Genetic counseling and testing in endometrial cancer: Are we capturing high-risk women?

1503 Background: Lynch syndrome accounts for the majority of inherited endometrial cancers and the identification of probands presents a unique opportunity to treat and prevent multiple cancers. This is now even more relevant with the potential of novel immunotherapy agents for women with germline mutations. The diagnosis of endometrial cancer (EC) can provide the indication for women with specific risk factors to undergo genetic testing (GT). We sought to evaluate genetic counseling referrals (GCR) and subsequent GT rates. Methods: All women with EC between 2012 and 2015 were identified. Statistical analyses were performed to evaluate risk factors including age, body mass index (BMI), positive family history defined as two or more family members with Lynch-related cancers, and tumor mismatch repair (MMR) protein expression loss. Results: A total of 447 women were diagnosed with EC and of these, 107 (24%) were given GCR by their gynecologic oncologist based on their discretion. Compared to non-GCR, GCR women were significantly younger (median 54 vs 65, p < 0.0001) and had lower BMI (median 28.2 vs 30.8, p= 0.007). Of the 107 GCR women, 71 (66%) underwent GT. Of the 71 GT women, 8 (11%) were found to have a germline mutation in one of the MMR genes. Table 1 lists GCR, GT and positive germline mutations among specific high-risk cohorts. Of these cohorts, 56% under 50 years of age, 28% with family history, and 61% with loss of tumor MMR proteins had GCR. Conclusions: Many young, thin EC women with a family history or a tumor MMR deficiency are not given GCR. Among GCR women, 66% underwent GT, despite there being a high rate of germline mutations among these women. It is imperative that high-risk women receive GCR with subsequent GT to capture the maximum number with Lynch syndrome to screen and prevent additional cancers as well as enable cascade testing in family members. Facilitated pathways may be helpful in increasing GCR, as well as GT in EC women. [Table: see text]

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Screening for Lynch syndrome in unselected women with endometrial cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.5508 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 5508-5508

Author(s):

Sarah E. Ferguson ◽

Melyssa Aronson ◽

Lua R Eiriksson ◽

Golnessa Mojtahedi ◽

Aaron Pollett ◽

...

Keyword(s):

Endometrial Cancer ◽

Family History ◽

High Risk ◽

Lynch Syndrome ◽

Germline Mutation ◽

Mutation Testing ◽

Low Grade ◽

Newly Diagnosed ◽

Mutation Status ◽

Family History Questionnaire

5508 Background: Endometrial cancer (EC) is often the sentinel cancer in women with Lynch Syndrome (LS) however it is often not recognized in this population. A prospective cohort study comparing family history, immunohistochemistry (IHC) for mismatch repair (MMR) proteins, and tumour morphology to germline mutation status in MMR genes was performed in unselected women with EC to determine which screening strategy was superior in identifying women with LS. Methods: All women with newly diagnosed EC between July 2010 and June 2011 were asked to participate in the prospective screening protocol for LS which included completing an extended family history questionnaire (eFHQ), tumor assessment for LS-associated morphologic features and IHC as well as germline mutation testing. Results: 119 (n = 182, 65%) consented to the study. The median age was 61 (26-91), 96 (81%) stage I, and 42 (35%) had high risk histology. There were 6 (7.4%, n = 81) women that were germline mutation positive (MLH1 N=3; MSH6 n = 2; MSH2 n =1), representing a mutation positive rate of at least 5% in this cohort (6/119). All 3 MLH1 mutation positive women had low grade histology while mutations in MSH2/6 were exclusively found in women with high risk histology. Two of the six mutation positive women were not identified by family history. Mutation positivity was higher in women under age 50 (23%; 5/22) compared to women > age 50 (1%; 1/97)( (p = 0.0008). LS-morphologic features were found in 58 (59%, n = 98) women. The sensitivity, specificity, PPV and NPV of the LS-associated features in predicting LS mutation status was 100%, 42.6%, 7.9% and 100% compared to IHC which was 100%, 76%, 18% and 100% and eFHQ which was 67%, 84%, 27%, 97%. Conclusions: In this unselected population of women with newly diagnosed EC the germline mutation rate for LS was 2-3 times that has previously been reported. Previously described LS-associated morphologic features were not specific to germline mutation status and family history missed one third of women with LS. IHC was the best strategy to identify women with EC who should undergo germline mutation testing.

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Importance of genetic counseling referrals for high-risk women with endometrial cancer despite intact mismatch repair immunohistochemistry.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.15_suppl.1537 ◽

2018 ◽

Vol 36 (15_suppl) ◽

pp. 1537-1537

Author(s):

Jessica Lee ◽

Allison L Brodsky ◽

Deanna Gerber ◽

Julia Fehniger ◽

Shabnam Asgari ◽

...

Keyword(s):

Endometrial Cancer ◽

Genetic Counseling ◽

High Risk ◽

Mismatch Repair ◽

High Risk Women

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P.02.21 EARLY- ONSET ENDOMETRIAL CANCER PATIENTS ARE AT HIGH RISK FOR LYNCH SYNDROME REGARDLESS OF FAMILY HISTORY

Digestive and Liver Disease ◽

10.1016/s1590-8658(19)30306-8 ◽

2019 ◽

Vol 51 ◽

pp. e156-e157

Author(s):

L. Sanchez Mete ◽

G. Vocaturo ◽

A. Martayan ◽

B. Casini ◽

M. Diodoro ◽

...

Keyword(s):

Endometrial Cancer ◽

Family History ◽

High Risk ◽

Lynch Syndrome ◽

Cancer Patients ◽

Early Onset

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Prediction of Preeclampsia and Delivery of Small for Gestational Age Babies Based on a Combination of Clinical Risk Factors in High-Risk Women

Hypertension in Pregnancy ◽

10.3109/10641955.2010.486460 ◽

2010 ◽

Vol 30 (1) ◽

pp. 58-73 ◽

Cited By ~ 11

Author(s):

Paul T. Seed ◽

Lucy C. Chappell ◽

Michael A. Black ◽

Katrina K. Poppe ◽

Yuan-Chun Hwang ◽

...

Keyword(s):

Risk Factors ◽

High Risk ◽

Gestational Age ◽

Small For Gestational Age ◽

Clinical Risk Factors ◽

High Risk Women ◽

Clinical Risk

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Cancer Previvors in an Active Duty Service Women Population: An Opportunity for Prevention and Increased Force Readiness

Military Medicine ◽

10.1093/milmed/usaa485 ◽

2020 ◽

Author(s):

Leann A Lovejoy ◽

Clesson E Turner ◽

Craig D Shriver ◽

Rachel E Ellsworth

Keyword(s):

Genetic Testing ◽

Family History ◽

High Risk ◽

Cancer Predisposition ◽

Clinical Genetic ◽

High Risk Women ◽

Clinical Genetic Testing ◽

Pathogenic Mutations ◽

History Of ◽

Risk Reducing

Abstract Background The majority of active duty service women (ADS) are young, have access to healthcare, and meet fitness standards set by the U.S. military, suggesting that ADS represent a healthy population at low risk of cancer. Breast cancer is, however, the most common cancer in ADS and may have a significant effect on troop readiness with lengthy absence during treatment and inability to return to duty after the treatment. The identification of unaffected ADS who carry germline mutations in cancer predisposition genes (“previvors”) would provide the opportunity to prevent or detect cancer at an early stage, thus minimizing effects on troop readiness. In this study, we determined (1) how many high-risk ADS without cancer pursued genetic testing, (2) how many previvors employed risk-reducing strategies, and (3) the number of undiagnosed previvors within an ADS population. Methods The Clinical Breast Care Project (protocol WRNMMC IRB #20704) database of the Murtha Cancer Center/Walter Reed National Military Medical Center was queried to identify all ADS with no current or previous history of cancer. Classification as high genetic risk was calculated using National Comprehensive Cancer Network 2019 guidelines for genetic testing for breast, ovary, colon, and gastric cancer. The history of clinical genetic testing and risk-reducing strategies was extracted from the database. Genomic DNA from ADS with blood specimens available for research purposes were subjected to next-generation sequencing technologies using a cancer predisposition gene panel. Results Of the 336 cancer-free ADS enrolled in the Clinical Breast Care Project, 77 had a family history that met National Comprehensive Cancer Network criteria for genetic testing for BRCA1/2 and 2 had a family history of colon cancer meeting the criteria for genetic testing for Lynch syndrome. Of the 28 (35%) high-risk women who underwent clinical genetic testing, 11 had pathogenic mutations in the breast cancer genes BRCA1 (n = 5), BRCA2 (n = 5), or CHEK2 (n = 1). Five of the six ADS who had a relative with a known pathogenic mutation were carriers of the tested mutation. All of the women who had pathogenic mutations detected through clinical genetic testing underwent prophylactic double mastectomy, and three also had risk-reducing salpingo-oophorectomy. Two (6%) of the 33 high-risk ADS tested only in the research setting had a family history of breast/ovarian cancer and carried pathogenic mutations: one carried a BRCA2 mutation, whereas the other carried a mutation in the colon cancer predisposition gene PMS2. No mutations were detected in the 177 low-risk women tested in the research setting. Discussion Within this unaffected cohort of ADS, 23% were classified as high risk. Although all of the previvors engaged in risk-reduction strategies, only one-third of the high-risk women sought genetic testing. These data suggest that detailed family histories of cancer should be collected in ADS and genetic testing should be encouraged in those at high risk. The identification of previvors and concomitant use of risk-reduction strategies may improve health in the ADS and optimize military readiness by decreasing cancer incidence.

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Study of risk factors and its correlation with constraint induced movement therapy for atherosclerosis in patients of coronary artery disease and their offspring

International Journal of Advances in Medicine ◽

10.18203/2349-3933.ijam20200656 ◽

2020 ◽

Vol 7 (3) ◽

pp. 446

Author(s):

Venugopal Margekar ◽

Shweta Thakur ◽

O. P. Jatav ◽

Pankaj Yadav

Keyword(s):

Risk Factors ◽

Family History ◽

Positive Family History ◽

Surrogate Marker ◽

Control Group ◽

Medical College ◽

Constraint Induced Movement Therapy ◽

Group Data ◽

History Of ◽

Artery Disease

Background: A significant percent of cardiovascular event occurs without well-known modifiable risk. A new tool for early identification for atherosclerosis is required for early intervention. Aims and objectives of the study was to study the risk factors for CAD and its correlation with CIMT.Methods: One hundred and forty subjects were studied for the risk factors of CAD in Department of Medicine of G.R. Medical College, Gwalior from 2012 to 2013. Out of 140 subjects, 100 were patients having CAD and 40 age matched subjects were included as control group. Data was also recorded from their offspring. High resolution B mode ultrasonography was performed to assess CIMT of carotid arteries. The maximum CIMT of any one side of carotid artery was taken for study.Results: CAD was more prevalent among males (78%). Majority of the offspring of cases had age between 28-42 years and majority were male (73%). Most common risk factors for CAD was dyslipidemia (48%), hypertension (24%), diabetes (12%) and smoking (21%), whereas in offspring’s of CAD patients, dyslipidemia was seen in 28%, hypertension in 3%, diabetes and tobacco smoking in 12% and 24% respectively. The CIMT of CAD patients was significantly increased with increasing the number of risk factors and the same pattern was also seen in controls. The CIMT of asymptomatic offspring’s having positive family history was significantly more than the asymptomatic offspring without positive family history of CAD.Conclusions: CIMT measurements can be used as a surrogate marker of atherosclerosis as it has showed a direct link with number of risk factors of CAD.

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Effects of Systematic Referral to Genetic Counseling in High-Risk Women With and Without a College Degree

Journal of Patient-Centered Research and Reviews ◽

10.17294/2330-0698.1330 ◽

2016 ◽

Vol 3 (3) ◽

pp. 193

Author(s):

Sarah Knerr ◽

M. Robyn Andersen ◽

Charles W Drescher ◽

Robert Resta ◽

Michelle Hager ◽

...

Keyword(s):

Genetic Counseling ◽

High Risk ◽

College Degree ◽

High Risk Women

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Parkinson’s disease determinants, prediction and gene–environment interactions in the UK Biobank

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2020-323646 ◽

2020 ◽

Vol 91 (10) ◽

pp. 1046-1054 ◽

Cited By ~ 2

Author(s):

Benjamin Meir Jacobs ◽

Daniel Belete ◽

Jonathan Bestwick ◽

Cornelis Blauwendraat ◽

Sara Bandres-Ciga ◽

...

Keyword(s):

Risk Factors ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Family History ◽

Genetic Risk ◽

Positive Family History ◽

Risk Scores ◽

Uk Biobank ◽

Gene Environment ◽

History Of

ObjectiveTo systematically investigate the association of environmental risk factors and prodromal features with incident Parkinson’s disease (PD) diagnosis and the interaction of genetic risk with these factors. To evaluate whether existing risk prediction algorithms are improved by the inclusion of genetic risk scores.MethodsWe identified individuals with an incident diagnosis of PD (n=1276) and controls (n=500 406) in UK Biobank. We determined the association of risk factors with incident PD using adjusted logistic regression models. We constructed polygenic risk scores (PRSs) using external weights and selected the best PRS from a subset of the cohort (30%). The PRS was used in a separate testing set (70%) to examine gene–environment interactions and compare predictive models for PD.ResultsStrong evidence of association (false discovery rate <0.05) was found between PD and a positive family history of PD, a positive family history of dementia, non-smoking, low alcohol consumption, depression, daytime somnolence, epilepsy and earlier menarche. Individuals with the highest 10% of PRSs had increased risk of PD (OR 3.37, 95% CI 2.41 to 4.70) compared with the lowest risk decile. A higher PRS was associated with earlier age at PD diagnosis and inclusion of the PRS in the PREDICT-PD algorithm led to a modest improvement in model performance. We found evidence of an interaction between the PRS and diabetes.InterpretationHere, we used UK Biobank data to reproduce several well-known associations with PD, to demonstrate the validity of a PRS and to demonstrate a novel gene–environment interaction, whereby the effect of diabetes on PD risk appears to depend on background genetic risk for PD.

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Male Breast Cancer: Surgical and Genetic Features and a Multidisciplinary Management Strategy

Breast Care ◽

10.1159/000501711 ◽

2019 ◽

Vol 15 (1) ◽

pp. 14-21 ◽

Cited By ~ 1

Author(s):

Francesca Pellini ◽

Eleonora Granuzzo ◽

Silvia Urbani ◽

Sara Mirandola ◽

Marina Caldana ◽

...

Keyword(s):

Breast Cancer ◽

Family History ◽

High Risk ◽

Male Breast Cancer ◽

Brca2 Mutation ◽

Positive Family History ◽

Male Breast ◽

Mutation Carriers ◽

History Of ◽

Clinical Records

Background: Male breast cancer (MBC) is a rare disease with a rising incidence trend. The major risk factors related to MBC are a positive family history of breast cancer (BC) and BRCA1/2 mutations, which indicate a relevant genetic role. Methods: In this retrospective series, we enrolled 69 male patients presenting with male breast cancer (MBC) between 01/01/1992 and 31/12/2018, and 26 high-risk not-affected men presenting between 01/01/2016 and 31/12/2018. Participants’ electronic clinical records were reviewed. Patients’ data reported age at diagnosis, tumor characteristics, therapeutic management, and BRCA1/2 status as well as a family history of breast, ovarian, or prostate cancer (PCa) in first-degree relatives. Results: We analyzed 69 MBC patients. Median age was 64 years. The majority of tumors diagnosed were of an early TNM stage. The most frequent histological subtype was invasive ductal carcinoma (76.7%). Hormone receptors were positive in >90% of MBC cases. Nearly all patients underwent modified radical mastectomy or total mastectomy. Adjuvant endocrine therapy was delivered in 59.4%. Among MBC-affected patients, we recorded a high percentage of a positive family history of BC. Mutational analysis for the BRCA1/2 genes was performed in 17 MBC patients; 11.8% were carriers of BRCA2 pathogenic mutations. Among 26 healthy high-risk subjects included in this case series, 4 were BRCA1 mutation carriers and 9 were BRCA2 mutation carriers. Discussion: We evaluated the distribution of clinicopathological characteristics in MBC subjects and assessed the frequency of mutations in the BRCA genes in affected patients and healthy high-risk subjects, with the aim of proposing a surveillance program for BC and PCa.

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