Low dose TamOxifen and LifestylE changes for bReast cANcer prevention (TOLERANT study): Study protocol of a randomized phase II biomarker trial in women at increased risk for breast cancer.

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.

An Unenhanced Breast MRI Protocol Based on Diffusion-Weighted Imaging: A Retrospective Single-Center Study on High-Risk Population for Breast Cancer.

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.

Germline pathogenic variants in metaplastic breast cancer patients and the emerging role of the BRCA1 gene.

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.

Metaplastic breast cancer: an all-round multidisciplinary consensus.

Metaplastic breast cancer (MpBC) is a rare and aggressive histologic subtype of breast cancer (BC) characterized by the presence of at least two cellular types, commonly epithelial and mesenchymal components. Despite growing evidence that MpBC is a unique entity, it has long been treated as a variant of nonspecial type (NST) BC. MpBC typically shows the phenotype of triple-negative breast cancer (TNBC), but compared to NST-TNBC, it is a relatively chemorefractory tumor associated with worse outcomes. Therefore, there is an urgent need to develop management guidelines specifically for MpBC to improve the prognosis of patients with early MpBC. This expert consensus aims to guide diagnosis and standardize clinical management of early MpBC among treating physicians. We provide guidance on the challenging radiological and pathological diagnosis of MpBC. Evidence on the involvement of genetic predisposition in the development of MpBC is also explored. We emphasize the importance of a multidisciplinary approach for the treatment of patients with early MpBC. The optimal surgery and radiotherapy approach is presented, as well as the opportunity offered by novel therapeutic approaches to increase treatment response in this chemoresistant subtype. Appropriate management of patients with MpBC is critical to reduce the high risk of local and distant recurrence that characterizes this disease.

Clinical Features of LMNA-Related Cardiomyopathy in 18 Patients and Characterization of Two Novel Variants.

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.

Corrigendum: Exome Sequencing in BRCA1-2 Candidate Familias: The Contribution of Other Cancer Susceptibility Genes.

[This corrects the article DOI: 10.3389/fonc.2021.649435.].

Exome sequencing in BRCA1-2 candidate familias: the contribution of other cancer susceptibility genes

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.