Adapting the BOADICEA breast and ovarian cancer risk models for the ethnically diverse UK population.

Background: BOADICEA is a widely used algorithm for predicting breast and ovarian cancer risks, using a combination of genetic and lifestyle, hormonal and reproductive risk factors. However, it has largely been developed using data from White/European individuals, limiting its applicability to other ethnicities. Here, we updated BOADICEA to provide ethnicity-specific risk estimates.

Analysis of , and related Fanconi anemia identifies scope to expand disease phenotypic features and predict breast cancer risk in heterozygotes.

Recessive Fanconi anemia (FA) phenotype is used in classification of , and variants with respect to dominant hereditary breast-ovarian cancer syndrome. We assessed its utility by examining the spectrum of phenotypes observed in individuals biallelic for , or pathogenic variants, and exploring the relationship between cancer presentation and allele severity score based on variant molecular features. A data collection instrument comprising 158 Human Phenotype Ontology (HPO) terms was used to document clinical features for individuals with FA from published and/or prospectively collected (total n=172, 43 previously unpublished) phenotypic data.

Clinical decision tree for optimizing endoscopic assessment of signet ring cell carcinoma in hereditary diffuse gastric cancer surveillance.

Prophylactic total gastrectomy is the definitive treatment for hereditary diffuse gastric cancer syndrome (HDGC). Endoscopic surveillance informs the requirement for and optimal timing of surgery. However, endoscopic recognition of early signet ring cell carcinoma (SRCC) remains challenging.

Cancer prognosis and treatment results in patients with PTEN Hamartoma Tumour Syndrome (PHTS)-a European cohort study.

Background: PTEN hamartoma tumour syndrome (PHTS) patients have a high hereditary risk of cancer, especially breast (BC), endometrial (EC), and thyroid cancer (TC). However, the prognosis of PHTS-related cancers is unknown.

Methods: This European cohort study included adult PHTS patients with data from medical files, registries, and/or questionnaires.

Associations between c.7271T>G and cancer risk: analysis of Breast Cancer Association Consortium and UK Biobank data.

Previous studies have suggested the missense variant NM_000051.4(ATM):c.7271T>G is associated with a high risk of breast cancer (BC), but the magnitude of the association, and the associations with other cancer types, are unclear.

The risk of a second primary cancer in PTEN Hamartoma Tumor Syndrome (PHTS).

Purpose: Patients with PTEN Hamartoma Tumor Syndrome (PHTS) have high hereditary cancer risks for breast, endometrial, and thyroid cancer. Patients develop multiple primary cancers, but these risks remain uncertain. We aimed to provide the second primary cancer risk.

Distribution of age at natural menopause, age at menarche, menstrual cycle length, height and BMI in BRCA1 and BRCA2 pathogenic variant carriers and non-carriers: results from EMBRACE.

Background: Carriers of germline pathogenic variants (PVs) in the BRCA1 and BRCA2 genes are at higher risk of developing breast and ovarian cancer than the general population. It is unclear if these PVs influence other breast or ovarian cancer risk factors, including age at menopause (ANM), age at menarche (AAM), menstrual cycle length, BMI or height. There is a biological rationale for associations between BRCA1 and BRCA2 PVs and reproductive traits, for example involving DNA damage and repair mechanisms.

Neoadjuvant PARP inhibitor scheduling in BRCA1 and BRCA2 related breast cancer: PARTNER, a randomized phase II/III trial.

Poly (ADP-ribose) polymerase inhibitors (PARPi) exploit DNA repair deficiency in germline BRCA1 and BRCA2 pathogenic variant (gBRCAm) cancers. Haematological toxicity limits chemotherapy-PARPi treatment combinations. In preclinical models we identified a schedule combining olaparib and carboplatin that avoids enhanced toxicity but maintains anti-tumour activity.

UK clinical practice guidelines for the management of patients with constitutional pathogenic variants.

Constitutional or germline pathogenic variants (GPVs) in ) are associated with a variety of tumours resulting in the recognition of POT1-tumour predisposition syndrome (POT1-TPDS). These tumours may include cutaneous melanoma, angiosarcoma, haematological malignancy and brain tumours. Due to the rarity of GPVs and limited available data, the overall lifetime cancer risks for individuals with POT1-TPDS are unclear.

Long-term health outcomes of bilateral salpingo-oophorectomy in BRCA1 and BRCA2 pathogenic variant carriers with personal history of breast cancer: a retrospective cohort study using linked electronic health records.

Background: Carriers of BRCA1 and BRCA2 pathogenic variants are at elevated risk of developing breast and ovarian cancers. To mitigate ovarian cancer risk, bilateral salpingo-oophorectomy (BSO) is commonly recommended for unaffected carriers and those with personal breast cancer history. Assessing BSO's long-term health outcomes in carriers with previous breast cancer history is essential.

Primary care online training on multifactorial breast cancer risk: pre-post evaluation study.

Background: It is estimated that>250,000 women in the United Kingdom (UK) are at increased risk of breast cancer, but only a small fraction are identified. Digital tools, such as CanRisk, enable multifactorial breast cancer risk assessment. Implementation of such tools within primary care would allow primary care professionals (PCPs) to reassure women at population-level risk and identify those at increased risk who will benefit most from targeted prevention or early detection.

Economic evaluation of personalised versus conventional risk assessment for women who have undergone testing for hereditary breast and ovarian cancer genes: a modelling study.

Background: The management of women with germline pathogenic variants (GPVs) in breast (BC) and ovarian cancer (OC) susceptibility genes is focused on surveillance and risk-reducing surgery/medication. Most women are assigned an average range of risk and treated accordingly, but it is possible to personalise this. Here, we explore the economic impact of risk personalisation.

Predictive biomarkers for the efficacy of PARP inhibitors in ovarian cancer: an updated systematic review.

Background: PARP inhibitors are effective in treating ovarian cancer, especially for BRCA1/2 pathogenic variant carriers and those with HRD (homologous recombination deficiency). Concerns over toxicity and costs have led to the search for predictive biomarkers. We present an updated systematic review, expanding on a previous ESMO review on PARP inhibitor biomarkers.

Long-term outcomes of bilateral salpingo-oophorectomy in women with personal history of breast cancer.

Objectives: To investigate the association between bilateral salpingo-oophorectomy (BSO) and long-term health outcomes in women with a personal history of breast cancer.

Methods And Analysis: We used data on women diagnosed with invasive breast cancer between 1995 and 2019 from the National Cancer Registration Dataset (NCRD) in England. The data were linked to the Hospital Episode Statistics-Admitted Patient Care dataset to identify BSO delivery.

Cancer and Overgrowth Manifestations of PTEN Hamartoma Tumor Syndrome: Management Recommendations from the International PHTS Consensus Guidelines Working Group.

Purpose: PTEN hamartoma tumor syndrome (PHTS) is an autosomal dominant cancer predisposition and overgrowth syndrome caused by pathogenic germline variants in the PTEN gene, with an increased risk of both benign and malignant tumors involving the breast, colon, endometrium, thyroid, skin, and kidney. The objective of these clinical guidelines was to use the latest knowledge to generate an international consensus resource for providers, researchers, and individuals with PHTS on the best practices in the surveillance and management of cancer and overgrowth in PHTS.

Experimental Design: The International PHTS Cancer and Overgrowth Guidelines Working Group was established, comprising a core group of six international experts in the diagnosis and management of PHTS.

Breast Cancer Susceptibility Gene Sequence Variations and Development of Contralateral Breast Cancer.

Importance: Heterogeneity in development of estrogen receptor (ER)-specific first primary breast cancer exists due to deleterious germline variants in moderate- to high-penetrance breast cancer susceptibility genes, but it is unknown if these associations occur in ER-specific CBC.

Objective: To determine the association of deleterious germline variants in breast cancer susceptibility genes with ER-specific CBC development and whether ER status of the first primary breast cancer modifies these associations.

Design, Setting, And Participants: This case-control study included CBC cases and matched unilateral breast cancer controls from The Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study, a population-based case-control study.

Management of individuals with heterozygous germline pathogenic variants in ATM: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).

Purpose: ATM germline pathogenic variants (GPVs) are associated with a moderately increased risk of female breast cancer, pancreatic cancer, and prostate cancer. Resources for managing ATM heterozygotes in clinical practice are limited.

Methods: An international workgroup developed a clinical practice resource to guide management of ATM heterozygotes using peer-reviewed publications and expert opinion.

Second Primary Cancer Risks After Breast Cancer in and Pathogenic Variant Carriers.

Purpose: Second primary cancer (SPC) risks after breast cancer (BC) in pathogenic variant (PV) carriers are uncertain. We estimated relative and absolute risks using a novel linkage of genetic testing data to population-scale National Disease Registration Service and Hospital Episode Statistics electronic health records.

Methods: We followed 25,811 females and 480 males diagnosed with BC and tested for germline PVs in NHS Clinical Genetics centers in England between 1995 and 2019 until SPC diagnosis, death, migration, contralateral breast/ovarian surgery plus 1 year, or the 31st of December 2020.

Lynch syndrome diagnostic testing pathways in endometrial cancers: a nationwide English registry-based study.

Background: For female patients with Lynch syndrome (LS), endometrial cancer (EC) is often their first cancer diagnosis. A testing pathway of somatic tumour testing triage followed by germline mismatch repair (MMR) gene testing is an effective way of identifying the estimated 3% of EC caused by LS.

Methods: A retrospective national population-based observational study was conducted using comprehensive national data collections of functional, somatic and germline MMR tests available via the English National Cancer Registration Dataset.