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Article ; Online: Release of reclassified VUS results of now deceased patients to family members: Practices and opinions.

Lascurain, Seth / Thull, Darcy / Durst, Andrea / Bear, Todd / Mai, Phuong L

2024

Abstract: Variants of uncertain significance (VUS) are commonly identified in genetic testing. The rate at which a VUS is reclassified depends on multiple factors. However, as the amount of time it might take for a VUS to be reclassified varies, some patients with ...

Abstract	Variants of uncertain significance (VUS) are commonly identified in genetic testing. The rate at which a VUS is reclassified depends on multiple factors. However, as the amount of time it might take for a VUS to be reclassified varies, some patients with a VUS genetic testing result might have passed away before the VUS is reclassified. A VUS that is reclassified after the patient's death has clinical implications for the deceased patient's family members. The disclosure of reclassified VUS results for a deceased patient has complex legal and ethical implications. There are no established guidelines on how the reclassified VUS result for a deceased patient should be disclosed to at-risk relatives. An online survey was sent to members of the National Society of Genetic Counselors (NSGCs) to elicit practices and opinions regarding this issue. A total of 153 (4%) NSGC members completed the survey. Thirty-seven (24.2%) respondents reported having received a reclassified VUS for a deceased patient. Respondents were more likely to attempt disclosure if the variant was reclassified as pathogenic (93.5%) versus benign (76.5%), although the difference did not reach statistical significance (p = 0.06). Respondents more often reported the impact on family members (85.5%) than the decedent's right to privacy (15.0%) as extremely important when considering disclosure to family members. A legal mechanism to allow disclosure to relatives was supported by 70.6% of respondents and 97.4% felt the issue was important enough to pursue if such a process was in place. Only 9.8% of respondents supported a legal requirement of consent before disclosing to family members when a VUS is reclassified after the patient has passed away. Our results indicate that there is no consensus for how these results should be handled and a mechanism for disclosure of reclassified results to family members is supported.
Language	English
Publishing date	2024-01-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	1117799-8
ISSN	1573-3599 ; 1059-7700
ISSN (online)	1573-3599
ISSN	1059-7700
DOI	10.1002/jgc4.1848
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Article ; Online: Timely cancer genetic counseling and testing for young women with breast cancer: impact on surgical decision-making for contralateral risk-reducing mastectomy.

Dettwyler, Shenin A / Thull, Darcy L / McAuliffe, Priscilla F / Steiman, Jennifer G / Johnson, Ronald R / Diego, Emilia J / Mai, Phuong L

Breast cancer research and treatment

2022 Volume 194, Issue 2, Page(s) 393–401

Abstract: Purpose: Genetic testing (GT) can identify individuals with pathogenic/likely pathogenic variants (PV/LPVs) in breast cancer (BC) predisposition genes, who may consider contralateral risk-reducing mastectomy (CRRM). We report on CRRM rates in young ... ...

Abstract	Purpose: Genetic testing (GT) can identify individuals with pathogenic/likely pathogenic variants (PV/LPVs) in breast cancer (BC) predisposition genes, who may consider contralateral risk-reducing mastectomy (CRRM). We report on CRRM rates in young women newly diagnosed with BC who received GT through a multidisciplinary clinic. Methods: Clinical data were reviewed for patients seen between November 2014 and June 2019. Patients with non-metastatic, unilateral BC diagnosed at age ≤ 45 and completed GT prior to surgery were included. Associations between surgical intervention and age, BC stage, family history, and GT results were evaluated. Results: Of the 194 patients, 30 (15.5%) had a PV/LPV in a BC predisposition gene (ATM, BRCA1, BRCA2, CHEK2, NBN, NF1), with 66.7% in BRCA1 or BRCA2. Of 164 (84.5%) uninformative results, 132 (68%) were negative and 32 (16.5%) were variants of uncertain significance (VUS). Overall, 67 (34.5%) had CRRM, including 25/30 (83.3%) PV/LPV carriers and 42/164 (25.6%) non-carriers. A positive test result (p < 0.01) and significant family history were associated with CRRM (p = 0.02). For the 164 with uninformative results, multivariate analysis showed that CRRM was not associated with age (p = 0.23), a VUS, (p = 0.08), family history (p = 0.10), or BC stage (p = 0.11). Conclusion: In this cohort of young women with BC, the identification of a PV/LPV in a BC predisposition gene and a significant family history were associated with the decision to pursue CRRM. Thus, incorporation of genetic services in the initial evaluation of young patients with a new BC could contribute to the surgical decision-making process.
MeSH term(s)	BRCA1 Protein/genetics ; Breast Neoplasms/diagnosis ; Breast Neoplasms/genetics ; Breast Neoplasms/surgery ; Female ; Genes, BRCA2 ; Genetic Counseling ; Genetic Predisposition to Disease ; Genetic Testing ; Humans ; Mastectomy
Chemical Substances	BRCA1 Protein
Language	English
Publishing date	2022-05-21
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	604563-7
ISSN	1573-7217 ; 0167-6806
ISSN (online)	1573-7217
ISSN	0167-6806
DOI	10.1007/s10549-022-06619-y
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Zs.A 1655: Show issues

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Article ; Online: Knowledge and opinions regarding BRCA1 and BRCA2 genetic testing among primary care physicians.

Dekanek, Erin W / Thull, Darcy L / Massart, Mylynda / Grubs, Robin E / Rajkovic, Aleksander / Mai, Phuong L

Journal of genetic counseling

2019 Volume 29, Issue 1, Page(s) 122–130

Abstract: BRCA1 and BRCA2 (BRCA1/2) testing is standard for individuals with personal and/or family history suggestive of hereditary breast and ovarian cancer syndrome. The indications for testing have been expanding. To accommodate the need, incorporation of ... ...

Abstract	BRCA1 and BRCA2 (BRCA1/2) testing is standard for individuals with personal and/or family history suggestive of hereditary breast and ovarian cancer syndrome. The indications for testing have been expanding. To accommodate the need, incorporation of cancer genetic services into the practice of non-genetic healthcare providers should be considered. We carried out a survey to evaluate the knowledge and opinions regarding BRCA1/2 testing among primary care providers. The survey was sent to 245 Obstetrics/Gynecology and 97 Family Medicine physicians in the UPMC network. Eighty-six completed the survey between July 2015 and September 2015. The average correct responses to knowledge questions was 73%. A few respondents reported being completely confident, and ~50% reported being somewhat confident, in providing BRCA1/2-related information. Respondents selected genetic specialists and oncologists as the most qualified to provide cancer genetic services. Several perceived barriers and motivating factors to the implementation of BRCA1/2 testing in primary care were identified. The findings from this study suggested that primary care providers were not uniformly ready to provide BRCA1/2 genetic testing. Availability of professional society guidelines and evidence of testing's usefulness might motivate the incorporation of BRCA1/2 genetic testing into primary care practices. These findings would help guide future educational efforts to promote provision of cancer genetic services by non-genetic professionals.
MeSH term(s)	Adult ; Attitude of Health Personnel ; Breast Neoplasms/genetics ; Female ; Genes, BRCA1 ; Genes, BRCA2 ; Genetic Predisposition to Disease ; Genetic Testing ; Humans ; Middle Aged ; Physicians, Primary Care/psychology ; Surveys and Questionnaires
Language	English
Publishing date	2019-11-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	1117799-8
ISSN	1573-3599 ; 1059-7700
ISSN (online)	1573-3599
ISSN	1059-7700
DOI	10.1002/jgc4.1189
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Article: Partner and Localizer of BRCA-2 (PALB-2) Mutation Analysis Is Rapidly Being Adopted into Clinical Practice.

Erel, Serap / Thull, Darcy L / Soran, Atilla

The journal of breast health

2014 Volume 10, Issue 4, Page(s) 189

Language	English
Publishing date	2014-10-01
Publishing country	Turkey
Document type	Journal Article
ISSN	1306-0945
ISSN	1306-0945
DOI	10.5152/tjbh.2014.0079
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Article ; Online: Personalising therapy for early-stage oestrogen receptor-positive breast cancer in older women.

Carleton, Neil / Nasrazadani, Azadeh / Gade, Kristine / Beriwal, Sushil / Barry, Parul N / Brufsky, Adam M / Bhargava, Rohit / Berg, Wendie A / Zuley, Margarita L / van Londen, G J / Marroquin, Oscar C / Thull, Darcy L / Mai, Phuong L / Diego, Emilia J / Lotze, Michael T / Oesterreich, Steffi / McAuliffe, Priscilla F / Lee, Adrian V

The lancet. Healthy longevity

2022 Volume 3, Issue 1, Page(s) e54–e66

Abstract: Age is one of the most important risk factors for the development of breast cancer. Nearly a third of all breast cancer cases occur in older women (aged ≥70 years), with most cases being oestrogen receptor-positive (ER+). Such tumours are often indolent ... ...

Abstract	Age is one of the most important risk factors for the development of breast cancer. Nearly a third of all breast cancer cases occur in older women (aged ≥70 years), with most cases being oestrogen receptor-positive (ER+). Such tumours are often indolent and unlikely to be the ultimate cause of death for older women, particularly when considering other comorbidities. This Review focuses on unique clinical considerations for screening, detection, and treatment regimens for older women who develop ER+ breast cancers-specifically, we focus on recent trends for de-implementation of screening, staging, surgery, and adjuvant therapies along the continuum of care. Additionally, we also review emerging basic and translational research that will further uncover the unique underlying biology of these tumours, which develop in the context of systemic age-related inflammation and changing hormone profiles. With prevailing trends of clinical de-implementation, new insights into mechanistic biology might provide an opportunity for precision medicine approaches to treat patients with well tolerated, low-toxicity agents to extend patients' lives with a higher quality of life, prevent tumour recurrences, and reduce cancer-related burdens.
MeSH term(s)	Aged ; Breast Neoplasms ; Combined Modality Therapy ; Female ; Humans ; Neoplasm Recurrence, Local ; Quality of Life ; Receptors, Estrogen
Chemical Substances	Receptors, Estrogen
Language	English
Publishing date	2022-01-05
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ISSN	2666-7568
ISSN (online)	2666-7568
DOI	10.1016/s2666-7568(21)00280-4
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Article: Recognition and management of hereditary breast cancer syndromes.

Thull, Darcy L / Vogel, Victor G

The oncologist

2004 Volume 9, Issue 1, Page(s) 13–24

Abstract: Clinicians should recognize the genetic syndromes that predispose to the development of breast cancer so that patients may be afforded the opportunity to have genetic testing to assist them and their family members in making medical management decisions. ...

Abstract	Clinicians should recognize the genetic syndromes that predispose to the development of breast cancer so that patients may be afforded the opportunity to have genetic testing to assist them and their family members in making medical management decisions. Approximately 80%-90% of hereditary breast cancer cases are caused by mutations in the BRCA1 and BRCA2 genes. Other important clinical genetic predispositions include Cowden syndrome, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, and ataxia-telangiectasia. The key to identifying women who are at risk for a hereditary breast cancer lies in obtaining an adequate, three-generation family history, including ethnic background. For unaffected women, breast cancer risks can be estimated using the quantitative models of Gail and Claus, but there are limitations to these models. Other quantitative models predict the likelihood that a patient is carrying a mutated gene. Genetic testing is available at selected laboratories for each of the hereditary syndromes described, and there are three possible outcomes to testing. These outcomes and their management implications are described in detail. Clinical management options for women at high risk for breast cancer include surveillance, chemoprevention, and prophylactic surgery. Application of these principles can reduce morbidity in women with genetic predispositions to breast cancer.
MeSH term(s)	Anticarcinogenic Agents/therapeutic use ; Breast Neoplasms/diagnosis ; Breast Neoplasms/genetics ; Breast Neoplasms/prevention & control ; Breast Neoplasms/surgery ; Chemoprevention ; Female ; Genes, BRCA1 ; Genes, BRCA2 ; Genetic Predisposition to Disease ; Humans ; Mastectomy ; Ovariectomy ; Risk Assessment ; Tamoxifen/therapeutic use
Chemical Substances	Anticarcinogenic Agents ; Tamoxifen (094ZI81Y45)
Language	English
Publishing date	2004-02-13
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S. ; Review
ZDB-ID	1409038-7
ISSN	1083-7159
ISSN	1083-7159
DOI	10.1634/theoncologist.9-1-13
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Article ; Online: Personalising therapy for early-stage oestrogen receptor-positive breast cancer in older women

Neil Carleton, BS / Azadeh Nasrazadani, MD / Kristine Gade, MD / Sushil Beriwal, MD / Parul N Barry, MD / Adam M Brufsky, ProfMD / Rohit Bhargava, ProfMD / Wendie A Berg, ProfMD / Margarita L Zuley, ProfMD / G J van Londen, MD / Oscar C Marroquin, MD / Darcy L Thull, MS / Phuong L Mai, MD / Emilia J Diego, MD / Michael T Lotze, ProfMD / Steffi Oesterreich, ProfPhD / Priscilla F McAuliffe, MD / Adrian V Lee, ProfPhD

The Lancet. Healthy Longevity, Vol 3, Iss 1, Pp e54-e

2022 Volume 66

Abstract: Summary: Age is one of the most important risk factors for the development of breast cancer. Nearly a third of all breast cancer cases occur in older women (aged ≥70 years), with most cases being oestrogen receptor-positive (ER+). Such tumours are often ... ...

Abstract	Summary: Age is one of the most important risk factors for the development of breast cancer. Nearly a third of all breast cancer cases occur in older women (aged ≥70 years), with most cases being oestrogen receptor-positive (ER+). Such tumours are often indolent and unlikely to be the ultimate cause of death for older women, particularly when considering other comorbidities. This Review focuses on unique clinical considerations for screening, detection, and treatment regimens for older women who develop ER+ breast cancers—specifically, we focus on recent trends for de-implementation of screening, staging, surgery, and adjuvant therapies along the continuum of care. Additionally, we also review emerging basic and translational research that will further uncover the unique underlying biology of these tumours, which develop in the context of systemic age-related inflammation and changing hormone profiles. With prevailing trends of clinical de-implementation, new insights into mechanistic biology might provide an opportunity for precision medicine approaches to treat patients with well tolerated, low-toxicity agents to extend patients’ lives with a higher quality of life, prevent tumour recurrences, and reduce cancer-related burdens.
Keywords	Geriatrics ; RC952-954.6 ; Medicine ; R
Subject code	610 ; 616
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A multidisciplinary clinic for individualizing management of patients at increased risk for breast and gynecologic cancer.

Engel, Natalie J / Gordon, Patricia / Thull, Darcy L / Dudley, Beth / Herstine, Judy / Jankowitz, Rachel C / Zorn, Kristin K

Familial cancer

2012 Volume 11, Issue 3, Page(s) 419–427

Abstract: Increasing awareness of the hereditary component of breast and ovarian cancer has driven interest in creating clinics for the patient population at high risk for these cancers. Identifying adequate space and appropriate staff, coordinating multiple ... ...

Abstract	Increasing awareness of the hereditary component of breast and ovarian cancer has driven interest in creating clinics for the patient population at high risk for these cancers. Identifying adequate space and appropriate staff, coordinating multiple providers' schedules, establishing referral criteria, and addressing billing and reimbursement concerns are just some of the issues that are involved in the creation of a multidisciplinary high risk breast and ovarian cancer program. We provide an overview of the clinic structure at the Magee-Womens Hospital High Risk Breast and Ovarian Cancer Program (HRBOCP), which was created in 2002 due to recognition of a need for a more coordinated model of providing care for women at increased risk for breast and ovarian cancer. The goals of the HRBOCP are to evaluate women at high risk for breast and ovarian cancer and to organize their clinical care in a multidisciplinary setting staffed by experts in the field; to provide updates on new data regarding screening recommendations, prevention options, and risk factors pertinent to an individual's cancer risk; to provide ongoing support to patients and to coordinate family communication when appropriate; and to facilitate enrollment in appropriate research studies and registries.
MeSH term(s)	Age Factors ; Breast Neoplasms/diagnosis ; Breast Neoplasms/genetics ; Female ; Genetic Counseling ; Genetic Predisposition to Disease ; Humans ; Outpatient Clinics, Hospital/organization & administration ; Ovarian Neoplasms/diagnosis ; Ovarian Neoplasms/genetics ; Pennsylvania ; Precision Medicine ; Risk Factors ; Workforce
Language	English
Publishing date	2012-05-29
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1502496-9
ISSN	1573-7292 ; 1389-9600
ISSN (online)	1573-7292
ISSN	1389-9600
DOI	10.1007/s10689-012-9530-x
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Zs.A 6099: Show issues

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Article ; Online: Long-term outcomes, branch-specific expressivity, and disease-related mortality in von Hippel-Lindau type 2A.

Nielsen, Sarah M / Rubinstein, Wendy S / Thull, Darcy L / Armstrong, Michaele J / Feingold, Eleanor / Yip, Linwah / Tisherman, Samuel A / Carty, Sally E

Familial cancer

2011 Volume 10, Issue 4, Page(s) 701–707

Abstract: Although a large kindred with familial pheochromocytoma (Pheo) and paraganglioma (PGL) was discovered in 1962 and later found to represent von Hippel-Lindau (VHL) type 2A (mutation Y112H), the phenotype lacks current characterization. Branch-specific ... ...

Abstract	Although a large kindred with familial pheochromocytoma (Pheo) and paraganglioma (PGL) was discovered in 1962 and later found to represent von Hippel-Lindau (VHL) type 2A (mutation Y112H), the phenotype lacks current characterization. Branch-specific expressivity was suspected based on oral family history. Family pedigree analysis, prospective interviews, and extensive record review were used to extend the pedigree, determine phenotype, examine branch-specific expression, and analyze mortality rates over 5 decades. In its 3 known affected branches the kindred now comprises 107 people with or at-risk for VHL, of whom 49 have been diagnosed and 35/49 (71%) are clinically affected. Phenotypic cumulative lifetime risk was 71% for Pheo/PGL, 15% for hemangioblastoma, 33% for retinal angioma, 3% for renal cell carcinoma, and 3% for pancreatic cysts. The mean ages for VHL and Pheo/PGL diagnosis were younger in successive generations. Branch II-4 predominately expressed RA, while branch II-5 predominantly expressed Pheo/PGL. Disease-specific mortality occurred early and was less frequent in successive generations. This analysis of Y112H VHL confirms a high cumulative risk for pheochromocytoma/paraganglioma. Over time, both age at diagnosis and disease-specific mortality have decreased. The observed branch-specific expressivity prompts further study of genetic and environmental disease modifiers in this large family.
MeSH term(s)	Adrenal Gland Neoplasms/genetics ; Age of Onset ; Female ; Humans ; Longitudinal Studies ; Male ; Neoplastic Syndromes, Hereditary ; Paraganglioma/genetics ; Paraganglioma/mortality ; Pedigree ; Phenotype ; Pheochromocytoma/genetics ; Pheochromocytoma/mortality ; Tumor Suppressor Proteins ; United States ; Von Hippel-Lindau Tumor Suppressor Protein ; von Hippel-Lindau Disease/genetics ; von Hippel-Lindau Disease/mortality
Chemical Substances	Tumor Suppressor Proteins ; Von Hippel-Lindau Tumor Suppressor Protein (EC 2.3.2.27)
Language	English
Publishing date	2011-06-29
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1502496-9
ISSN	1573-7292 ; 1389-9600
ISSN (online)	1573-7292
ISSN	1389-9600
DOI	10.1007/s10689-011-9465-7
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Article ; Online: Genotype-phenotype correlations of pheochromocytoma in two large von Hippel-Lindau (VHL) type 2A kindreds with different missense mutations.

Nielsen, Sarah M / Rubinstein, Wendy S / Thull, Darcy L / Armstrong, Michaele J / Feingold, Eleanor / Stang, Michael T / Gnarra, James R / Carty, Sally E

American journal of medical genetics. Part A

2010 Volume 155A, Issue 1, Page(s) 168–173

Abstract: Von Hippel-Lindau (VHL) disease type 2A is an inherited tumor syndrome characterized by predisposition to pheochromocytoma (pheo), retinal hemangioma (RA), and central nervous system hemangioblastoma (HB). Specific VHL subtypes display genotype-phenotype ...

Abstract	Von Hippel-Lindau (VHL) disease type 2A is an inherited tumor syndrome characterized by predisposition to pheochromocytoma (pheo), retinal hemangioma (RA), and central nervous system hemangioblastoma (HB). Specific VHL subtypes display genotype-phenotype correlations but, unlike other familial syndromes such as MEN-2, the phenotype in VHL has not yet been stratified at the codon level. Over decades, we have managed two very large VHL type 2A regional kindreds with nearly adjacent but distinct VHL missense mutations. We determined the phenotype of Family 2 and compared the clinical and pathologic parameters of pheo between 30 members of Family 1 (Y112H mutation) and 33 members of Family 2 (Y98H mutation) with mean follow-up of 15.5 and 12.1 years, respectively (P = 0.24). In Family 2, pheo was the most frequent VHL manifestation (79%) and all pheo diagnoses occurred by age 50. Age at first diagnosis was younger in Family 2 than in Family 1 (mean 19.7 vs. 28.8 years; P = 0.02). Pheo expressivity differed by genotype: Family 1 pheo was more likely to be multifocal (P = 0.04), as well as malignant (P < 0.01) and lethal (P = 0.02). Family 1 pheo was also more likely to secrete vanillylmandelic acid (VMA) alone (P = 0.05). This analysis of 130 pheochromocytomas in 63 VHL type 2A patients demonstrates that mutation-specific malignancy and expression patterns exist within the VHL type 2A subtype, and provides information that may help tailor the screening and management algorithms of affected members and those at risk.
MeSH term(s)	Adrenal Gland Neoplasms/genetics ; Age Factors ; Family ; Female ; Genotype ; Humans ; Magnetic Resonance Imaging ; Male ; Mutation, Missense/genetics ; Pedigree ; Penetrance ; Phenotype ; Pheochromocytoma/genetics ; Survival Analysis ; Von Hippel-Lindau Tumor Suppressor Protein/genetics ; von Hippel-Lindau Disease/genetics
Chemical Substances	Von Hippel-Lindau Tumor Suppressor Protein (EC 2.3.2.27) ; VHL protein, human (EC 6.3.2.-)
Language	English
Publishing date	2010-11-30
Publishing country	United States
Document type	Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2108614-X
ISSN	1552-4833 ; 0148-7299 ; 1552-4825
ISSN (online)	1552-4833
ISSN	0148-7299 ; 1552-4825
DOI	10.1002/ajmg.a.33760
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