Strategies to Assess Risk for Hereditary Cancer in Primary Care Clinics: A Cluster Randomized Clinical Trial.

Importance: Best practices for improving access to assessment of hereditary cancer risk in primary care are lacking.

Objective: To compare 2 population-based engagement strategies for identifying primary care patients with a family or personal history of cancer and offering eligible individuals genetic testing for cancer susceptibility.

Design, Setting, And Participants: The EDGE (Early Detection of Genetic Risk) clinical trial cluster-randomized 12 clinics from 2 health care systems in Montana, Wyoming, and Washington state to 1 of 2 engagement approaches for assessment of hereditary cancer risk in primary care.

Primary care provider practices, attitudes, and confidence with hereditary cancer risk assessment and testing: A mixed methods study.

Purpose: This study sought to better understand primary care providers' readiness to conduct population-based risk assessment and offer genetic testing for hereditary cancer.

Methods: Sixty primary care providers completed a survey assessing their current practices, attitudes, and confidence with cancer risk assessment and testing. Sixteen participated in follow-up interviews.

Long-read DNA and cDNA sequencing identify cancer-predisposing deep intronic variation in tumor-suppressor genes.

The vast majority of deeply intronic genomic variants are benign, but some extremely rare or private deep intronic variants lead to exonification of intronic sequence with abnormal transcriptional consequences. Damaging variants of this class are likely underreported as causes of disease for several reasons: Most clinical DNA and RNA testing does not include full intronic sequences; many of these variants lie in complex repetitive regions that cannot be aligned from short-read whole-genome sequence; and, until recently, consequences of deep intronic variants were not accurately predicted by in silico tools. We evaluated the frequency and consequences of rare deep intronic variants for families severely affected with breast, ovarian, pancreatic, and/or metastatic prostate cancer, but with no causal variant identified by any previous genomic or cDNA-based approach.

Increased TP53 somatic evolution in peritoneal washes of individuals with BRCA1 germline mutations.

Background: Individuals with germline BRCA1 and BRCA2 pathogenic variants (BRCA carriers) are at high risk of developing high grade serous ovarian carcinoma (HGSC). HGSC is predominantly driven by TP53 mutations, but mutations in this gene are also commonly found in non-cancerous tissue as a feature of normal human aging. We hypothesized that HGSC predisposition in BRCA carriers may be related to increased TP53 somatic evolution, which could be detectable by ultra-deep sequencing of TP53 mutations in gynecological liquid biopsies.

Prevention of Ovarian Cancer: Where are We Now and Where are We Going?

Purpose Of Review: To describe current and future strategies to reduce the burden of ovarian cancer through prevention.

Recent Findings: Current strategies in genetic testing are missing a substantial number of individuals at risk, representing a missed opportunity for ovarian cancer prevention. Past efforts at screening and early detection have thus far failed to improve ovarian cancer mortality, and novel techniques are needed.

TP53 somatic evolution in cervical liquid-based cytology and blood from individuals with and without ovarian cancer and BRCA1 or BRCA2 germline mutations.

Somatic TP53 mutations are prevalent in normal tissue but little is known about their association with cancer risk. Cervical liquid-based cytology (LBC), commonly known as Pap test, provides an accessible gynecological sample to test the value of TP53 somatic mutations as a biomarker for high-grade serous ovarian cancer (HGSC), a cancer type mostly driven by TP53 mutations. We used ultra-deep duplex sequencing to analyze TP53 mutations in LBC and blood samples from 70 individuals (30 with and 40 without HGSC) undergoing gynecologic surgery, 30 carrying BRCA1 or BRCA2 germline pathogenic variants (BRCApv).

Cost-Effectiveness of Unselected Multigene Germline and Somatic Genetic Testing for Epithelial Ovarian Cancer.

Background: Parallel panel germline and somatic genetic testing of all patients with ovarian cancer (OC) can identify more pathogenic variants (PVs) that would benefit from PARP inhibitor (PARPi) therapy, and allow for precision prevention in unaffected relatives with PVs. In this study, we estimate the cost-effectiveness and population impact of parallel panel germline and somatic BRCA testing of all patients with OC incorporating PARPi therapy in the United Kingdom and the United States compared with clinical criteria/family history (FH)-based germline BRCA testing. We also evaluate the cost-effectiveness of multigene panel germline testing alone.

Germline Testing in Patients With Breast Cancer: ASCO-Society of Surgical Oncology Guideline.

Purpose: To develop recommendations for germline mutation testing for patients with breast cancer.

Methods: An ASCO-Society of Surgical Oncology (SSO) panel convened to develop recommendations based on a systematic review and formal consensus process.

Results: Forty-seven articles met eligibility criteria for the germline mutation testing recommendations; 18 for the genetic counseling recommendations.

Adoption of Universal Testing in Endometrial Cancers for Microsatellite Instability Using Next-Generation Sequencing.

Purpose: To assess implementation of a next-generation sequencing (NGS) assay to detect microsatellite instability (MSI) as a screen for Lynch syndrome (LS) in endometrial cancer (EC), while determining and comparing characteristics of the four molecular subtypes.

Methods: A retrospective review was performed of 408 total patients with newly diagnosed EC: 140 patients who underwent universal screening with NGS and 268 patients who underwent screening via mismatch repair immunohistochemistry (MMR IHC) as part of a historical screening paradigm. In the NGS cohort, incidental and mutations along with MSI were identified and used to characterize EC into molecular subtypes: -ultramutated, MSI high (MSI-H), -mutated, and no specific molecular profile (NSMP).

Remotely Delivered Cancer Genetic Testing in the Making Genetic Testing Accessible (MAGENTA) Trial: A Randomized Clinical Trial.

Importance: Requiring personalized genetic counseling may introduce barriers to cancer risk assessment, but it is unknown whether omitting counseling could increase distress.

Objective: To assess whether omitting pretest and/or posttest genetic counseling would increase distress during remote testing.

Design, Setting, And Participants: Making Genetic Testing Accessible (MAGENTA) was a 4-arm, randomized noninferiority trial testing the effects of individualized pretest and/or posttest genetic counseling on participant distress 3 and 12 months posttest.

Care after premenopausal risk-reducing salpingo-oophorectomy in high-risk women: Scoping review and international consensus recommendations.

Women at high inherited risk of ovarian cancer are offered risk-reducing salpingo-oophorectomy (RRSO) from age 35 to 45 years. Although potentially life-saving, RRSO may induce symptoms that negatively affect quality of life and impair long-term health. Clinical care following RRSO is often suboptimal.

TUBectomy with delayed oophorectomy as an alternative to risk-reducing salpingo-oophorectomy in high-risk women to assess the safety of prevention: the TUBA-WISP II study protocol.

Background: Risk-reducing salpingectomy with delayed oophorectomy has gained interest for individuals at high risk for tubo-ovarian cancer as there is compelling evidence that especially high-grade serous carcinoma originates in the fallopian tubes. Two studies have demonstrated a positive effect of salpingectomy on menopause-related quality of life and sexual health compared with standard risk-reducing salpingo-oophorectomy.

Primary Objective: To investigate whether salpingectomy with delayed oophorectomy is non-inferior to the current standard salpingo-oophorectomy for the prevention of tubo-ovarian cancer among individuals at high inherited risk.

Society of Gynecologic Oncology Journal Club: Controversial conversations in gynecologic cancer - Navigating maintenance therapy for homologous recombinant proficient ovarian cancer.

The Society of Gynecologic Oncology (SGO) Journal Club is an open forum to review pertinent studies relevant to controversial topics in the management of gynecologic cancers. On August 3rd, 2022, SGO hosted a Journal Club focused on the role of maintenance therapy for homologous recombinant proficient (HRP) patients with ovarian cancer. Navigating optimal therapies has become more complex with the emergence of new clinical trial data and the evolving understanding of how to classify ovarian cancers as HRP.

Genetic Testing Among Patients with High-Risk Breast, Ovarian, Pancreatic, and Prostate Cancers.

Background: The National Comprehensive Cancer Network recommends genetic testing in patients with potentially hereditary breast, ovarian, pancreatic, and prostate cancers (HBOPP). Knowledge of genetic mutations impacts decisions about screening and treatment.

Methods: A retrospective cohort study of 28,586 HBOPP patients diagnosed from 2013 to 2019 was conducted using a linked administrative-cancer database in the Seattle-Puget Sound SEER area.

Uterine lavage identifies cancer mutations and increased somatic mutation burden in individuals with ovarian cancer.

Current screening methods for ovarian cancer (OC) have failed to demonstrate a significant reduction in mortality. Uterine lavage combined with ultra-deep sequencing for the detection of disseminated OC cells has emerged as a promising tool, but this approach has not been tested for early-stage disease or non-serous histologies. In addition, lavages carry multiple background mutations, the significance of which is poorly understood.

An Accessible Communication System for Population-Based Genetic Testing: Development and Usability Study.

Background: Genetic testing uptake is low, despite the well-established connection between pathogenic variants in certain cancer-linked susceptibility genes and ovarian cancer risk. Given that most major insurers cover genetic testing for those with a family history suggestive of hereditary cancer, the issue may lie in access to genetic testing. Remotely accessible web-based communication systems may improve awareness, and uptake, of genetic testing services.

Using Social Media to Facilitate Communication About Women's Testing: Tool Validation Study.

Background: Strong participant recruitment practices are critical to public health research but are difficult to achieve. Traditional recruitment practices are often time consuming, costly, and fail to adequately target difficult-to-reach populations. Social media platforms such as Facebook are well-positioned to address this area of need, enabling researchers to leverage existing social networks and deliver targeted information.

Risk of Peritoneal Carcinomatosis After Risk-Reducing Salpingo-Oophorectomy: A Systematic Review and Individual Patient Data Meta-Analysis.

Purpose: After risk-reducing salpingo-oophorectomy (RRSO), / pathogenic variant (PV) carriers have a residual risk to develop peritoneal carcinomatosis (PC). The etiology of PC is not yet clarified, but may be related to serous tubal intraepithelial carcinoma (STIC), the postulated origin for high-grade serous cancer. In this systematic review and individual patient data meta-analysis, we investigate the risk of PC in women with and without STIC at RRSO.

Germline mutations in Black patients with ovarian, fallopian tube and primary peritoneal carcinomas.

Objective: Routine genetic testing for ovarian cancer and identification of germline mutations can help improve early detection of cancer as well as guide treatment. Knowledge of genetic counseling and referral rates for genetic testing has been lower for Black patients, compared to White patients. We aimed to describe the demographics and presence of germline mutations in Black individuals with ovarian, fallopian tube or peritoneal carcinoma at two large academic institutions.

Joint IARC/NCI International Cancer Seminar Series Report: expert consensus on future directions for ovarian carcinoma research.

Recently, ovarian cancer research has evolved considerably because of the emerging recognition that rather than a single disease, ovarian carcinomas comprise several different histotypes that vary by etiologic origin, risk factors, molecular profiles, therapeutic approaches and clinical outcome. Despite significant progress in our understanding of the etiologic heterogeneity of ovarian cancer, as well as important clinical advances, it remains the eighth most frequently diagnosed cancer in women worldwide and the most fatal gynecologic cancer. The International Agency for Research on Cancer and the United States National Cancer Institute jointly convened an expert panel on ovarian carcinoma to develop consensus research priorities based on evolving scientific discoveries.

Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies.

Characterizing TP53 mutations in ovarian carcinomas with and without concurrent BRCA1 or BRCA2 mutations.

Objectives: Mutations in the TP53 tumor suppressor gene are common in ovarian carcinoma (OC) but their impact on outcomes is controversial. We sought to define the relationship of TP53 mutations to cancer outcomes and their interactions with co-occurrent BRCA1 or BRCA2 (BRCA) mutations, comparing three different TP53 mutation classification schemes.

Methods: We performed next generation sequencing on 393 cases of OC prospectively followed for survival.

Design of a study to implement population-based risk assessment for hereditary cancer genetic testing in primary care.

Identifying patients with high genetic risk for cancer has important clinical ramifications, but hereditary cancer risk is often not identified because of testing barriers at both the provider and patient level. It is unknown how to best implement appropriate genetic testing and follow-up care into an operating primary care clinic. Implementation studies to date have been conducted in high resourced facilities under optimal conditions, often not at the clinic level.