to 69 years to undergo mammography every two years.

Although mammography has become standard of care in BC screening, its limitations are well recognized (overdiagnosis, the use of ionizing radiation, poor accuracy in women with dense breast tissue, a relatively high rate of false positives, and personal discomfort). In addition, the current screening protocols are based on woman's age only, ignoring other risk factors and defining a single screening periodicity within the prespecified age range.

Current challenges in the management of BC include searching for sensitive and specific minimally invasive biomarkers associated with early neoplastic changes. A number of circulating tumour markers (such as carcino-embryonic antigen, CEA or carbohydrate antigen 15-3, CA 15-3) are widely used in BC handling, but their sensitivity is very low. MicroRNAs (miRNAs) are small, noncoding RNAs (about 18-25 nucleotide long), that regulate gene expression inside cells by degrading mRNA or inhibiting protein synthesis. Since they may have hundreds of targets, they are able to control several biological processes inside cells. There is growing evidence that miRNAs may also be released outside cells, and increased levels of miRNAs released by tumour and its microenvironment as well as decrease in physiologic circulating miRNA levels have already been detected in serum/plasma of cancer patients. The potential use of such molecules for diagnostic/prognostic purposes in regard to breast cancer has been extensively evaluated and their stability in body fluids has opened new opportunities for anticipating BC diagnosis, with minimally invasive intervention especially for women at higher risk.

Hypothesis: Risk-based screening programmes according to different BC risk criteria (i.e. breast density, model based estimates of absolute risk, life-styles) may maximize the impact of screening in groups of women characterized by different risks. Gathering data for risk stratification in population based screening programmes requires large amount of resources. Non independent criteria which identify the same women at higher risk are redundant and should be considered as mutually exclusive. Validated highly accurate blood molecular biomarkers associated with BC risk may represent a complementary tool to mammography in the primary screening setting.

The first objective of the study is to evaluate and compare, in a large cohort of women, the predictive value of available criteria to define BC risk in order to identify appropriate risk-based stratifications for personalised screening. The criteria considered are: