The e-BRAVE study: A prospective web-based cohort and biobank of women carriers of BRCA mutations.

Background: Women carriers of mutations face a very high lifetime risk (penetrance) of developing breast and/or ovarian cancer. A sizeable proportion of carriers, however, does not develop cancer at all or develop it only late in life, thus suggesting a potential modulation of this risk. Epidemiological studies have suggested that other genetic (polymorphisms) and environmental factors (lifestyle) affect penetrance.

Real-World Outcomes of Molecular Tumor Board Treatment Recommendations.

Purpose: The Molecular Tumor Board (MTB) is an important tool for the selection of molecularly targeted agents (MTAs), but its clinical utility is unconfirmed in real-world practice.

Materials And Methods: We explored the clinical relevance of MTAs in patients discussed by the MTB of the National Cancer Institute of Milan. Patients were stratified into eligible (ie, at least one actionable molecular alteration identified) and treated with MTA (group A), eligible but not treated (group B), or not eligible (group C).

Impact of comprehensive genomic profiling and molecular tumour board on costs and access to tailored therapies: real-world observational study.

Objective: There is limited evidence on the economic implications of assessing patients' access to personalised treatments through Comprehensive Genomic Profiling (CGP) and Molecular Tumour Board (MTB), prompting the need to analyse their impact on the cost of the cancer diagnostic journey (from hospital admission to MTB evaluation) and accessibility to personalised therapies.

Design: Retrospective observational cohort.

Setting: Patients discussed from April 2020 to September 2021 by the institutional MTB operating at Fondazione IRCCS Istituto Nazionale Tumori of Milan, an Italian centre of excellence in oncology pertaining to the national health system.

Overlap of high-risk individuals across family history, genetic & non-genetic breast cancer risk models: Analysis of 180,398 women from European & Asian ancestries.

Background: Breast cancer is multifactorial. Focusing on limited risk factors may miss high-risk individuals.

Methods: We assessed the performance and overlap of various risk factors in identifying high-risk individuals for invasive breast cancer (BrCa) and ductal carcinoma in situ (DCIS) in 161,849 European-ancestry and 18,549 Asian-ancestry women.

Is tumour sequencing effective for the identification of germline pathogenic variant carriers?

Introduction: Tumour /2 sequencing has progressively increased along with the expanding indications for poly(ADP-ribose) polymerase inhibitors. In our study, we investigated the feasibility and outcomes of a workflow for the identification of germline carriers based on tumour sequencing results.

Methods: Between April 2020 and December 2022, tumour testing results from 2020 patients were reviewed.

Atypical cancer risk profile in carriers of Italian founder BRCA1 variant p.His1673del: Implications for classification and clinical management.

Background: BRCA1:c.5017_5019del (p.His1673del) is a founder variant relatively frequent in Northern Italy.

Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk.

Background: Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS).

Methods: We analyzed >22 million variants for 398,238 women.

Breast cancers arising in subjects with germline BRCA1 or BRCA2 mutations: Different biological and clinical entities with potentially diverse therapeutic opportunities.

Breast cancers (BCs) arising in carriers of germline BRCA1 and BRCA2 pathogenic variants (PVs) have long been considered as indistinguishable biological and clinical entities. However, the loss of function of BRCA1 or BRCA2 proteins has different consequences in terms of tumor cell reliance on estrogen receptor signaling and tumor microenvironment composition. Here, we review accumulating preclinical and clinical data indicating that BRCA1 or BRCA2 inactivation may differentially affect BC sensitivity to standard systemic therapies.

Molecular Tumor Board as a Clinical Tool for Converting Molecular Data Into Real-World Patient Care.

Purpose: The investigation of multiple molecular targets with next-generation sequencing (NGS) has entered clinical practice in oncology, yielding to a paradigm shift from the histology-centric approach to the mutational model for personalized treatment. Accordingly, most of the drugs recently approved in oncology are coupled to specific biomarkers. One potential tool for implementing the mutational model of precision oncology in daily practice is represented by the Molecular Tumor Board (MTB), a multidisciplinary team whereby molecular pathologists, biologists, bioinformaticians, geneticists, medical oncologists, and pharmacists cooperate to generate, interpret, and match molecular data with personalized treatments.

Male breast cancer risk associated with pathogenic variants in genes other than BRCA1/2: an Italian case-control study.

Background: Germline pathogenic variants (PVs) in BRCA1/2 genes are associated with breast cancer (BC) risk in both women and men. Multigene panel testing is being increasingly used for BC risk assessment, allowing the identification of PVs in genes other than BRCA1/2. While data on actionable PVs in other cancer susceptibility genes are now available in female BC, reliable data are still lacking in male BC (MBC).

Prevalence of BRCA homopolymeric indels in an ION Torrent-based tumour-to-germline testing workflow in high-grade ovarian carcinoma.

Tumour DNA sequencing is essential for precision medicine since it guides therapeutic decisions but also fosters the identification of patients who may benefit from germline testing. Notwithstanding, the tumour-to-germline testing workflow presents a few caveats. The low sensitivity for indels at loci with sequences of identical bases (homopolymers) of ion semiconductor-based sequencing techniques represents a well-known limitation, but the prevalence of indels overlooked by these techniques in high-risk populations has not been investigated.

Treating secondary malignant neoplasms: A burden of childhood cancer survivors.

Each year approximately 35,000 children and adolescents are diagnosed with cancer in Europe. Five-year survival rates have improved and now reach 80% in most European countries, thanks to a combination of chemotherapy, radiotherapy, and surgery. To date, there are more than 44,000 Italians still living several years after being diagnosed with cancer in developmental age.

FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women.

Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCM confer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCM missense variants (MVs) and breast cancer risk has been postulated. In this study, we further used the BRIDGES study to test 689 FANCM MVs for association with breast cancer risk, overall and in ER-negative and TNBC subtypes, in 39,885 cases (7566 selected for family history) and 35,271 controls of European ancestry.

Efficacy and Safety of First-line Carboplatin-paclitaxel and Carboplatin-gemcitabine in Patients With Advanced Triple-negative Breast Cancer: A Monocentric, Retrospective Comparison.

Background: Platinum-based chemotherapy is widely used in patients with advanced triple-negative breast cancer (TNBC). However, the most effective platinum-based combination in the first-line treatment setting remains unclear.

Materials And Methods: We evaluated the efficacy of first-line carboplatin-paclitaxel (CP) or carboplatin-gemcitabine (CG) combinations in advanced TNBC patients treated between April 2007 and April 2021.

Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers.

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation.

Management of BRCA Tumour Testing in an Integrated Molecular Tumour Board Multidisciplinary Model.

Tumour testing of the genes is routinely performed in patients with different cancer histological subtypes. To accurately identify patients with tumour-detected germline pathogenic variants (PVs) is a relevant issue currently under investigation. This study aims at evaluating the performance of the tumour-to-germline diagnostic flowchart model defined at our Institutional Molecular Tumour Board (MTB).

The Impact of Mediterranean Dietary Intervention on Metabolic and Hormonal Parameters According to Variant Type.

The female carriers of pathogenic variants (mutations) face a high lifetime risk of developing breast and/or ovarian cancer. However, the risk may differ depending on various genetic and non-genetic elements, including metabolic and hormonal factors. We previously showed that a 6-month Mediterranean dietary intervention trial reduced body weight and the levels of insulin-like growth factor I and other metabolic factors in BRCA mutation carriers.

Rare germline copy number variants (CNVs) and breast cancer risk.

Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.

Polygenic risk modeling for prediction of epithelial ovarian cancer risk.

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction.

Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants.

Purpose: Germline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants.

Methods: We collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2.