NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines

Editor—Anderson-Fabry disease (AFD) is a sphingolipid storage disorder resulting from the deficiency of the lysosomal enzyme α-galactosidase. Unlike most other lysosomal diseases, the inheritance is X linked. Disease manifestations in female heterozygotes have been reported, but are considered to be rare and usually mild.1 Asymptomatic corneal dystrophy (cornea verticillata and posterior lenticular cataract) is present in about 70% and is useful for heterozygote detection. About 30% of women have minimal angiokeratomas and <10% have infrequent attacks of neuropathic pains.1 However, female heterozygotes with severe and early cerebrovascular disease, strokes, and renal failure have been documented, but these serious manifestations were estimated to occur in only 1%.1 Because this is an X linked disorder, these severe manifestations in females were explained by skewed X inactivation.2 

Case reports are open to selection bias and there are no reported data on the frequency and severity of AFD manifestations in a large cohort of carriers. Women are not usually evaluated in the clinic unless they present with serious AFD complications, but they do attend for genetic counselling when their son or male relative is diagnosed with the disease.

During regular reviews of AFD families in the genetic clinic, we have observed multiple and more frequent AFD manifestations in female carriers than expected. Owing to the lack of clinical data and present health care policy, we were unable to perform clinical investigations. Therefore, a large cohort study using an AFD specific questionnaire was performed to establish the mortality and the frequency of all AFD manifestations in obligate carrier females.

All known (n=80) obligate carrier females, who were over the age of 18 and had demographic data recorded in the AFD register, were asked to participate in this study. Sixty (75%) agreed and provided data; non-responders were reminded on one …

Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females

Background An age-related progression from C-cell hyperplasia to medullary thyroid carcinoma is associated with various germ-line mutations in the rearranged during transfection (RET) proto-oncogene that could be used to identify the optimal time for prophylactic surgery. Methods In this European multicenter study conducted from July 1993 to February 2001, we enrolled patients who had a RET point mutation in the germ line, were 20 years of age or younger, were asymptomatic, and had undergone total thyroidectomy after confirmation of the RET mutation. Exclusion criteria were medullary thyroid carcinomas of more than 10 mm in greatest dimension and distant metastasis. Results Altogether, 207 patients from 145 families were identified. There was a significant age-related progression from C-cell hyperplasia to medullary thyroid carcinoma and, ultimately, nodal metastasis in patients whose RET mutations were grouped according to the extracellular- and intracellular-domain codons affected and in those with the ...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa012915

Early malignant progression of hereditary medullary thyroid cancer.

https://cyberleninka.org/article/n/777302.pdf

Sherloc: a comprehensive refinement of the ACMG–AMP variant classification criteria

Cardiovascular disease (CVD) remains the leading cause of mortality in women, yet many people perceive breast cancer to be the number one threat to women’s health. CVD and breast cancer have several overlapping risk factors, such as obesity and smoking. Additionally, current breast cancer treatments can have a negative impact on cardiovascular health (eg, left ventricular dysfunction, accelerated CVD), and for women with pre-existing CVD, this might influence cancer treatment decisions by both the patient and the provider. Improvements in early detection and treatment of breast cancer have led to an increasing number of breast cancer survivors who are at risk of long-term cardiac complications from cancer treatments. For older women, CVD poses a greater mortality threat than breast cancer itself. This is the first scientific statement from the American Heart Association on CVD and breast cancer. This document will provide a comprehensive overview of the prevalence of these diseases, shared risk factors, the cardiotoxic effects of therapy, and the prevention and treatment of CVD in breast cancer patients.

Cardiovascular Disease and Breast Cancer: Where These Entities Intersect: A Scientific Statement From the American Heart Association.

Updated from their original publication in 2004, these cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of counseling at-risk individuals through genetic cancer risk assessment with or without genetic testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors Familial Cancer Risk Counseling Special Interest Group. The information contained in this document is derived from extensive review of the current literature on cancer genetic risk assessment and counseling as well as the personal expertise of genetic counselors specializing in cancer genetics. The recommendations are intended to provide information about the process of genetic counseling and risk assessment for hereditary cancer disorders rather than specific information about individual syndromes. Essential components include the intake, cancer risk assessment, genetic testing for an inherited cancer syndrome, informed consent, disclosure of genetic test results, and psychosocial assessment. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. These recommendations do not displace a health care provider’s professional judgment based on the clinical circumstances of a client.

https://www.onlinelibrary.wiley.com/doi/epdf/10.1007/s10897-011-9462-x

Essential Elements of Genetic Cancer Risk Assessment, Counseling, and Testing: Updated Recommendations of the National Society of Genetic Counselors

Hereditary breast and ovarian cancer due to mutations in BRCA1 and BRCA2

Clinical characteristics BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome (HBOC) is characterized by an increased risk for female and male breast cancer, ovarian cancer (includes fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate cancer, pancreatic cancer, and melanoma primarily in individuals with a BRCA2 pathogenic variant. The exact cancer risks differ slightly depending on whether HBOC is caused by a BRCA1 or BRCA2 pathogenic variant. Diagnosis/testing The diagnosis of BRCA1 and BRCA2 HBOC is established in a proband by identification of a heterozygous germline pathogenic variant in BRCA1 or BRCA2 on molecular genetic testing. Management Treatment of manifestations: National Comprehensive Cancer Network guidelines suggest that women with a BRCA1/2 pathogenic variant could consider bilateral mastectomy as a primary surgical treatment of breast cancer because of their elevated rate of ipsilateral and contralateral breast cancer. Treatment of ovarian and other cancers in individuals with a BRCA1/2 pathogenic variant is similar to that for sporadic cancers. Prevention of primary manifestations: Prophylactic bilateral mastectomy, prophylactic oophorectomy, and chemoprevention (e.g., tamoxifen) have been used for breast cancer prevention, but have not been assessed by randomized trials in high-risk women. Prophylactic oophorectomy for ovarian cancer prevention. Surveillance: Breast cancer screening in women relies on a combination of monthly breast self-examination, annual or semiannual clinical breast examination, annual mammography, and breast MRI. Annual transvaginal ultrasound and CA-125 concentration beginning at age 35 years may be considered for ovarian cancer screening. However, this screening has not been effective in detecting early-stage ovarian cancer, either in high-risk or average-risk women. For men, breast cancer screening includes breast self-examination education and training and annual clinical breast examination beginning at age 35. Annual prostate cancer screening should begin at age 45. Screening for melanoma should be individualized based on the family history. Screening of asymptomatic individuals for pancreatic cancer is not generally recommended. Evaluation of relatives at risk: Once a cancer-predisposing BRCA1 or BRCA2 germline pathogenic variant has been identified in a family, testing of at-risk relatives can identify those family members who also have the familial pathogenic variant and thus need increased surveillance and early intervention when a cancer is identified. Genetic counseling Germline pathogenic variants in BRCA1 and BRCA2 are inherited in an autosomal dominant manner. The vast majority of individuals with a BRCA1 or BRCA2 pathogenic variant have inherited it from a parent. However, because of incomplete penetrance, variable age of cancer development, cancer risk reduction resulting from prophylactic surgery, or early death, not all individuals with a BRCA1 or BRCA2 pathogenic variant have a parent affected with cancer. Offspring of an individual with a BRCA1 or BRCA2 germline pathogenic variant have a 50% chance of inheriting the variant. Prenatal testing is possible for a pregnancy at increased risk if the cancer-predisposing variant in the family is known; however, requests for prenatal testing for adult-onset diseases are uncommon and require careful genetic counseling.

BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer

Breast cancer is a significant cause of morbidity and mortality in the United States. Although breast cancer is more common among White American (WA) women, incidence rates are higher among young African American (AA) women. Approximately 5-10% of all breast cancer can be accounted for by germline mutations in the breast cancer (BRCA)1 and BRCA2 genes responsible for hereditary breast and ovarian cancer (HBOC) syndrome. Although genetic counseling (GC) and genetic testing (GT) for HBOC have become widely accepted by the WA population, cancer genetic services are underused among AA. Many investigators have evaluated a wide spectrum of BRCA1 and BRCA2 mutations in the AA and African population with the possible identification of African founder mutations. Barriers to GC and GT include lack of knowledge and/or negative attitudes regarding genetics and genetics research, and concerns regarding the potential for racial discrimination. It is important for future research to focus on ways in which to eliminate barriers to GC and GT to alleviate disparity in the use of genetic services among high-risk AA women.

Nancie Petrucelli

Papers

Essential Elements of Genetic Cancer Risk Assessment, Counseling, and Testing: Updated Recommendations of the National Society of Genetic Counselors

Hereditary breast and ovarian cancer due to mutations in BRCA1 and BRCA2

BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer

Hereditary breast and ovarian cancer syndrome : the impact of race on uptake of genetic counseling and testing.

BRCA1 and BRCA2 Hereditary Breast and Ovarian Cancer