Why Is Cancer Genetic Counseling Underutilized by Women Identified as at Risk for Hereditary Breast Cancer? Patient Perceptions of Barriers Following a Referral Letter.

Family history information comprises an important tool in identifying and referring patients at risk for hereditary breast and ovarian cancer (HBOC) to cancer genetic counseling. Despite recommendations and support provided by numerous professional organizations, cancer genetic counseling services are underutilized by atrisk patients. This study aimed to: (1) determine the rate of genetic counseling utilization following a referral letter, (2) characterize factors (barriers and supports) which influenced uptake of services, and (3) identify potential strategies for increasing utilization. This study evaluated the uptake of cancer genetic counseling among 603 screening mammography patients identified as having an increased risk for HBOC based on National Comprehensive Cancer Network (NCCN) guidelines. At risk individuals and their primary care providers were mailed a referral letter recommending genetic counseling. Three focus groups (N = 24) were conducted to identify responses to receiving a letter recommending genetic counseling, barriers to seeking genetic counseling, and facilitating factors to utilizing these services. Participant responses were qualitatively analyzed using thematic and cross case analysis. Within one year, 50/603 (8 %) of the identified at-risk women completed a genetic counseling appointment. Participant-perceived barriers which influenced their decision not to seek genetic counseling included lack of relevance and utility, limited knowledge about genetic counseling, concerns about the genetic counseling process, and concerns about cost and insurance coverage. Participant-perceived facilitating factors which would support a decision to seek genetic counseling included greater awareness and education about genetic counseling services when receiving a referral, and improved follow up and guidance from their provider. Findings from this study support the need for patient and primary care provider education, and improved provider-patient communication to increase uptake of genetic counseling services.

Judicious DICER1 testing and surveillance imaging facilitates early diagnosis and cure of pleuropulmonary blastoma.

Pleuropulmonary blastoma (PPB) and Sertoli-Leydig cell tumor (SLCT) are both associated with germline mutations in DICER1. In this brief report, a maternal history of SLCT led to identification of a deleterious DICER1 mutation in the patient and her asymptomatic infant. Radiographic screening revealed a large Type I PPB, which was completely resected. Identification of DICER1 mutation carriers and imaging of children at risk for PPB may allow detection of PPB in its earliest and most curable form, leading to increased likelihood of surgical cure and decreased risks of treatment-related late effects.

An Electronic Health Record Tool Increases Genetic Counseling Referral of Individuals at Hereditary Cancer Risk: An Intervention Study.

INTRODUCTION: There is widespread under-identification of individuals at hereditary cancer risk despite national guidelines calling for screening. We evaluated the utilization of a tool embedded in the electronic health record (EHR) to assist primary care providers in screening patients for cancer genetic counseling referral. METHODS: We designed BestPractice Advisories linked to a Genetic Cancer Screening Tool (GCST) in EpicCare Ambulatory. The GCST identifies individuals for evaluation for BRCA1/2, Lynch syndrome, and other risk mutations due to personal and family history. We tested the tool in a 7-week intervention in adult wellness visits at two clinics, one urban and one rural. RESULTS: Out of 687 eligible patients, the screening survey was completed for 469 (67%), and of these, 150 (32%) screened positive for a personal and/or family history meeting genetic counseling referral criteria. Of individuals screening positive, a referral order was placed for 20 (13%). GCST screen-positive rate varied by patient gender but not race or age. Referral rate varied by provider and clinic but was not significantly affected by patient demographics. In the previous year over an equivalent date range, 0.1% of wellness visits (1 of 1,086) led to a referral, and this rate increased to 2.1% (22 of 1,062) during the intervention. The proportion of providers referring patients also increased, from 3.8% (1 of 26) to 42.3% (11 of 26). DISCUSSION/CONCLUSION: Genetic counseling referral of individuals at hereditary cancer risk was increased by use of an EHR-integrated tool. These findings add evidence for the benefit of clinical decision support for cancer genetic risk screening in primary care.

Effects of Germline Pathogenic Variants, Cancer Subtypes, Tumor-related Characteristics, and Pregnancy-associated Diagnosis on Outcomes.

BACKGROUND: Although breast cancer (BC) is uncommon in women age ≤ 35 years, women in this age group may have more aggressive cancer subtypes and high-risk pathogenic variants (HRPVs). Higher recurrence and mortality rates in young patients may be related to differences in tumor biology, pathologic mutation status, or treatment. The purpose of this study was to evaluate germline mutation status and other factors that affect recurrence-free survival (RFS) and overall survival (OS) in young women with BC. MATERIALS AND METHODS: This was a retrospective study of women diagnosed with BC at age ≤ 35 years at Allina Health System from 2000 through 2017 (n = 306). Information was collected on germline mutation status, tumor characteristics (grade, hormone receptor, and human epidermal growth factor receptor 2), molecular subtype, pregnancy-associated cancers, and treatment. Survival analyses using Kaplan-Meier curves were conducted for RFS and OS. RESULTS: With mean follow-up of 6.5 years, OS was 87.0% for invasive cancers, RFS was 84.7%; 69% obtained genetic testing, and 26.9% had HRPVs. There were no differences in RFS or OS between patients with HRPV versus unknown/low/moderate risk variants. Recurrence analysis showed increased recurrence rates in luminal B-like cancers followed by triple negative and human epidermal growth factor receptor 2-positive cancers (P = .041). Pregnancy-associated BC diagnoses, angiolymphatic invasion, and tumor stage were associated with reduced OS. In spite of young age at diagnosis, nearly one-third of patients did not receive germline genetic testing. CONCLUSIONS: Similar survival patterns were found between women with HRPV versus no known mutations. Luminal B-like subtype, pregnancy-associated BC, angiolymphatic invasion, and cancer stage were associated with reduced OS.

Predictors of risk-reducing surgery intentions following genetic counseling for hereditary breast and ovarian cancer.

Risk-reducing mastectomy (RRM) and salpingo-oophorectomy (RRSO) are increasingly used to reduce breast and ovarian cancer risk following BRCA1/BRCA2 testing. However, little is known about how genetic counseling influences decisions about these surgeries. Although previous studies have examined intentions prior to counseling, few have examined RRM and RRSO intentions in the critical window between genetic counseling and test result disclosure. Previous research has indicated that intentions at this time point predict subsequent uptake of surgery, suggesting that much decision-making has taken place prior to result disclosure. This period may be a critical time to better understand the drivers of prophylactic surgery intentions. The aim of this study was to examine predictors of RRM and RRSO intentions. We hypothesized that variables from the Health Belief Model would predict intentions, and we also examined the role of affective factors. Participants were 187 women, age 21-75, who received genetic counseling for hereditary breast and ovarian cancer. We utilized multiple logistic regression to identify independent predictors of intentions. 49.2% and 61.3% of participants reported intentions for RRM and RRSO, respectively. Variables associated with RRM intentions include: newly diagnosed with breast cancer (OR = 3.63, 95% CI = 1.20-11.04), perceived breast cancer risk (OR = 1.46, 95% CI = 1.17-1.81), perceived pros (OR = 1.79, 95% CI = 1.38-2.32) and cons of RRM (OR = 0.81, 95% CI = 0.65-0.996), and decision conflict (OR = 0.80, 95% CI = 0.66-0.98). Variables associated with RRSO intentions include: proband status (OR = 0.28, 95% CI = 0.09-0.89), perceived pros (OR = 1.35, 95% CI = 1.11-1.63) and cons of RRSO (OR = 0.72, 95% CI = 0.59-0.89), and ambiguity aversion (OR = 0.79, 95% CI = 0.65-0.95). These data provide support for the role of genetic counseling in fostering informed decisions about risk management, and suggest that the role of uncertainty should be explored further.

DICER1 and Associated Conditions: Identification of At-risk Individuals and Recommended Surveillance Strategies.

Pathogenic germline DICER1 variants cause a hereditary cancer predisposition syndrome with a variety of manifestations. In addition to conferring increased cancer risks for pleuropulmonary blastoma (PPB) and ovarian sex cord-stromal tumors, particularly Sertoli-Leydig cell tumor, individuals with pathogenic germline DICER1 variants may also develop lung cysts, cystic nephroma, renal sarcoma and Wilms tumor, nodular hyperplasia of the thyroid, nasal chondromesenchymal hamartoma, ciliary body medulloepithelioma, genitourinary embryonal rhabdomyosarcoma, and brain tumors including pineoblastoma and pituitary blastoma. In May 2016, the International PPB Registry convened the inaugural International DICER1 Symposium to develop consensus testing and surveillance and treatment recommendations. Attendees from North America, Europe, and Russia provided expert representation from the disciplines of pediatric oncology, endocrinology, genetics, genetic counseling, radiology, pediatric surgery, pathology, and clinical research. Recommendations are provided for genetic testing; prenatal management; and surveillance for DICER1-associated pulmonary, renal, gynecologic, thyroid, ophthalmologic, otolaryngologic, and central nervous system tumors and gastrointestinal polyps. Risk for most DICER1-associated neoplasms is highest in early childhood and decreases in adulthood. Individual and caregiver education and judicious imaging-based surveillance are the primary recommended approaches. These testing and surveillance recommendations reflect a consensus of expert opinion and current literature. As DICER1 research expands, guidelines for screening and treatment will continue to be updated. Clin Cancer Res; 24(10); 2251-61. ©2018 AACR.

Ovarian tumors related to intronic mutations in DICER1: a report from the international ovarian and testicular stromal tumor registry.

Germline DICER1 mutations have been described in individuals with pleuropulmonary blastoma (PPB), ovarian Sertoli-Leydig cell tumor (SLCT), sarcomas, multinodular goiter, thyroid carcinoma, cystic nephroma and other neoplastic conditions. Early results from the International Ovarian and Testicular Stromal Tumor Registry show germline DICER1 mutations in 48 % of girls and women with SLCT. In this report, a young woman presented with ovarian undifferentiated sarcoma. Four years later, she presented with SLCT. She was successfully treated for both malignancies. Sequence results showed a germline intronic mutation in DICER1. This mutation results in an exact duplication of the six bases at the splice site at the intron 23 and exon 24 junction. Predicted improper splicing leads to inclusion of 10 bases of intronic sequence, frameshift and premature truncation of the protein disrupting the RNase IIIb domain. A second individual with SLCT was found to have an identical germline mutation. In each of the ovarian tumors, an additional somatic mutation in the RNase IIIb domain of DICER1 was found. In rare patients, germline intronic mutations in DICER1 that are predicted to cause incorrect splicing can also contribute to the pathogenesis of SLCT.

Refined genotype-phenotype correlations in cases of chromosome 6p deletion syndromes.

Clinical reports of cases with deletions in chromosome 6p are relatively rare. We present a detailed study by fluorescent in situ hybridisation (FISH) of six new cases with distinct but overlapping 6p deletions involving the 6p24-pter chromosomal segment. Chromosomal breakpoints in individual cases were investigated using a large panel of probes previously mapped and characterised in our laboratory to cover the distal region of 6p. These cases have allowed refinement of genotype-phenotype correlations and strongly suggest a gene involved in regulating the development of hearing is localised within 6p25. There is also evidence for one or more loci involved in heart, skeletal and craniofacial development in the 6p24-p25 region. Furthermore, the Dandy-Walker malformation is associated with deletion of 6p24-pter.

Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood.

The clinical, cytogenetic, and molecular findings of 2 Fanconi anemia (FA) subtype D1 kindreds, initially identified through a young child with a solid tumor (medullobastoma, Wilms tumor), are described. Each kindred subsequently had a second affected child; one developed Wilms tumor followed by a medulloblastoma, and the other developed T-lineage acute lymphoblastic leukemia. Cytogenetic studies revealed an unusually high spontaneous chromosome aberration rate, contrasting with other FA subtypes. Molecular analysis revealed biallelic BRCA2/FANCD1 mutations. The patients did not exhibit bone marrow failure. Our studies suggest that the D1 subtype represents a severe end of the cytogenetic spectrum within FA, consistent with a critical downstream role of BRCA2 in the FA pathway. Furthermore, this FA subgroup may be preferentially associated with an increased predisposition to solid tumors in early childhood. Recognition of this constellation of findings has significant implications for medical management and genetic counseling of FA families.