Cell-free DNA screening for trisomies 21, 18, and 13 in pregnancies at low and high risk for aneuploidy with genetic confirmation.

BACKGROUND: Cell-free DNA noninvasive prenatal screening for trisomies 21, 18, and 13 has been rapidly adopted into clinical practice. However, previous studies are limited by a lack of follow-up genetic testing to confirm the outcomes and accurately assess test performance, particularly in women at a low risk for aneuploidy. OBJECTIVE: To measure and compare the performance of cell-free DNA screening for trisomies 21, 18, and 13 between women at a low and high risk for aneuploidy in a large, prospective cohort with genetic confirmation of results STUDY DESIGN: This was a multicenter prospective observational study at 21 centers in 6 countries. Women who had single-nucleotide-polymorphism-based cell-free DNA screening for trisomies 21, 18, and 13 were enrolled. Genetic confirmation was obtained from prenatal or newborn DNA samples. The test performance and test failure (no-call) rates were assessed for the cohort, and women with low and high previous risks for aneuploidy were compared. An updated cell-free DNA algorithm blinded to the pregnancy outcome was also assessed. RESULTS: A total of 20,194 women were enrolled at a median gestational age of 12.6 weeks (interquartile range, 11.6-13.9). The genetic outcomes were confirmed in 17,851 cases (88.4%): 13,043 (73.1%) low-risk and 4808 (26.9%) high-risk cases for aneuploidy. Overall, 133 trisomies were diagnosed (100 trisomy 21; 18 trisomy 18; 15 trisomy 13). The cell-free DNA screen positive rate was lower in the low-risk vs the high-risk group (0.27% vs 2.2%; P<.0001). The sensitivity and specificity were similar between the groups. The positive predictive value for the low- and high-risk groups was 85.7% vs 97.5%; P=.058 for trisomy 21; 50.0% vs 81.3%; P=.283 for trisomy 18; and 62.5% vs 83.3; P=.58 for trisomy 13, respectively. Overall, 602 (3.4%) patients had no-call result after the first draw and 287 (1.61%) after including cases with a second draw. The trisomy rate was higher in the 287 cases with no-call results than patients with a result on a first draw (2.8% vs 0.7%; P=.001). The updated algorithm showed similar sensitivity and specificity to the study algorithm with a lower no-call rate. CONCLUSION: In women at a low risk for aneuploidy, single-nucleotide-polymorphism-based cell-free DNA has high sensitivity and specificity, positive predictive value of 85.7% for trisomy 21 and 74.3% for the 3 common trisomies. Patients who receive a no-call result are at an increased risk of aneuploidy and require additional investigation.

Physicians' perception on using a multi-cancer early detection blood test to reduce disparities in cancer screening.

 INTRODUCTION: Cancer causes significant morbidity and mortality in the United States. It is the second most common cause of death in the United States, after heart disease. African Americans are disproportionately affected by malignancy, with overall higher death rates compared to other racial and ethnic groups. Screening tests can identify early stage malignancy allowing for timely intervention. However, African Americans less frequently undergo cancer screening. Advancement in genomic technology has led to the identification of signals for cancer in the blood. This has resulted in the development of multi-cancer early detection (MCED) tests which evaluate for circulating cell-free DNA (cfDNA). This study evaluated physicians' perception of the use of a multi-cancer early detection test (MCED). METHODS: An anonymous, 29 question survey was administered to African American / Black physicians and medical students. Survey participants were identified through the National Medical Association and other professional organizations that included primarily African American physicians. Surveys were excluded from analysis if respondent was non-African American / Black or was not a physician or medical student. The survey collected physician demographics, percentage of African American / Black patients in their practice, patient barriers to screening, potential use of MCED tests and factors influencing decision to recommend testing. Descriptive statistics were generated. Additional analysis was performed using Chi-Square with statistical significance set at p-value <0.05. The survey was pilot tested for reliability and validity. RESULTS: 1196 (681 female, 515 male) physicians and medical students completed the survey. 95.8 % were physicians who were or had been in clinical practice. Fifty-three percent of physicians reported that >40 % of their patients were African American / Black. Barriers to cancer screening included lack of understanding of the importance (33.8 %), lack of or limited insurance coverage (23.5 %), socioeconomic factors unrelated to insurance coverage (16.2 %), fear of cancer (8.8 %), history of racism and bias in the health care system (7.4 %) with 8.8 % reporting 'other' and 1.5 % reporting no perceived barriers. There was a significant difference (p<0.03) in the rate that physicians' perceived racism and bias in the health care system as barrier for cancer screening in African American / Black patients when compared to other patients. Most physicians and medical students indicated that a MCED test would benefit all patients (86.8 %), would encourage further cancer screening tests (83.8 %), and would be beneficial for minority and under-represented patients regardless of socioeconomics or health care access (83.8 %). Seventy-five percent of survey respondents indicated that a MCED test would be beneficial in promoting further cancer screening and early detection in African American / Black patients. Factors that would impact the ordering of an MCED test included scientific evidence and test validity (63.2 %), efficiency, accessibility, ease of ordering and ease of receiving results (11.8 %), insurance coverage (13.2 %) and 'other factors' (11.8 %). DISCUSSION: This is one of the largest surveys to assess physicians' perceptions about MCED testing and is the first study to evaluate the perspectives of African American physicians. It offers insight about physician acceptance and potential incorporation of MCED into clinical practice. It is important that a multifaceted approach is employed to improve cancer outcomes and reduce disparities in survival. MCED tests, a relatively new advancement in genomic technology, have the potential to be an important component in cancer screening strategies.

Epigenetics in women's health care.

Epigenetics refers to structural modifications to genes that do not change the nucleotide sequence itself but instead control and regulate gene expression. DNA methylation, histone modification, and RNA regulation are some of the mechanisms involved in epigenetic modification. Epigenetic changes are believed to be a result of changes in an organism's environment that result in fixed and permanent changes in most differentiated cells. Some environmental changes that have been linked to epigenetic changes include starvation, folic acid, and various chemical exposures. There are periods in an organism's life cycle in which the organism is particularly susceptible to epigenetic influences; these include fertilization, gametogenesis, and early embryo development. These are also windows of opportunity for interventions during the reproductive life cycle of women to improve maternal-child health. New data suggest that epigenetic influences might be involved in the regulation of fetal development and the pathophysiology of adult diseases such as cancer, diabetes, obesity, and neurodevelopmental disorders. Various epigenetic mechanisms may also be involved in the pathogenesis of preeclampsia and intrauterine growth restriction. Additionally, environmental exposures are being held responsible for causing epigenetic changes that lead to a disease process. Exposure to heavy metals, bioflavonoids, and endocrine disruptors, such as bisphenol A and phthalates, has been shown to affect the epigenetic memory of an organism. Their long-term effects are unclear at this point, but many ongoing studies are attempting to elucidate the pathophysiological effects of such gene-environment interactions.