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Background: Breast Cancer (BC) prevention strategies range from lifestyle changes such as increasing physical activity and reducing body weight to preventive drugs like tamoxifen, known to reduce BC incidence in high-risk women. Sex Hormone Binding Globulin (SHBG) is related to BC risk due to its ability to bind circulating estradiol at high affinity and to regulate estradiol action. A study protocol is presented based on the assessment of the effect of different interventions such as tamoxifen at 10 mg every other day (LDT), intermittent caloric restriction (ICR) two days per week, lifestyle intervention (LI, step counter use) and their combination on the modulation of SHBG and several other biomarkers associated to BC. Methods: A randomized phase II biomarker study will be conducted in 4 Italian centers. Unaffected women aged between 18 and 70 years, carriers of a germline pathogenetic variant (BRCA1, BRCA2, PALB2, or other moderate penetrance genes), or with a >5% BC risk at 10 years (according to the Tyrer-Cuzick or the Breast Cancer Surveillance Consortium Risk models) or with a previous diagnosis of intraepithelial neoplasia will be eligible. A total of 200 participants will be randomized to one of the four arms: LDT; LDT + ICR; LI; LI + ICR. Interventions will span six months, with baseline and follow-up clinic visits and interim phone calls. Discussion: The aim of the study is to verify whether LDT increases circulating SHBG more than LI with or without ICR after 6 months. Secondary objectives include assessing HOMA-index, inflammatory markers, adiponectin/leptin ratio, quality of life (QoL), safety, toxicity, mammographic density, and changes in microbiome composition across groups. The study's innovation lies in its inclusion of diverse BC risk categories and combination of pharmaceutical and behavioral interventions, potentially enhancing intervention efficacy while balancing tamoxifen's side effects on QoL, especially menopausal symptoms. Trial registration: EuCT number:2023-503994-39-00; Clinical trials.gov NCT06033092. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to investigate the use of contrast-free magnetic resonance imaging (MRI) as an innovative screening method for detecting breast cancer in high-risk asymptomatic women. Specifically, the researchers evaluated the diagnostic performance of diffusion-weighted imaging (DWI) in this population. Methods: MR images from asymptomatic women, carriers of a germline mutation in either the BRCA1 or BRCA2 gene, collected in a single center from January 2019 to December 2021 were retrospectively evaluated. A radiologist with experience in breast imaging (R1) and a radiology resident (R2) independently evaluated DWI/ADC maps and, in case of doubts, T2-WI. The standard of reference was the pathological diagnosis through biopsy or surgery, or ≥1 year of clinical and radiological follow-up. Diagnostic performances were calculated for both readers with a 95% confidence interval (CI). The agreement was assessed using Cohen's kappa (κ) statistics. Results: Out of 313 women, 145 women were included (49.5 ± 12 years), totaling 344 breast MRIs with DWI/ADC maps. The per-exam cancer prevalence was 11/344 (3.2%). The sensitivity was 8/11 (73%; 95% CI: 46–99%) for R1 and 7/11 (64%; 95% CI: 35–92%) for R2. The specificity was 301/333 (90%; 95% CI: 87–94%) for both readers. The diagnostic accuracy was 90% for both readers. R1 recalled 40/344 exams (11.6%) and R2 recalled 39/344 exams (11.3%). Inter-reader reproducibility between readers was in moderate agreement (κ = 0.43). Conclusions: In female carriers of a BRCA1/2 mutation, breast DWI supplemented with T2-WI allowed breast cancer detection with high sensitivity and specificity by a radiologist with extensive experience in breast imaging, which is comparable to other screening tests. The findings suggest that DWI and T2-WI have the potential to serve as a stand-alone method for unenhanced breast MRI screening in a selected population, opening up new perspectives for prospective trials. [ABSTRACT FROM AUTHOR]

Hereditary Breast and Ovarian Cancer (HBOC) syndrome is a condition in which the risk of breast and ovarian cancer is higher than in the general population. The prevalent pathogenesis is attributable to inactivating variants of the BRCA1-2 highly penetrant genes, however, other cancer susceptibility genes may also be involved. By Whole Exome Sequencing (WES) we analyzed a series of 200 individuals selected for genetic testing in BRCA1-2 genes according to the updated National Comprehensive Cancer Network (NCCN) guidelines. Analysis by MLPA was performed to detect large BRCA1-2 deletions/duplications. Focusing on BRCA1-2 genes, data analysis identified 11 cases with pathogenic variants (4 in BRCA1 and 7 in BRCA1-2) and 12 with uncertain variants (7 in BRCA1 and 5 in BRCA2). Only one case was found with a large BRCA1 deletion. Whole exome analysis allowed to characterize pathogenic variants in 21 additional genes: 10 genes more traditionally associated to breast and ovarian cancer (ATM , BRIP1 , CDH1 , PALB2 , PTEN , RAD51C , and TP53) (5% diagnostic yield) and 11 in candidate cancer susceptibility genes (DPYD , ERBB3 , ERCC2 , MUTYH , NQO2 , NTHL1 , PARK2 , RAD54L , and RNASEL). In conclusion, this study allowed a personalized risk assessment and clinical surveillance in an increased number of HBOC families and to broaden the spectrum of causative variants also to candidate "non-canonical" genes. [ABSTRACT FROM AUTHOR]

Keywords: BRCA1; BRCA2; cancer susceptibility genes; HBOC; ES (Exome Sequencing) EN BRCA1 BRCA2 cancer susceptibility genes HBOC ES (Exome Sequencing) 1 3 3 08/19/21 20210817 NES 210817 In the original article, there was an error. A correction has been made to B I Result i b : B I Pathogenic Variants in Canonical HBOC Genes i b B I Paragraph 1 i b : Beyond I BRCA1-2 i genes, ES data analysis revealed 10 pathogenic variants in 7 HBOC-related genes (canonical genes): I ATM, BRIP1, CDH1, PALB2, PTEN, RAD51C i , and I TP53 i . However, multigene panel allows a limited gene analysis while Exome Sequencing (ES) allows the simultaneous assessment of virtually an unlimited number of genes. [Extracted from the article]

Hereditary Breast and Ovarian Cancer (HBOC) syndrome is a condition in which the risk of breast and ovarian cancer is higher than in the general population. The prevalent pathogenesis is attributable to inactivating variants of the BRCA1-2 highly penetrant genes, however, other cancer susceptibility genes may also be involved. By Exome Sequencing (WES) we analyzed a series of 200 individuals selected for genetic testing in BRCA1-2 genes according to the updated National Comprehensive Cancer Network (NCCN) guidelines. Analysis by MLPA was performed to detect large BRCA1-2 deletions/duplications. Focusing on BRCA1-2 genes, data analysis identified 11 cases with pathogenic variants (4 in BRCA1 and 7 in BRCA1-2 ) and 12 with uncertain variants (7 in BRCA1 and 5 in BRCA2 ). Only one case was found with a large BRCA1 deletion. Whole exome analysis allowed to characterize pathogenic variants in 21 additional genes: 10 genes more traditionally associated to breast and ovarian cancer ( ATM , BRIP1 , CDH1 , PALB2 , PTEN , RAD51C , and TP53 ) (5% diagnostic yield) and 11 in candidate cancer susceptibility genes ( DPYD , ERBB3 , ERCC2 , MUTYH , NQO2 , NTHL1 , PARK2 , RAD54L , and RNASEL ). In conclusion, this study allowed a personalized risk assessment and clinical surveillance in an increased number of HBOC families and to broaden the spectrum of causative variants also to candidate non-canonical genes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright 2021 Doddato, Valentino, Giliberti, Papa, Tita, Bruno, Resciniti, Fallerini, Benetti, Palmieri, Mencarelli, Fabbiani, Bruttini, Orrico, Baldassarri, Fava, Lopergolo, Lo Rizzo, Lamacchia, Mannucci, Pinto, Curr, Mancini, Oncologic Multidisciplinary Team, Azienda Ospedaliera Universitaria Senese, Oncologic Multidisciplinary Team, Azienda Usl Toscana Sud Est, Mari, Renieri and Ariani.)