Hormone Receptor-Positive Breast Cancer Sensitive to Pembrolizumab: Evidence of the Pathogenicity of the MLH1 Variant 1835del3.

A woman with estrogen/progesterone receptor-positive, ERBB2-negative metastatic breast cancer developed progressive disease despite treatment with multiple hormonal and chemotherapeutic modalities. She carried a germline variant of MLH1 (1835del3), also known as c.1835_1837del and v612del, the pathogenicity of which has not been conclusively determined. MLH1 staining was not seen on immunohistochemical staining of her tumor tissue. The patient experienced a >5-year dramatic response to 4 doses of pembrolizumab. Family studies revealed multiple other relatives with the MLH1 1835del3 variant, as well as multiple relatives with colon cancer. The one relative with colon cancer who underwent genetic testing demonstrated the same variant. Laboratory studies revealed that the patient's tumor showed loss of heterozygosity (LOH) in the MLH1 region, high levels of microsatellite instability, and a high tumor mutational burden. LOH in the MLH1 region, along with the remarkable clinical response to pembrolizumab treatment and the presence of the same MLH1 variant in affected relatives, supports the hypothesis that the MLH1 1835del3 variant is pathogenic. Given the patient's family history, this likely represents an uncommon presentation of Lynch syndrome. Physicians should be alert to evaluate patients for targetable genetic variants even in unlikely clinical situations such as the one described here.

Practice resource-focused revision: Standardized pedigree nomenclature update centered on sex and gender inclusivity: A practice resource of the National Society of Genetic Counselors.

This focused revision builds on the expert opinions from the original publications of 'Recommendations for human standardized pedigree nomenclature' published in 1995 and updated in 2008. Our review of medical publications since 2008 did not identify any fundamental systematic alternative pedigree nomenclature. These findings attest to the relevance of most of the nomenclature with the critical exception of the nomenclature used to denote sex assigned at birth and gender. While we are not recommending the creation of any new pedigree symbols, a major focus of this publication is clarification of the use of symbols and language in the description of the distinction between sex and gender, with a view to ensuring safe and inclusive practice for people who are gender-diverse or transgender. In addition, we recommend modifications to the way that carrier status is depicted. Our goal is to respect individual differences and identities while maintaining biologically, clinically, and genetically meaningful information.

Birds of a Feather? Genetic Counseling, Genetic Testing, and Humanism.

Humanism is a philosophy that emphasizes rational, scientific, and empiric analysis of the world we live in to improve the physical, social, and psychological life of humanity. Although individual genetic counselors may or may not identify as humanists, genetic counseling and genetic testing are primarily humanistic endeavors because they are situated in the context of humanistic medicine in the westernized world. Humanistic goals are also implicit and explicit in the profession and practice of genetic counselors. This review examines the relationship between humanism and genetic counseling, highlighting situations in which the two may be discordant, and suggests ways that genetic counselors can reconcile these discordances.

What have we been trying to do and have we been any good at it? A history of measuring the success of genetic counseling.

Genetic counseling as a formal clinical service was defined in 1947, though the first study of its effectiveness was not published until 1966. This history can be broadly divided in to 3 periods: 1) 1947-1980, when the focus was primarily on prevention of disability, 2) 1981-1995, when the rationales for counseling began to shift and the first studies on the psychosocial effects of genetic counseling started to appear, albeit still largely focused on reproduction, and 3) 1996 - Present, when genetic counselors increased their presence in oncology, cardiology, and other non-reproductive areas of genetic counseling. Changes in outcome measures of genetic counseling have been intertwined with technological advances in genetic testing, better and more sophisticated outcome measures, the growing professional independence and clinical positions of genetic counselors, and the influence of social scientists particularly from behavioral psychology. Despite advances, assessment of the effectiveness of genetic counseling continues is complicated by a lack of widespread agreement about the most appropriate outcome measures as well as research design problems. Broadly speaking though, genetic counseling tends to improve information recall, improve psychological well-being, and is generally well-regarded by patients.

The effect of referral for genetic counseling on genetic testing and surgical prevention in women at high risk for ovarian cancer: Results from a randomized controlled trial.

BACKGROUND: Guidelines recommend genetic counseling and testing for women who have a pedigree suggestive of an inherited susceptibility for ovarian cancer. The authors evaluated the effect of referral to genetic counseling on genetic testing and prophylactic oophorectomy in a randomized controlled trial. METHODS: Data from an electronic mammography reporting system identified 12,919 women with a pedigree that included breast cancer, of whom 625 were identified who had a high risk for inherited susceptibility to ovarian cancer using a risk-assessment questionnaire. Of these, 458 women provided informed consent and were randomized 1:1 to intervention consisting of a genetic counseling referral (n = 228) or standard clinical care (n = 230). RESULTS: Participants were predominantly aged 45 to 65 years, and 30% and 20% reported a personal history of breast cancer or a family history of ovarian cancer, respectively. Eighty-five percent of women in the intervention group participated in a genetic counseling session. Genetic testing was reported by 74 (33%) and 20 (9%) women in the intervention and control arms (P < .005), respectively. Five women in the intervention arm and 2 in the control arm were identified as germline mutation carriers. Ten women in the intervention arm and 3 in the control arm underwent prophylactic bilateral salpingo-oophorectomy (P < .05). CONCLUSIONS: Routine referral of women at high risk for ovarian cancer to genetic counseling promotes genetic testing and prophylactic surgery. The findings from the current randomized controlled trial demonstrate the value of implementing strategies that target women at high risk for ovarian cancer to ensure they are offered access to recommended care. CA Cancer J Clin 2016. © 2016 American Cancer Society, Inc. Cancer 2016;122:3509-3518. © 2016 American Cancer Society.

Cancer Risk Awareness and Concern among Women with a Family History of Breast or Ovarian Cancer.

Women with a documented deleterious mutation in BRCA1 or BRCA2 are at substantially elevated risk for ovarian cancer. To understand what percentage of women with high-risk family histories know their risk is elevated we surveyed 1,885 women with a high- or moderate-risk family history and no personal history of breast or ovarian cancer, and asked about their perceived risk of breast and ovarian cancer. Among high-risk women, fewer than 20% reported use of genetic counseling, and knowledge of elevated risk of ovarian cancer was low. Prior genetic counseling was associated with greater perceived risk for ovarian cancer. Results suggest that most high-risk women (>75%) do not know their risk for ovarian cancer. Identification of potentially high-risk women for referral to genetic counseling may improve informed ovarian cancer risk management.

Prophylactic oophorectomy rates in relation to a guideline update on referral to genetic counseling.

OBJECTIVE: We sought to determine whether prophylactic oophorectomy rates changed after the introduction of a 2007 health plan clinical guideline recommending systematic referral to a genetic counselor for women with a personal or family history suggestive of an inherited susceptibility to breast/ovarian cancer. METHODS: We conducted a retrospective cohort study of female members of Group Health, an integrated delivery system in Washington State. Subjects were women aged ≥ 35 years during 2004-2009 who reported a personal or family history consistent with an inherited susceptibility to breast/ovarian cancer. Personal and family history information was collected on a questionnaire completed when the women had a mammogram. We ascertained oophorectomies from automated claims data and determined whether surgeries were prophylactic by medical chart review. Rates were age-adjusted and age-adjusted incidence rate ratios (IRR) and 95% confidence intervals (CI) were computed using Poisson regression. RESULTS: Prophylactic oophorectomy rates were relatively unchanged after compared to before the guideline change, 1.0 versus 0.8/1000 person-years, (IRR=1.2; 95% CI: 0.7-2.0), whereas bilateral oophorectomy rates for other indications decreased. Genetic counseling receipt rates doubled after the guideline change (95% CI: 1.7-2.4) from 5.1 to 10.2/1000 person-years. During the study, bilateral oophorectomy rates were appreciably greater in women who saw a genetic counselor compared to those who did not regardless of whether they received genetic testing as part of their counseling. CONCLUSION: A doubling in genetic counseling receipt rates lends support to the idea that the guideline issuance contributed to sustained rates of prophylactic oophorectomies in more recent years.

Generation n + 1: Projected numbers of babies born to women with PKU compared to babies with PKU in the United States in 2009.

Newborn PKU screening has been available since the mid-1960s, and the first group of screened babies is now a complete reproductive cohort (age 15-44). Untreated maternal PKU (MPKU) often results in significant developmental and physical disabilities in exposed fetuses, and could potentially offset some or all of the benefits produced by newborn PKU screening and dietary treatment. Based on the age distribution of the United States population in 2009, and using different estimates of PKU frequency (1/10,000; 1/15,000; 1/20,000), the projected number of babies born to women with PKU was compared to the projected number of babies born with PKU. In 2009, there were about 62,000,000 women age 15-44, with a fertility rate of 66.7 births/1,000 women. Of these women, depending on the incidence of PKU, 3,097-6,195 were estimated to have PKU, and they would have delivered 207-413 babies. In that same year, the number of births was 4,118,055, which would have resulted in 206-412 babies with PKU. Thus, in the United States, at all estimates of PKU frequency, the number of babies exposed to MPKU is equal to the number of babies born with PKU. This ratio varies with the fertility rate but is not dependent on the incidence of PKU. The benefits of newborn PKU screening and treatment could be significantly curtailed if adequate resources, education, and funding are not available to follow and monitor women with MPKU and their babies.

Publishing a master's thesis: a guide for novice authors.

Publication of original research, clinical experiences, and critical reviews of literature are vital to the growth of the genetic counseling field, delivery of genetic counseling services, and professional development of genetic counselors. Busy clinical schedules, lack of time and funding, and training that emphasizes clinical skills over research skills may make it difficult for new genetic counselors to turn their thesis projects into publications. This paper summarizes and elaborates upon a presentation aimed at de-mystifying the publishing process given at the 2008 National Society of Genetic Counselors Annual Education Conference. Specific topics include familiarizing prospective authors, particularly genetic counseling students, with the basics of the publication process and related ethical considerations. Former students' experiences with publishing master's theses also are described in hopes of encouraging new genetic counselors to submit for publication papers based on their thesis projects.

Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors.

In 1995, the Pedigree Standardization Task Force (PSTF) of the National Society of Genetic Counselors (NSGC) proposed a system of pedigree nomenclature. Recently, the PSTF (now called the Pedigree Standardization Work Group or PSWG) sought evidence that the published symbols met the needs of health professionals, were incorporated into health professional training and were utilized in publications. We searched PubMed and reference lists of select publications, reviewed the Instructions for Authors of several journals, searched the websites of professional societies, sought comment from the membership of the NSGC, and looked at recommendations and training practices of various health professional organizations. Many journals still do not cite specific standards for pedigrees, but those found cited the PSTF nomenclature. We did not find significant objections or alternatives to the 1995 nomenclature. Based on our review, we propose only a few minor stylistic changes to the pedigree symbols. The pedigree nomenclature of the NSGC is the only consistently acknowledged standard for drawing a family health history. We recommend regular and continued review of these pedigree standards to determine if additional symbols are needed to accommodate changes in clinical practice to ensure that the symbols continue to meet the needs of health professionals and researchers as well as adhere to evolving ethical and privacy standards. All health professionals, trainees, and researchers should be made aware of the utility of using a common pedigree nomenclature in clinical practice and publication. This will become particularly important as electronic medical records become more widely utilized.

Defining and redefining the scope and goals of genetic counseling.

Many definitions of genetic counseling have been proposed since Sheldon Reed first defined the term in 1947. This study reviews selected definitions of genetic counseling including the most recent definition proposed by a committee of the National Society of Genetic Counselors. The analysis focuses on the professional background of who was formulating the definition; the reasons why the definition was created; medical, historical, and social factors; and the definer's implicit or explicit goals of genetic counseling. No definition of genetic counseling is ideal, and any definition can only reflect the values, ethics, goals, and medical practices of the person or group defining the practice of genetic counseling.