The discovery of genes underlying inherited predisposition to breast and ovarian cancer has revolutionized the ability to identify women at high risk for these diseases before they become affected. Women who are carriers of deleterious variants in these genes can undertake surveillance and prevention measures that have been shown to reduce morbidity and mortality. However, under current strategies, the vast majority of women carriers remain undetected until they become affected. In this review, we show that universal testing, particularly of the BRCA1 and BRCA2 genes, fulfills classical disease screening criteria. This is especially true for BRCA1 and BRCA2 in Ashkenazi Jews but is translatable to all populations and may include additional genes. Utilizing genetic information for large-scale precision prevention requires a paradigmatic shift in health-care delivery. To address this need, we propose a direct-to-patient model, which is increasingly pertinent for fulfilling the promise of utilizing personal genomic information for disease prevention.

BACKGROUND: Smokers are generally more susceptible to infectious respiratory diseases and are at higher risk of developing severe complications from these infections. Conflicting reports exist regarding the impact of smoking on the risk of Coronavirus disease 2019 (COVID-19). METHODS: We carried out a population-based study among over 3,000,000 adult members of Clalit Health Services, the largest health provider in Israel. Since the beginning of the disease outbreak, and until May 16, 2020, over 145,000 adults underwent RT-PCR testing for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), and 3.3% had positive results. We performed a case-control study among patients who underwent SARS-CoV-2 testing, to assess the impact of smoking on infection incidence and severity. Individuals with positive tests were matched in a 1:5 ratio to individuals tested negative, of the same sex, age, and ethnicity/religion. Conditional logistic regressions were performed to evaluate odds ratios for current and previous smoking on the risk of testing positive. Multivariable logistic regressions were performed among patients infected with COVID-19 to estimate the association between smoking and fatal or severe disease requiring ventilation. Regressions were performed with and without adjustment for preexisting medical conditions. RESULTS: Current smokers (9.8%) were significantly less prevalent among members tested positive compared to the general population (19.4%, P<0.001), and to matched members tested negative (18.2%, P<0.001). Current smoking was associated with significantly reduced odds ratio (OR) for testing positive OR=0.447 (95% confidence interval (CI) 0.400-0.501). Among patients tested positive, there was no evidence of significantly increased risk of developing severe or fatal disease. CONCLUSION: The risk of infection by COVID-19 appears to be reduced by half among current smokers. This intriguing finding may reveal unique infection mechanisms present for COVID-19 which may be targeted to combat the disease and reduce its infection rate.

Background: Denmark and Israel both have highly rated and well-performing healthcare systems with marked differences in funding and organization of primary healthcare. Although better population health outcomes are seen in Israel, Denmark has a substantially higher healthcare expenditure. This has caused Danish policy makers to take an interest in Israeli community care organization. Consequently, we aim to provide a more detailed insight into differences between the two countries’ healthcare organization and cost, as well as health outcomes. Methods: A comparative analysis combining data from OECD, WHO, and official sources. World Health Organization (WHO) and the Organisation for Economic Co-operation and Development (OECD) statistics were used, and national official sources were procured from the two healthcare systems. Literature searches were performed in areas relevant to expenditure and outcome. Data were compared on health care expenditure and selected outcome measures. Expenditure was presented as purchasing power parity and as percentage of gross domestic product, both with and without adjustment for population age, and both including and excluding long-term care expenditure. Results: Denmark’s healthcare expenditure is higher than Israel’s. However, corrected for age and long-term care the difference diminishes. Life expectancy is lower in Denmark than in Israel, and Israel has a significantly better outcome regarding cancer as well as a lower number of Years of Potential Life Lost. Israelis have a healthier lifestyle, in particular a much lower alcohol consumption. Conclusion: Attempting to correct for what we deemed to be the most important influencing factors, age and different inclusions of long-term care costs, the Israeli healthcare system still seems to be 25% less expensive, compared to the Danish one, and with better health outcomes. This is not necessarily a function of the Israeli healthcare system but may to a great extent be explained by cultural factors, mainly a much lower Israeli alcohol consumption.

Pathogenic TP53 germline variants cause young-onset breast cancer and other cancers of the Li-Fraumeni syndrome (LFS) spectrum, but the clinical consequences of partial-loss-of function TP53 variants are incompletely understood. In the consecutive cohort of Palestinian breast cancer patients of the Middle East Breast Cancer Study (MEBCS), breast cancer risk among TP53 p.R181C heterozygotes was 50% by age 50 years and 81% by age 80 years. In contrast, prevalence of pediatric cancers in the MEBCS was similar among first-degree relatives of TP53 p.R181C carriers (3/519 = 0.0058) and first-degree relatives of MEBCS patients with no pathogenic germline variant in any known breast cancer gene (7/1082 = 0.0065; odds ratio [OR] = 0.90, 95% confidence interval [CI] [0.23 to 3.49], Fisher P = .90 [2-tailed]). This result suggests that in families harboring this TP53 allele, genetic testing in children is unwarranted, and screening children for LFS tumors is unnecessary. More generally, some TP53 missense alleles can predispose to very high risk of breast cancer without pleiotropic effects.

Identifying carriers of pathogenic BRCA1/BRCA2 variants reduces cancer morbidity and mortality through surveillance and prevention. We analyzed the cost-effectiveness of BRCA1/BRCA2 population screening (PS) in Ashkenazi Jews (AJ), for whom carrier rate is 2.5%, compared with two existing strategies: cascade testing (CT) in carrier’s relatives (≥25% carrier probability) and international family history (IFH)-based guidelines (>10% probability). We used a decision analytic-model to estimate quality-adjusted life-years (QALY) gained, and incremental cost-effectiveness ratio for PS vs. alternative strategies. Analysis was conducted from payer-perspective, based on actual costs. Per 1000 women, the model predicted 21.6 QALYs gained, a lifetime decrease of three breast cancer (BC) and four ovarian cancer (OC) cases for PS vs. CT, and 6.3 QALYs gained, a lifetime decrease of 1 BC and 1 OC cases comparing PS vs. IFH. PS was less costly compared with CT (−3097 USD/QALY), and more costly than IFH (+42,261 USD/QALY), yet still cost-effective, from a public health policy perspective. Our results are robust to sensitivity analysis; PS was the most effective strategy in all analyses. PS is highly cost-effective, and the most effective screening strategy for breast and ovarian cancer prevention. BRCA testing should be available to all AJ women, irrespective of family history.