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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. 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. 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. EuCT number:2023-503994-39-00; Clinical trials.gov NCT06033092.

Hereditary breast and ovarian cancer (HBOC) syndrome accounts for 5–10% of all breast and ovarian cancers, with BRCA1 and BRCA2 pathogenic variants being the most common genetic alterations. However, additional genes such as BARD1, whose protein product interacts with BRCA1 via its N-terminal RING domain, have been implicated as low-penetrance contributors to cancer risk. This study aimed to investigate the frequency and distribution of the BARD1 variant c.1518_1519delinsCA (p.Val507Met) in a cohort of 920 patients undergoing genetic testing for hereditary cancer predisposition. Next Generation Sequencing (NGS) was performed using a 28-gene panel, and allelic frequencies of BARD1 were analyzed. Among 920 patients, 159 (17.28%) were pure heterozygous for the c.1518_1519delinsCA variant. Notably, c.1519G>A was never observed without c.1518T>C, suggesting a strong linkage between the two variants. The allele frequencies observed (34.51% for A at c.1519 and 77.88% for C at c.1518) challenge current reference genome expectations. Data from the ALFA database confirmed that these frequencies are consistent with population-level variation, not sample bias. Our findings raise the hypothesis that the reference allele at position c.1518 may not reflect the true wild-type sequence. While both c.1518T>C and c.1519G>A are individually classified as benign, their combined occurrence as a dinucleotide substitution (c.1518_1519delinsCA) warrants further investigation. These results underscore the importance of accurate variant annotation and population-specific frequency data for clinical interpretation of NGS findings. Although BARD1 remains a low-frequency contributor to HBOC compared to BRCA1/2, its inclusion in multigene panels is supported by the potential relevance of such complex variants.

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.

Metaplastic breast cancer (MpBC) is a rare, aggressive breast cancer (BC) histotype. Scarce information is available about MpBC genetic predisposition. Previous studies, mainly consisting of case reports, retrospective reviews and others on target therapies, pointed to a possible involvement of the BRCA1 gene in increasing MpBC risk, without ever confirming it. In this study, we retrospectively reviewed all BC patients counseled at our Institute for genetic testing of at least BRCA1 or BRCA2 (BRCA) genes and we found that 23 (23/5226 = 0.4%) were affected by MpBC. About 65% (15/23) of MpBC patients harbored a germline pathogenic variant (PV): 13 in BRCA1 (86.7%), including two patients who received genetic testing for known familial PV, one in TP53 (6.7%), and one in MLH1 (6.7%). We observed a statistically different frequency of MpBC in patients who carried a PV in the BRCA genes (13/1114 = 1.2%) vs. all other BC patients (10/4112 = 0.2%) (p = 0.0002). BRCA carriers proved to have an increased risk of developing MpBC compared to all other BC patients who were tested for BRCA genes (OR = 4.47; 95% CI: 1.95–10.23). Notably, MpBCs were diagnosed in 2.1% (13/610) of BRCA1 carriers. No MpBCs were observed in BRCA2 carriers (0/498 = 0%), revealing a statistically significant difference between the prevalence of MpBCs in BRCA1 and BRCA2 carriers (p = 0.0015). Our results confirmed that BRCA1 is involved in MpBC predisposition. Further studies on unselected patients are needed to elucidate the authentic role of BRCA1 and to explore the possible implication of other genes in MpBC predisposition.

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. 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. 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.

Women carrying pathogenic/likely pathogenic (P/LP) variants in moderate- or high-penetrance genes have an increased risk of developing breast cancer. However, most P/LP variants associated with breast cancer risk show incomplete penetrance. Age, gender, family history, polygenic risk, lifestyle, reproductive, hormonal, and environmental factors can affect the expressivity and penetrance of the disease. However, there are gaps in translating how individual genomic variation affects phenotypic presentation. The expansion of criteria for genetic testing and the increasing utilization of comprehensive genetic panels may enhance the identification of individuals carrying P/LP variants linked to hereditary breast cancer. Individualized risk assessment could facilitate the implementation of personalized risk-reduction strategies for these individuals. Preventive interventions encompass lifestyle modifications, chemoprevention, enhanced surveillance through breast imaging, and risk-reducing surgeries. This review addresses the current literature’s inconsistencies and limitations, particularly regarding risk factors and the intensity of preventive strategies for women with P/LP variants in moderate- and high-penetrance genes. In addition, it synthesizes the latest evidence on risk assessment and primary and secondary prevention in women at high risk of breast cancer.

Background/Objectives: Compared to single gene testing (SGT), multigene panel testing (MGPT) improves pathogenic variants (PVs) detection. However, MGPT yields complex results, including secondary findings, heterozygous PVs in recessive genes, low-penetrance PVs, and variants of uncertain significance. We reported our mono-institutional experience of germline testing in breast cancer (BC), comparing SGT and MGPT. Methods: We retrospectively analyzed clinical and molecular data from 1084 BC patients: 308 underwent SGT (BRCA1/BRCA2) and 776 MGPT (for 28 cancer-related genes). We compared these approaches regarding the genetic classification of the findings (positive, uncertain, uninformative) and their impact on clinical management (primary findings (PFs); complex and inconclusive results). Additionally, we described clinical features supporting one approach over the other and focused on copy number variation (CNV) frequency in non-BRCA genes. Results: We found ≥1 PV in 165 patients (165/1084 = 15.2%), including 91 in BRCA1/BRCA2 (91/1084 = 8.4%), with 42 identified by SGT (42/308 = 13.6%) and 49 by MGPT (49/776 = 6.3%). MGPT detected PVs in non-BRCA genes in 74 patients (74/776 = 9.5%), including 40 PFs. Overall, MGPT identified 89 PFs (89/776 = 11.5%). We observed complex results in 21 patients (21/308 = 6.8%) with SGT and in 300 (300/776 = 38.7%) with MGPT. Compared to MGPT, SGT detected a similar percentage of PFs (13.6% vs. 11.5%) but a significantly reduced percentage of complex results (6.8% vs. 38.7%) (p < 0.001). Triple-negative BCs prevailed in BRCA1 carriers, while ER-positive BCs were more prevalent in ATM/CHEK2 carriers. Concerning non-BRCA genes, MGPT detected CNVs in PALB2, representing 20% of PVs in this gene. Conclusions: Although MGPT increases hereditary BC detection, its complexity requires clear guidelines for optimal clinical management and strategies for merging the benefits of SGT and MGPT.

Dilated cardiomyopathy (DCM) refers to a spectrum of heterogeneous myocardial disorders characterized by ventricular dilation and depressed myocardial performance in the absence of hypertension, valvular, congenital, or ischemic heart disease. Mutations in LMNA gene, encoding for lamin A/C, account for 10% of familial DCM. LMNA-related cardiomyopathies are characterized by heterogeneous clinical manifestations that vary from a predominantly structural heart disease, mainly mild-to-moderate left ventricular (LV) dilatation associated or not with conduction system abnormalities, to highly pro-arrhythmic profiles where sudden cardiac death (SCD) occurs as the first manifestation of disease in an apparently normal heart. In the present study, we select, among 77 DCM families referred to our center for genetic counselling and molecular screening, 15 patient heterozygotes for LMNA variants. Segregation analysis in the relatives evidences other eight heterozygous patients. A genotype–phenotype correlation has been performed for symptomatic subjects. Lastly, we perform in vitro functional characterization of two novel LMNA variants using dermal fibroblasts obtained from three heterozygous patients, evidencing significant differences in terms of lamin expression and nuclear morphology. Due to the high risk of SCD that characterizes patients with lamin A/C cardiomyopathy, genetic testing for LMNA gene variants is highly recommended when there is suspicion of laminopathy.

Background To evaluate the efficacy and safety of upadacitinib monotherapy versus methotrexate (MTX) monotherapy over 5 years among MTX-naïve patients with moderately to severely active rheumatoid arthritis (RA) in the long-term extension (LTE) of the phase 3 SELECT-EARLY trial. Methods Patients were randomized to receive upadacitinib 15 mg or 30 mg or MTX. Patients who did not achieve CDAI remission and had < 20% improvement in tender and swollen joint counts at week 26 received rescue therapy (addition of MTX in the upadacitinib group and addition of upadacitinib in the MTX group). Efficacy assessments were evaluated over 5 years and are reported as observed (AO) for patients who received continuous monotherapy with upadacitinib 15/30 mg or MTX and by randomized group applying non-responder imputation (NRI). Treatment-emergent adverse events (TEAEs) per 100 patient-years were summarized over 5 years. Results Of 945 patients randomized and treated, 775 (82%) completed week 48 and entered the LTE on study drug. Higher proportions of patients consistently achieved disease activity targets over 5 years with upadacitinib than MTX. In AO analyses, 53%/59% of patients attained CDAI remission with upadacitinib 15/30 mg versus 43% with MTX at week 260. NRI analyses showed better CDAI, DAS28(CRP), and ACR responses with upadacitinib relative to MTX at week 260 (all comparisons, nominal P  < .001). Upadacitinib treatment also resulted in numerically greater inhibition of structural joint progression through week 260 compared to MTX. Most TEAEs, serious AEs, and AEs leading to discontinuation were numerically higher in patients receiving upadacitinib 30 mg. Rates of serious infections, herpes zoster, creatine phosphokinase elevation, nonmelanoma skin cancer, and neutropenia were numerically higher with upadacitinib than MTX. The observed safety profile of upadacitinib over 5 years was consistent with earlier trial results and integrated phase 3 safety analyses. Conclusions Upadacitinib showed better clinical responses versus MTX in patients with RA throughout the 5-year trial. Higher rates of several AEs were observed with upadacitinib, especially in the 30 mg group, compared to MTX. When used as monotherapy in MTX-naïve patients, the approved upadacitinib 15 mg dose showed better long-term efficacy versus MTX and an overall favorable benefit-risk profile. Trial registration NCT02706873.