Multigene panels in Ashkenazi Jewish patients yield high rates of actionable mutations in multiple non-BRCA cancer-associated genes.

OBJECTIVE: To evaluate the results of multigene panel testing among Ashkenazi Jewish compared with non-Ashkenazi Jewish patients. METHODS: We reviewed the medical records for all patients who underwent multigene panel testing and targeted BRCA1/2 testing at a single institution between 6/2013-1/2015. Clinical actionability for identified pathogenic mutations was characterized based on the National Comprehensive Cancer Network (NCCN) guidelines and consensus statements and expert opinion for genes not addressed by these guidelines. RESULTS: Four hundred and fifty-four patients underwent multigene panel screening, including 138 Ashkenazi Jewish patients. The median patient age was fifty-two years. Three hundred and fifty-four patients (78%) had a personal history of cancer. Two hundred and fifty-one patients had breast cancer, 49, ovarian cancer, 26, uterine cancer and 20, colorectal cancer. We identified 62 mutations in 56 patients and 291 variants of uncertain significance in 196 patients. Among the 56 patients with mutations, 51 (91%) had actionable mutations. Twenty mutations were identified by multigene panels among Ashkenazi Jewish patients, 18 of which were in genes other than BRCA1/2. A review of targeted BRCA1/2 testing performed over the same study period included 103 patients and identified six mutations in BRCA1/2, all of which occurred in Ashkenazi Jewish patients. Among all Ashkenazi Jewish patients undergoing genetic testing, 25/183 (14%) had a mutation, 24/25 of which were actionable (96%) and 17/25 patients (68%) had mutations in non BRCA1/2 genes. CONCLUSIONS: With the rapid acceptance of multigene panels there is a pressing need to understand how this testing will affect patient management. While traditionally many Ashkenazi Jewish patients have undergone targeted BRCA1/2 testing, our data suggest consideration of multigene panels in this population as the majority of the results are clinically actionable and often in genes other than BRCA1/2.

Availability and scope of integrated screening for patients with Lynch syndrome.

OBJECTIVE: To assess the availability and capacity of US-based integrated centers for the management of Lynch syndrome. METHODS: A cross-sectional survey of practice patterns in the care of patients with Lynch syndrome was conducted at 33 National Cancer Institute-designated cancer centers in the USA from March 1 to June 1, 2013. Each cancer center was contacted by telephone and the caller used a uniform scripted greeting and survey format. RESULTS: All centers routinely recommended colonoscopy. Other recommended screening modalities were hysterectomy and bilateral salpingo-oophorectomy (29/33; 88%), endoscopy (27/33; 82%), urinalysis (23/33; 70%), endometrial sampling (21/33; 64%), dermatologic examination (19/32; 59%), pelvic ultrasonography (18/33; 55%), serum CA125 level (14/33; 42%), urine cytology (14/33; 42%), computed tomography (1/33; 3%), and magnetic resonance imaging (1/33; 3%). Each center had a multidisciplinary team but the composition varied. A designated team leader was present at 21 centers (64%). Having a team leader was associated with an increased likelihood of recommending endoscopy (P=0.04) and dermatologic surveillance (P=0.01). Only 23 centers (70%) had a system in place for communicating follow-up with patients. CONCLUSION: The lack of consensus in practice patterns recorded among participating centers probably reflected the limited existing evidence on the usefulness of most screening modalities.

Early and total neonatal mortality in relation to birth setting in the United States, 2006-2009.

OBJECTIVE: We examined neonatal mortality in relation to birth settings and birth attendants in the United States from 2006 through 2009. STUDY DESIGN: Data from the Centers for Disease Control and Prevention-linked birth and infant death dataset in the United States from 2006 through 2009 were used to assess early and total neonatal mortality for singleton, vertex, and term births without congenital malformations delivered by midwives and physicians in the hospital and midwives and others out of the hospital. Deliveries by hospital midwives served as the reference. RESULTS: Midwife home births had a significantly higher total neonatal mortality risk than deliveries by hospital midwives (1.26 per 1000 births; relative risk [RR], 3.87 vs 0.32 per 1000; P < .001). Midwife home births of 41 weeks or longer (1.84 per 1000; RR, 6.76 vs 0.27 per 1000; P < .001) and midwife home births of women with a first birth (2.19 per 1000; RR, 6.74 vs 0.33 per 1000; P < .001) had significantly higher risks of total neonatal mortality than deliveries by hospital midwives. In midwife home births, neonatal mortality for first births was twice that of subsequent births (2.19 vs 0.96 per 1000; P < .001). Similar results were observed for early neonatal mortality. The excess total neonatal mortality for midwife home births compared with midwife hospital births was 9.32 per 10,000 births, and the excess early neonatal mortality was 7.89 per 10,000 births. CONCLUSION: Our study shows a significantly increased total and early neonatal mortality for home births and even higher risks for women of 41 weeks or longer and women having a first birth. These significantly increased risks of neonatal mortality in home births must be disclosed by all obstetric practitioners to all pregnant women who express an interest in such births.

Apgar score of 0 at 5 minutes and neonatal seizures or serious neurologic dysfunction in relation to birth setting.

OBJECTIVE: To examine the occurrence of 5-minute Apgar scores of 0 and seizures or serious neurologic dysfunction for 4 groups by birth setting and birth attendant (hospital physician, hospital midwife, free-standing birth center midwife, and home midwife) in the United States from 2007-2010. METHODS: Data from the United States Centers for Disease Control's National Center for Health Statistics birth certificate data files were used to assess deliveries by physicians and midwives in and out of the hospital for the 4-year period from 2007-2010 for singleton term births (≥37 weeks' gestation) and ≥2500 g. Five-minute Apgar scores of 0 and neonatal seizures or serious neurologic dysfunction were analyzed for 4 groups by birth setting and birth attendant (hospital physician, hospital midwife, freestanding birth center midwife, and home midwife). RESULTS: Home births (relative risk [RR], 10.55) and births in free-standing birth centers (RR, 3.56) attended by midwives had a significantly higher risk of a 5-minute Apgar score of 0 (P < .0001) than hospital births attended by physicians or midwives. Home births (RR, 3.80) and births in freestanding birth centers attended by midwives (RR, 1.88) had a significantly higher risk of neonatal seizures or serious neurologic dysfunction (P < .0001) than hospital births attended by physicians or midwives. CONCLUSION: The increased risk of 5-minute Apgar score of 0 and seizures or serious neurologic dysfunction of out-of-hospital births should be disclosed by obstetric practitioners to women who express an interest in out-of-hospital birth. Physicians should address patients' motivations for out-of-hospital delivery by continuously improving safe and compassionate care of pregnant, fetal, and neonatal patients in the hospital setting.