Genetic testing for breast and ovarian cancer susceptibility: a family experience

The purpose of this article is to provide an overview of current knowledge concerning genetic testing for breast and ovarian cancer susceptibility. This overview includes 1) a brief history of genetic testing for breast and ovarian cancer susceptibility, 2) a review of factors that midwives and other health care providers need to consider before offering this type of testing to their clients, 3) management options for clients at high risk for hereditary breast and ovarian cancers, and 4) a discussion of preliminary findings from an ongoing study concerning the family experience of genetic testing, which illustrates some of the ethical issues that emerge for individuals and families during the family experience of genetic testing for breast and ovarian cancer susceptibility.     

Population-based genetic testing for Women's cancer prevention

Germline mutations in cancer-susceptibility-genes (CSG) can dramatically increase womens' lifetime risk of ovarian, endometrial, breast and bowel cancers. Identification of unaffected carriers is important to enable proactive engagement with highly effective screening and preventive options to minimise cancer risk. Currently, a family-history model is used to identify individuals with CSGs. Complex regional referral guidelines specify the family-history criteria required before an individual is eligible for genetic-testing. This model is ineffective, resource intense, misses >50% CSG carriers, is associated with underutilisation of genetic-testing services and delays detection of mutation carriers. Although awareness and detection of CSG-carriers has improved, over 97% carriers remain unidentified. This reflects significant missed opportunities for precision-prevention. Population-based genetic-testing (PBGT) represents a novel healthcare strategy with the potential to dramatically improve detection of unaffected CSG-carriers along with enabling population risk-stratification for cancer precision-prevention. Several research studies have assessed the impact, feasibility, acceptability, long-term psychological outcomes and cost-effectiveness of population-based BRCA-testing in the Ashkenazi-Jewish population. Initial data on PBGT in the general-population is beginning to emerge and large implementation studies investigating PBGT in the general-population are needed. This review will summarise the current research into the clinical, psycho-social, health-economic, societal and ethical consequences of a PBGT model for women's cancer precision-prevention.     

不同分子学筛查方法在Lynch综合征相关子宫内膜癌患者中的对比分析#br#

Objective?Compare the accuracy of immunohistochemical staining (IHC), microsatellite instability detection (MSI), and the combined detection of the two in the screening of Lynch Syndrome-related endometrial cancer (LS-EC), and analyze the advantages and disadvantages of actual clinical applications, to identify a routine and reasonable screening strategy. This study also reveals the incidence of LS-EC and the mutations of different mismatch repair (MMR) genes in the Chinese population in this region. Methods?IHC MMR protein detection and MSI detection were performed on the pathological tissues of diagnosed EC patients from the Second Hospital of Jilin University from November 2019 to November 2020, and the preoperative venous blood was subjected to next-generation sequencing (NGS) of Lynch syndrome-related mutations. Results?After NGS testing, 8 cases of LS were confirmed, with an incidence rate of 7.90%. 28 cases had lack of expression of MMR protein, 7 cases were diagnosed as LS, 1 case was missed diagnosis; 13 cases had high microsatellite instability (MSI-H), 3 cases were diagnosed as LS, 5 cases were missed; the combined detection of the two tests can screen out all LS patients. Conclusion?IHC combined with MSI screening is highly sensitive but not cost-effective. IHC alone is recommended as the first clinical screening method.     

A self-administered family history questionnaire improves identification of women who warrant referral to genetic counseling for hereditary cancer risk

Objectives

This study was undertaken to assess a self-administered family history questionnaire in order to better identify women within a gynecologic oncology practice for referral to genetic counseling services.

Methods

Returning patients at an outpatient gynecologic oncology clinic completed a self-administered family health history questionnaire and a detailed telephone interview. A genetic counselor separately assessed blinded information garnered from the questionnaire, structured genetic interview, and electronic medical records to determine whether these data warranted referral to genetic counseling based on established criteria. The structured genetic interview was considered the gold standard to which the questionnaire and medical record information were compared.

Results

Of the 45 total participants in the study, 26 (58%) were identified from the structured genetic interview as meeting criteria for referral to genetic counseling. The questionnaire identified 21 (81%) of these 26 referrals, while the medical record identified 13 (50%) of these 26 referrals. This led to a 62% increase in referral capture by the questionnaire. The median time to complete the questionnaire was 17 min (range 5-57 min). Thirty-four participants (75.6%) had more family members with cancer identified on the questionnaire compared to the electronic medical record. The questionnaire identified fewer family members with cancer in the five cases that were missed for appropriate referral.

Conclusions

Current standard clinical practices are insufficient at identifying patients in need of referral to genetic counseling. A self-administered questionnaire improves recognition of candidates for genetic counseling in a gynecologic oncology practice.     

Contraception in cancer survivors – an expert review Part I. Breast and gynaecological cancers

Objective: The efficacy of treatment for many cancers has increased dramatically in recent decades and there are a growing number of cancer survivors who need effective contraception. In this paper, a group of experts from the European Society of Contraception set out to define the most frequent cancers in women and summarise the guidelines, reviews and studies that provide information and guidance on contraception for each cancer.

Methods: Epidemiological studies were analysed to determine the frequency of cancers in women of reproductive age. A narrative review was performed for each cancer, collecting data about the treatment of the disease, its impact on fertility, and the efficacy, health risks, possible benefits and contraindications of the contraceptive methods available. The recommendations were then summarised.

Results: Owing to a large amount of information, the results are presented in two parts. Part 1 includes contraception after breast and gynaecological cancers. Part 2 summarises the findings and recommendations regarding contraception in women with skin, gastrointestinal, haematological and endocrine cancers.     

The polycystic ovary syndrome and gynecological cancer risk

Abstract

This review updates the knowledge regarding the association between the polycystic ovary syndrome (PCOS) and the risk of gynecological cancer. We performed a literature review of clinical and epidemiological studies concerning PCOS and the risk of breast, endometrial and ovarian cancer after selecting information by quality of scientific methodology. It was found that evidence does not support a link between PCOS and breast cancer risk. There is an increased risk of endometrial cancer, while data concerning ovarian cancer are contradictory. Regarding PCOS and its association to cervical, fallopian tube, and vulvar cancer, the quality of evidence is heterogeneous. In conclusion, women with PCOS should be screened for endometrial cancer and more research is warranted to determine in this population the true risk of developing other gynecological cancers such as breast and ovarian.     

Outcomes of screening endometrial cancer patients for Lynch syndrome by patient-administered checklist

Objective

The aims of this study were to implement a patient-administered checklist designed to identify endometrial cancer patients at elevated risk for Lynch syndrome; measure subsequent genetic counseling and testing; and identify differences between those who attended genetic counseling and those who did not.

Methods

We developed a 4-item yes/no checklist of personal and family history risk factors for Lynch syndrome-associated endometrial cancer and recommended referral for genetic counseling for patients meeting any of the criteria. Retrospective chart review was performed to determine subsequent genetic counseling and testing outcomes over a 15 month period.

Results

6/387 (1.6%) of endometrial cancer patients tested positive for a Lynch syndrome mutation. 4/24 (17%) of endometrial cancer patients who met referral criteria and attended genetic counseling tested positive. 38/70 (55%) of patients who met referral criteria were not seen for genetic counseling. Patients who were diagnosed with endometrial cancer at younger ages, who had primary surgery at our institution, or who met more than one referral criteria were more likely to be seen for genetic counseling.

Conclusions

Endometrial cancer patients who met referral criteria and attended genetic counseling comprised a population enriched for Lynch syndrome. This approach allowed Lynch syndrome evaluation resources to be targeted to a population of patients that is high risk and interested in the information. The referral rate of at-risk patients needs to be improved, and allocating resources towards this goal could increase the identification of Lynch syndrome while avoiding some of the pitfalls of universal screening.     

Treatments for gynaecological cancers

Gynaecological cancers account for a significant amount of morbidity and mortality in the world, with varying incidences and outcomes depending on the country. These malignancies consist of vulval, vaginal, cervical, endometrial, fallopian and ovarian cancers, and account for between 10 and 15% of women's cancers. Although mainly a disease of post-menopausal women, when affecting younger women, fertility-related consequences exist. Therapeutic interventions for gynaecological cancers include surgery, chemotherapy and radiotherapy, with combination modalities often required. The basis for certain therapies are derived from appropriately conducted randomized clinical trial, whereas in some settings, therapy is based on clinical experience and intuition. This review will endeavour to focus on the evidence base, though inevitably, non-evidence based practice is unavoidable.     

Common risk factors of breast and ovarian cancer: recent view

Clinicians, epidemiologists, and public health specialists tend to examine breast and ovarian cancer separately. Although this seems fairly rational and expected, both malignancies are estrogen related and thus share many risk factors. In this review, we investigate the common familial, reproductive, anthropometric, nutritional, and lifestyle risk factors of breast and ovarian cancer. We believe that the parallel examination of the two cancer types could significantly contribute to an improved prevention of "gynecological cancer" as a whole.     

Genetic testing for epithelial ovarian cancer

As the treatment of epithelial ovarian cancer (OC) moves further into personalised medicine, the importance of determining the presence or absence of inherited mutations in cancer susceptibility genes has grown. It is now becoming routine to test for germline mutations in the BRCA1 and BRCA2 genes, which are responsible for a significant proportion of hereditary epithelial OC and are established predictive biomarkers of potential benefit from poly ADP ribose polymerase (PARP) inhibitors. The identification of patients with hereditary OC allows the patient to benefit from personalised treatment, while allowing family members to undergo cascade testing, where identification of unaffected carriers can allow early detection, risk-reduction or prevention for both breast and OC, and ultimately improve long-term outcomes. Other susceptibility genes, include the Lynch Syndrome (mismatch repair) genes and several other genes involved in the homologous recombination pathway (HRD genes), are implicated in OC genesis, and are also becoming of increasing interest as therapeutic options grow for these patients. This review will highlight the importance of the early detection of a germline gene pathogenic variant, which informs on the clinical course of disease in a particular patient, and therefore, guides therapeutic management including risk reducing and personalised treatment.     

Polycystic ovary syndrome and gynecological cancers: Is there a link?

Polycystic ovary syndrome [PCOS] is the most common endocrinopathy of women in reproductive age. An association between PCOS and type-1 endometrial cancer has often been reported in the literature. The prolonged anovulation with consequent continued secretion of estrogen unopposed by progesterone may enhance the development and growth of this malignancy, particularly in young women. Hypersecretion of luteinizing hormone [LH], chronic hyperinsulinemia and increased serum insulin-like growth factor [IGF]-I levels may represent risk factors for endometrial cancer. However, data available in the literature do not allow a meta-analysis to be carried out to calculate an estimate of the relative risk of endometrial cancer in women with PCOS. Anecdotal cases of low-grade endometrial stromal sarcoma and carcinosarcoma have been reported in association with prolonged unopposed estrogen stimulation, and in particular with PCOS. A few studies have addressed the possibility of an association between PCOS and epithelial ovarian cancer risk, and the results are conflicting but generally reassuring, and similarly the few available data appear to exclude a strong association between PCOS and breast cancer.     

Multiple primary malignancies in patients with gynecologic cancer

A retrospective analysis was made of 1044 patients with gynecologic malignancies treated in our department over a 12-year period, in order to review the frequency and types of multiple primary neoplasms. Multiple primary neoplasms were detected in 45 (4.3%) cases, including 16 (2.1%) out of 733 cervical cancers, 14 (8.2%) out of 166 endometrial cancers, three (15%) out of 20 vaginal cancers and 12 (9.8%) out of 123 ovarian cancers. Fifteen cases were synchronous and the remaining 24 cases were heterochronous, with an average 4.9-year interval. The most frequent other site of neoplasm was the breast, particularly in patients with endometrial or ovarian cancer. We conclude that gynecologic malignancies are often associated with primary cancers elsewhere, especially in the breast, stomach, colon and thyroid. A patient presenting with a gynecologic malignancy should be thoroughly examined for a second cancer, as should patients being followed-up after treatment for genital tract cancer.     

Benefits and risks of ovarian function and reproduction for cancer development and prevention

Ovarian function and menstrual cycle disturbances, pregnancy, and reproductive medicine procedures can either increase gynecological cancer risk or prevent cancer development. For ovarian cancer development, there are two hypotheses, which are connected with ovulation and gonadotropin secretion. Most of the ovarian cancers seem to be derived from displaced ovarian surfice epithelial cells. One year of ovulatory cycles increases the ovarian cancer risk by 6%. Ovulation between 22 and 29 years of age causes the highest risk increase per year. In contrast, progesterone or progestins appear to create protection. Lifestyle can affect or modify ovarian cancer risk. Breast cancer risk is very much related to age of menarche and menopause, pregnancy, and breast feeding. All of which are related to ovarian function and progestogenic impact that translates either into breast cancer risk increase or decrease. This is modified by body mass index, physical activity, and lifestyle in general. The risk of endometrial cancer is most closely related to endogenous progesterone during the menstrual cycle and pregnancy or by exogenous progestogens as in oral contraceptives. These effects are progestogen dose and time dependent. Endometrial cancer risk can also be increased by estrogen-producing tumors or long-term estrogen treatment.     

Palliative care in gynaecological oncology

Women with a gynaecological malignancy often suffer significant symptom burden, both physically and psychologically, throughout the course of their disease. Despite advances in treatment, up to 25% of women diagnosed with a gynaecological malignancy will die from recurrent disease. Early palliative care involvement can provide a holistic approach to care with the benefit of improving symptom control and quality of life for both the patient and carer as well as lowering resource utilisation at the end of life. Palliative care can be offered alongside curative or life prolonging treatment as well as at end of life. This article reviews the management of common physical symptoms and complications experienced by patients with advanced gynaecological malignancy.     

Palliative care in gynaecological oncology

Women with a gynaecological malignancy often suffer significant symptom burden, both physically and psychologically, throughout the course of their disease. Despite advances in treatment, up to 25% of women diagnosed with a gynaecological malignancy will die from recurrent disease. Early palliative care involvement provides a holistic approach to care with the benefit of improving symptom control and quality of life for the patient and their carers, as well as lowering resource utilisation at the end of life. Palliative care can be offered alongside curative or life prolonging treatment as well as at end of life. This article reviews the management of common physical symptoms and complications experienced by patients with advanced gynaecological malignancy.     

An NRG Oncology/GOG study of molecular classification for risk prediction in endometrioid endometrial cancer

Objectives

The purpose of this study was to assess the prognostic significance of a simplified, clinically accessible classification system for endometrioid endometrial cancers combining Lynch syndrome screening and molecular risk stratification.

Implications of multigene testing for hereditary breast cancer in primary care

Approximately 1 in 8 women will develop breast cancer during their lifetime and the risk factors include age, family history, and reproductive factors. In women with a family history of breast cancer, there is a proportion in which a gene mutation can be the cause of the predisposition for breast cancer. A careful assessment of family and clinical history should be performed in these women in order to determine if a genetic counseling referral is indicated. In cases of hereditary breast cancer, genetic testing with a multigene panel can identify specific genetic mutations in over 100 genes. The most common genes mutated in hereditary breast cancer are the high-penetrance BRCA1 and BRCA2 genes. In addition, other mutations in high-penetrance genes in familial cancer syndromes and mutations in DNA repair genes can cause hereditary breast cancer. Mutations in low-penetrance genes and variants of uncertain significance may play a role in breast cancer development, but the magnitude and scope of risk in these cases remain unclear, thus the clinical utility of testing for these mutations is uncertain. In women with high-penetrance genetic mutations or lifetime risk of breast cancer > 20%, risk-reducing interventions, such as intensive screening, surgery, and chemoprevention, can decrease the incidence and mortality of breast cancer.