Improving cascade genetic testing for families with inherited pancreatic cancer (PDAC) risk: The genetic education, risk assessment and testing (GENERATE) study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS4162-TPS4162
Author(s):  
Matthew B. Yurgelun ◽  
C. Sloane Furniss ◽  
Barbara Kenner ◽  
Alison Klein ◽  
Catherine C. Lafferty ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Cancer Susceptibility ◽  
Genetic Counselor ◽  
Cancer Worry ◽  
Genetic Education ◽  
Degree Relative ◽  
Cascade Testing ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Germline Testing

TPS4162 Background: 4-10% of PDAC patients harbor pathogenic germline variants in cancer susceptibility genes, including APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, and TP53. For families with such pathogenic variants, the greatest potential impact of germline testing is to identify relatives with the same pathogenic variant (cascade testing), thereby providing the opportunity for early detection and cancer interception of PDAC and other associated malignancies. Numerous factors limit cascade testing in real-world practice, including family dynamics, widespread geographic distribution of relatives, access to genetic services, and misconceptions about the importance of germline testing, such that the preventive benefits of cascade testing are often not fully realized. The primary aim of this study is to analyze two alternative strategies for cascade testing in families with inherited PDAC susceptibility. Methods: 1000 individuals (from approximately 200 families) with a confirmed pathogenic germline variant in any of the above genes in a 1st/2nd degree relative and a 1st/2nd degree relative with PDAC will be remotely enrolled through the study website (www.generatestudy.org) and randomized between two different methods of cascade testing (individuals with prior genetic testing will be ineligible): Arm 1 will undergo pre-test genetic education with a pre-recorded video and live interactive session with a genetic counselor via a web-based telemedicine platform (Doxy.me), followed by germline testing through Color Genomics; Arm 2 will undergo germline testing through Color Genomics without dedicated pre-test genetic education. Color Genomics will disclose results to study personnel and directly to participants in both arms. Participants in both arms will have the option of pursuing additional telephone-based genetic counseling through Color Genomics. The primary outcome will be uptake of cascade testing. Secondary outcomes will include participant self-reported genetic knowledge, cancer worry, distress, decisional preparedness, familial communication, and screening uptake, which will be measured via longitudinal surveys. Enrollment will begin February, 2019. Clinical trial information: NCT03762590.

Improving cascade genetic testing for families with inherited pancreatic cancer (PDAC) risk: The GENetic Education, Risk Assessment and TEsting (GENERATE) study.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. TPS779-TPS779
Author(s):  
Matthew B. Yurgelun ◽  
Chinedu I. Ukaegbu ◽  
C. Sloane Furniss ◽  
Barbara Kenner ◽  
Alison Klein ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Cancer Susceptibility ◽  
Genetic Counselor ◽  
Cancer Worry ◽  
Genetic Education ◽  
Degree Relative ◽  
Cascade Testing ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Germline Testing

TPS779 Background: 4-10% of PDAC patients harbor pathogenic germline variants in cancer susceptibility genes, including APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, and TP53. For families with such pathogenic variants, the greatest potential impact of germline testing is to identify relatives with the same variant (cascade testing), thereby providing the opportunity for early detection and interception of PDAC and other associated cancers. Numerous factors limit cascade testing in real-world practice, including family dynamics, widespread geographic distribution of relatives, access to genetic services, and misconceptions about the importance of germline testing, such that the preventive benefits of cascade testing are often not fully realized. The primary aim of this study is to analyze two alternative strategies for cascade testing in families with inherited PDAC risk. Methods: 1000 individuals with a confirmed pathogenic germline variant in any of the above genes in a 1st/2nd degree relative and a 1st/2nd degree relative with PDAC will be remotely enrolled through the study website (www.GENERATEstudy.org) and randomized between two methods of cascade testing (individuals with prior genetic testing will be ineligible): Arm 1 will undergo pre-test genetic education with a pre-recorded video and live interactive session with a genetic counselor via a web-based telemedicine platform (Doxy.me), followed by germline testing through Color Genomics; Arm 2 will undergo germline testing through Color Genomics without dedicated pre-test genetic education. Color Genomics will disclose results to study personnel and directly to participants in both arms. All participants will have the option of pursuing additional telephone-based genetic counseling through Color Genomics. The primary outcome will be uptake of cascade testing. Secondary outcomes will include self-reported genetic knowledge, cancer worry, distress, decisional preparedness, familial communication, and screening uptake, which will be measured via longitudinal surveys. Enrollment is underway nationwide as of May, 2019. Clinical trial information: NCT03762590.

scholarly journals Germline and Somatic Tumor Testing in Epithelial Ovarian Cancer: ASCO Guideline

2020 ◽  
Vol 38 (11) ◽  
pp. 1222-1245 ◽  
Author(s):  
Panagiotis A. Konstantinopoulos ◽  
Barbara Norquist ◽  
Christina Lacchetti ◽  
Deborah Armstrong ◽  
Rachel N. Grisham ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Genetic Testing ◽  
Epithelial Ovarian Cancer ◽  
Health Care Providers ◽  
Systematic Reviews ◽  
Clinical Decision Making ◽  
Cancer Susceptibility ◽  
Care Providers ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes

PURPOSE To provide recommendations on genetic and tumor testing for women diagnosed with epithelial ovarian cancer based on available evidence and expert consensus. METHODS A literature search and prospectively defined study selection criteria sought systematic reviews, meta-analyses, randomized controlled trials (RCTs), and comparative observational studies published from 2007 through 2019. Guideline recommendations were based on the review of the evidence. RESULTS The systematic review identified 19 eligible studies. The evidence consisted of systematic reviews of observational data, consensus guidelines, and RCTs. RECOMMENDATIONS All women diagnosed with epithelial ovarian cancer should have germline genetic testing for BRCA1/2 and other ovarian cancer susceptibility genes. In women who do not carry a germline pathogenic or likely pathogenic BRCA1/2 variant, somatic tumor testing for BRCA1/2 pathogenic or likely pathogenic variants should be performed. Women with identified germline or somatic pathogenic or likely pathogenic variants in BRCA1/2 genes should be offered treatments that are US Food and Drug Administration (FDA) approved in the upfront and the recurrent setting. Women diagnosed with clear cell, endometrioid, or mucinous ovarian cancer should be offered somatic tumor testing for mismatch repair deficiency (dMMR). Women with identified dMMR should be offered FDA-approved treatment based on these results. Genetic evaluations should be conducted in conjunction with health care providers familiar with the diagnosis and management of hereditary cancer. First- or second-degree blood relatives of a patient with ovarian cancer with a known germline pathogenic cancer susceptibility gene variant should be offered individualized genetic risk evaluation, counseling, and genetic testing. Clinical decision making should not be made based on a variant of uncertain significance. Women with epithelial ovarian cancer should have testing at the time of diagnosis.

Breast cancer treatment according to pathogenic variants in cancer susceptibility genes in a population-based cohort.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 560-560 ◽  
Author(s):  
Allison W. Kurian ◽  
Kevin C. Ward ◽  
Paul Abrahamse ◽  
Ann S Hamilton ◽  
Dennis Deapen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
Genetic Test ◽  
Cancer Susceptibility ◽  
Population Based ◽  
Susceptibility Genes ◽  
Breast Cancer Treatment ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
To Receive

560 Background: Increasing use of germline genetic testing may have unintended consequences on breast cancer treatment. We do not know whether treatment deviates from guidelines for women with pathogenic variants (PV) in cancer susceptibility genes. Methods: SEER data for all women aged ≥20 years, diagnosed with breast cancer in 2014-15 and reported to Georgia and California registries (N = 77,588) by December 1, 2016 were linked to germline genetic testing results from 4 laboratories that did nearly all clinical testing. We examined first course of therapy (before recurrence or progression) of stage < IV patients who linked to a genetic test: bilateral mastectomy (BLM) in candidates for surgery (unilateral, stages 0-III); post-lumpectomy radiation in those with an indication (all but age ≥70, stage I, hormone receptor (HR)-positive and HER2-negative); and chemotherapy in those without a definitive indication (stage I-II, HR-positive, HER2-negative and 21-gene recurrence score < 30). We report the percent treated based on multivariable modeling, adjusted for age, race, stage, grade, insurance and socioeconomic status. Results: The table shows that 9% of patients who linked to a genetic test result had a PV (N = 1,283). Compared to women with negative results,women with BRCA1/2 PVs were more likely to receive BLM, more likely to receive chemotherapy without definitive indication, and less likely to receive indicated radiation in their first course of therapy. Lower-magnitude effects were seen with other PVs but not variants of uncertain significance (VUS). Conclusions: In a population-based setting, women with PVs in BRCA1/2 or other cancer susceptibility genes may have a higher risk of receiving locoregional and systemic treatment that does not follow guidelines. [Table: see text]

scholarly journals Cascading After Peridiagnostic Cancer Genetic Testing: An Alternative to Population-Based Screening

2020 ◽  
Vol 38 (13) ◽  
pp. 1398-1408 ◽  
Author(s):  
Kenneth Offit ◽  
Kaitlyn A. Tkachuk ◽  
Zsofia K. Stadler ◽  
Michael F. Walsh ◽  
Hector Diaz-Zabala ◽  
...  
Keyword(s):  
United States ◽  
Genetic Testing ◽  
Family Size ◽  
Cancer Susceptibility ◽  
The United States ◽  
Susceptibility Genes ◽  
Cancer Genetic ◽  
Patients With Cancer ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes

PURPOSE Despite advances in DNA sequencing technology and expanded medical guidelines, the vast majority of individuals carrying pathogenic variants of common cancer susceptibility genes have yet to be identified. An alternative to population-wide genetic screening of healthy individuals would exploit the trend for genetic testing at the time of cancer diagnosis to guide therapy and prevention, combined with augmented familial diffusion or “cascade” of genomic risk information. METHODS Using a multiple linear regression model, we derived the time interval to detect an estimated 3.9 million individuals in the United States with a pathogenic variant in 1 of 18 cancer susceptibility genes. We analyzed the impact of the proportion of incident patients sequenced, varying observed frequencies of pathogenic germline variants in patients with cancer, differential rates of diffusion of genetic information in families, and family size. RESULTS The time to detect inherited cancer predisposing variants in the population is affected by the extent of cascade to first-, second-, and third-degree relatives (FDR, SDR, TDR, respectively), family size, prevalence of mutations in patients with cancer, and the proportion of patients with cancer sequenced. In a representative scenario, assuming a 7% prevalence of pathogenic variants across cancer types, an average family size of 3 per generation, and 15% of incident patients with cancer in the United States undergoing germline testing, the time to detect all 3.9 million individuals with pathogenic variants in 18 cancer susceptibility genes would be 46.2, 22.3, 13.6, and 9.9 years if 10%, 25%, 50%, and 70%, respectively, of all FDR, SDR, and TDR were tested for familial mutations. CONCLUSION Peridiagnostic and cascade cancer genetic testing offers an alternative strategy to achieve population-wide identification of cancer susceptibility mutations.

scholarly journals Pathogenic Variants in Less Familiar Cancer Susceptibility Genes: What Happens After Genetic Testing?

2018 ◽  
pp. 1-10
Author(s):  
Evan T. Hall ◽  
Divya Parikh ◽  
Jennifer L. Caswell-Jin ◽  
Tanya Gupta ◽  
Meredith A. Mills ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Lynch Syndrome ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Susceptibility Genes ◽  
Pathogenic Variant ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Risk Reducing

Purpose As genetic testing expands, patients are increasingly found to carry pathogenic variants in cancer susceptibility genes that are less familiar to most clinicians, specifically genes other than those causing hereditary breast ovarian cancer syndrome ( BRCA1 and BRCA2) and Lynch syndrome. Little is known about the subsequent behaviors of such patients in terms of managing cancer risks and informing relatives. Methods All adult patients who were counseled and tested at the Stanford Cancer Genetics Clinic from January 2013 to July 2015 and had a pathogenic variant in a non- BRCA1/2, non–Lynch syndrome gene were invited to participate in a telephone interview about adherence to risk-reducing recommendations, genetic testing by relatives, and new cancer incidence. Results Fifty-seven (40%) of 142 eligible patients were successfully contacted, and all 57 patients participated; median follow-up was 677 days (range, 247 to 1,401 days). Most patients (82%; 95% CI, 70% to 90%) recalled that a risk-reducing intervention (screening, medication, or surgery) was recommended, and most patients (85%; 95% CI, 72% to 93%) adhered to the recommendation. Nearly all patients (91%; 95% CI, 81% to 97%) shared results with relatives, and most patients (78%; 95% CI, 64% to 88%) reported that a relative was subsequently tested. During the follow-up period, 9% of patients (95% CI, 3% to 19%) developed second cancers, and in 14% of patients (95% CI, 7% to 26%), a first-degree relative developed cancer, some of which were detected by recommended screening. Conclusion Patients with a pathogenic variant in a less familiar cancer susceptibility gene report high adherence to risk-reducing interventions. Furthermore, in the 57 carriers and subsequently tested relatives with two years of follow-up, a total of three cancers (one in a proband and two in relatives) were detected through interventions recommended on the basis of the pathogenic variant. These results suggest a potential benefit of genetic counseling and testing for pathogenic variants in less familiar genes.

Adherence to breast cancer treatment guidelines according to pathogenic variants in cancer susceptibility genes in a population-based cohort.

2019 ◽  
Vol 37 (27_suppl) ◽  
pp. 34-34
Author(s):  
Steven J. Katz ◽  
Monica Morrow ◽  
Allison W. Kurian
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
Genetic Test ◽  
Cancer Susceptibility ◽  
Population Based ◽  
Susceptibility Genes ◽  
Breast Cancer Treatment ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
To Receive

34 Background: Increasing use of germline genetic testing may have unintended consequences on breast cancer treatment. We do not know whether treatment deviates from guidelines for women with pathogenic variants (PV) in cancer susceptibility genes. Methods: SEER data for all women aged ≥20 years, diagnosed with breast cancer in 2014-15 and reported to Georgia and California registries (N=77,588) by December 1, 2016 were linked to germline genetic testing results from 4 laboratories that did nearly all clinical testing. We examined first course of therapy of stage <IV patients who linked to a genetic test: bilateral mastectomy (BLM) in candidates for surgery (unilateral, stages 0-III); post-lumpectomy radiation in those with an indication (all but age ≥70, stage I, hormone receptor (HR)-positive and HER2-negative); and chemotherapy in those without definitive indication (stage I-II, HR-positive, HER2-negative and 21-gene recurrence score <30). We report the percent treated based on multivariable modeling, adjusted for age, race, stage, grade, insurance and socioeconomic status. Results: The table shows that 9% of patients who linked to a genetic test result had a PV (N=1,283). Compared to women with negative results, those with BRCA1/2 PVs were more likely to receive BLM, more likely to receive chemotherapy without definitive indication, and less likely to receive indicated radiation as initial treatment. Lower-magnitude effects were seen with other PVs but not variants of uncertain significance (VUS). Conclusions: In a population-based setting, women with PVs in BRCA1/2 or other cancer susceptibility genes may have higher risk of receiving locoregional and systemic treatment that does not follow guidelines. [Table: see text]

scholarly journals Returning Individual Genetic Research Results to Research Participants: Uptake and Outcomes Among Patients With Breast Cancer

2018 ◽  
pp. 1-24 ◽  
Author(s):  
Angela R. Bradbury ◽  
Linda Patrick-Miller ◽  
Brian L. Egleston ◽  
Kara N. Maxwell ◽  
Laura DiGiovanni ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Susceptibility ◽  
Genetic Counselor ◽  
Genetic Research ◽  
Informed Choice ◽  
Multiple Primary Cancers ◽  
Research Results ◽  
Cancer Susceptibility Genes ◽  
Cancer Multiple ◽  
To Receive

Purpose Understanding the outcomes of returning individual genetic research results to participants is critical because some genetic variants are found to be associated with health outcomes and have become available for clinical testing. Materials and Methods BRCA1/2-negative women with early-onset breast cancer, multiple primary cancers, or a family history of breast cancer who participated in a gene discovery cancer registry were offered the opportunity to learn their individual genetic research results of 24 breast cancer susceptibility genes with a genetic counselor after predisclosure genetic counseling. Outcomes included uptake of research results, knowledge, informed choice, psychosocial adjustment, uncertainty, satisfaction, and uptake of clinical confirmation testing. Results Four hundred two potential participants were contacted. One hundred ninety-four participants (48%) did not respond despite multiple attempts, and 85 participants (21%) actively or passively declined. One hundred seven participants (27%) elected for predisclosure counseling and were more likely to be younger, married, and white. Ninety percent of participants who had predisclosure counseling elected to receive their genetic research results, and 89% made an informed choice. Knowledge increased significantly after predisclosure counseling, and anxiety, intrusive cancer-specific distress, uncertainty, and depression declined significantly after receipt of results. General anxiety and intrusive cancer-specific distress declined significantly for both participants with a positive result and those with a negative result. Sixty-four percent of participants had clinical confirmation testing when recommended, including all participants with a mutation in a high-penetrance gene. Conclusion Uptake of genetic research results may be lower than anticipated by hypothetical reports and small select studies. Participants who elected to receive research results with genetic providers did not experience increases in distress or uncertainty, but not all patients return for confirmation testing.

scholarly journals Prevalence of Pathogenic Variants in Cancer Susceptibility Genes Among Women With Postmenopausal Breast Cancer

JAMA ◽  
2020 ◽  
Vol 323 (10) ◽  
pp. 995 ◽  
Author(s):  
Allison W. Kurian ◽  
Ryan Bernhisel ◽  
Katie Larson ◽  
Jennifer L. Caswell-Jin ◽  
Aladdin H. Shadyab ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Susceptibility ◽  
Postmenopausal Breast Cancer ◽  
Susceptibility Genes ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes

Management of germline findings revealed throughout the course of tumor-normal whole genome sequencing in oncology.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13113-e13113
Author(s):  
Howard John Lim ◽  
Kasmintan A Schrader ◽  
Sean Young ◽  
Jessica Nelson ◽  
Alexandra Fok ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Susceptibility Genes ◽  
Genomic Research ◽  
Whole Genome ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes

e13113 Background: The Personalized OncoGenomics (POG) project at the BC Cancer Agency utilizes tumor-normal whole genome sequencing (WGS) to understand key driver pathways and guide personalized treatment decisions. Analysis of the germline data can reveal variants; these may be presumed pathogenic, presumed benign or of unknown significance (VUS). We have developed a process for evaluating and returning presumed pathogenic variants in known cancer susceptibility genes to patients, for counseling and validation in a clinical-accredited laboratory. Methods: Patients receive germline cancer related information as part of the consent process for participation in the POG program. A sub-committee comprised of medical geneticists, bioinformaticians, pathologists, oncologists and an ethicist review the germline results. Any variants suspicious of being an artifact undergo a technical validation step. Presumed pathogenic findings of known cancer susceptibility genes are returned to the patient by their treating oncologist and patients are referred to the Hereditary Cancer Program (HCP), for genetic counseling and clinical confirmation. Results: From June 2012 - January 2017 – 466 patients have consented to the project. To date, 39 cases (8.4%) had at least one variant that was deemed pathogenic, 86 cases had at least one VUS in a known cancer susceptibility gene. 11 out of 23 cases (47.8%) with high penetrance mutations were already known to HCP. All VUS were reviewed by the sub-committee taking in to consideration the VUS and clinical context. 8 of the subjects with pathogenic results and 3 with VUS were known to HCP before POG data was generated. A VUS in 7 cases (1.5%) was returned after review. Conclusions: The number of pathogenic variants in known cancer susceptibility genes is consistent with published oncology results. We created a process to manage clinically relevant germline findings discovered during the course of genomic research to ensure appropriate care for patients. Genetic counseling within HCP and validation of variants in the clinically accredited Cancer Genetics Laboratory enables seamless return of research generated clinically relevant germline results to affected subjects. Clinical trial information: NCT02155621.

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