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  • 1
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    Comprehensive germline panel testing across cancer types: Diagnostic yield and clinical utility in 100,000 patient dataset.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. e13013-e13013
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. e13013-e13013
    Abstract: e13013 Background: Over 608,000 patients with ovarian, breast, pancreatic, prostate and colorectal cancer are diagnosed each year. NCCN guidelines recommend offering germline genetic testing to all patients with ovarian and pancreatic cancer, and patients with prostate and breast cancer who meet specific criteria. We present data from ~113,000 patients who were tested on a comprehensive multigene panel and compare the diagnostic yield and clinical actionability with that of a limited gene panel strategy. Methods: We analyzed de-identified sequence data for 83 cancer-risk genes in patients with breast, ovarian, prostate and pancreatic cancer referred for germline genetic testing. Positive rates for a minimal gene panel for the respective indication were computed and compared to the positive rates when the comprehensive 83 gene panel was analyzed. Results: Four percent of 103,428 patients with breast, ovarian, pancreatic and prostate cancer harbored a BRCA1 or BRCA2 germline mutation including: breast 3.7%, ovarian 8.2%, prostate 5.2% and pancreatic 4.2%. When the comprehensive panel is applied, the overall diagnostic yield for all 113,107 patients increased to 16%. Excluding mono-allelic P/LP variants in recessive cancer-risk genes (e.g. MUTYH) reduces the diagnostic yield to 13%. Stratified by cancer type, and removing mono-allelic recessives, positive yield was: breast 11.8%, ovarian 18%, prostate 15%, and pancreatic 16%. Conclusions: These data show that comprehensive panel testing in patients with a broad range of cancers more than doubles the diagnostic yield, providing actionable results for an additional 9,737 per 113,107 patients tested. Potential germline-based clinical actionability for these patients includes: 1) pan-cancer eligibility for PARP inhibitor clinical trials, 2) FDA approved PD1 blockade for advanced cancer of ANY type and a molecular diagnosis of Lynch syndrome, 3) cascade family variant testing.This study suggests that genetic testing guidelines should be expanded to include recommendations supporting multigene panel testing in patients with cancer to improve the care of patients and their family members.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.e13013
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 2
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    Genetic Testing to Inform Epilepsy Treatment Management From an International Study of Clinical Practice
    American Medical Association (AMA) ; 2022
    In:  JAMA Neurology Vol. 79, No. 12 ( 2022-12-01), p. 1267-
    Details
    In: JAMA Neurology, American Medical Association (AMA), Vol. 79, No. 12 ( 2022-12-01), p. 1267-
    Abstract: It is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes. Objective To evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes. Design, Setting, and Participants This was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals. Exposures Genetic test results. Main Outcomes and Measures Clinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms. Results Among 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595 (368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%] ), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%] ), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584 [365] days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%] ), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%] ). No clinical management changes were reported for 178 patients (42.6%). Conclusions and Relevance Results of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes.
    Type of Medium: Online Resource
    ISSN: 2168-6149
    URL: Article
    DOI: 10.1001/jamaneurol.2022.3651
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2022
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  • 3
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    Germline Pathogenic Variant Prevalence Among Latin American and US Hispanic Individuals Undergoing Testing for Hereditary Breast and Ovarian Cancer: A Cross-Sectional Study
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  JCO Global Oncology , No. 8 ( 2022-07)
    Details
    In: JCO Global Oncology, American Society of Clinical Oncology (ASCO), , No. 8 ( 2022-07)
    Abstract: To report on pathogenic germline variants detected among individuals undergoing genetic testing for hereditary breast and/or ovarian cancer (HBOC) from Latin America and compare them with self-reported Hispanic individuals from the United States. METHODS In this cross-sectional study, unrelated individuals with a personal/family history suggestive of HBOC who received clinician-ordered germline multigene sequencing were grouped according to the location of the ordering physician: group A, Mexico, Central America, and the Caribbean; group B, South America; and group C, United States with individuals who self-reported Hispanic ethnicity. Relatives who underwent cascade testing were analyzed separately. RESULTS Among 24,075 unrelated probands across all regions, most were female (94.9%) and reported a personal history suggestive of HBOC (range, 65.0%-80.6%); the mean age at testing was 49.1 ± 13.1 years. The average number of genes analyzed per patient was highest in group A (A 63 ± 28, B 56 ± 29, and C 40 ± 28). Between 9.1% and 18.7% of patients had pathogenic germline variants in HBOC genes (highest yield in group A), with the majority associated with high HBOC risk. Compared with US Hispanics individuals the overall yield was significantly higher in both Latin American regions (A v C P = 1.64×10 –9 , B v C P 〈 2.2×10 –16 ). Rates of variants of uncertain significance were similar across all three regions (33.7%-42.6%). Cascade testing uptake was low in all regions (A 6.6%, B 4.5%, and C 1.9%). CONCLUSION This study highlights the importance of multigene panel testing in Latin American individuals with newly diagnosed or history of HBOC, who can benefit from medical management changes including targeted therapies, eligibility to clinical trials, risk-reducing surgeries, surveillance and prevention of secondary malignancy, and genetic counseling and subsequent cascade testing of at-risk relatives.
    Type of Medium: Online Resource
    ISSN: 2687-8941
    URL: Article
    DOI: 10.1200/GO.22.00104
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 3018917-2
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  • 4
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    Clinical Impact of Pathogenic Variants in DNA Damage Repair Genes beyond BRCA1 and BRCA2 in Breast and Ovarian Cancer Patients
    MDPI AG ; 2022
    In:  Cancers Vol. 14, No. 10 ( 2022-05-13), p. 2426-
    Details
    In: Cancers, MDPI AG, Vol. 14, No. 10 ( 2022-05-13), p. 2426-
    Abstract: Consensus guidelines for hereditary breast and ovarian cancer include management recommendations for pathogenic/likely pathogenic (P/LP) variants in ATM, CHEK2, PALB2, and other DNA damage repair (DDR) genes beyond BRCA1 or BRCA2. We report on clinical management decisions across three academic medical centers resulting from P/LP findings in DDR genes in breast/ovarian cancer patients. Among 2184 patients, 156 (7.1%) carried a P/LP variant in a DDR gene. Clinical follow-up information was available for 101/156 (64.7%) patients. Genetic test result-based management recommendations were made for 57.8% (n = 59) of patients and for 64.7% (n = 66) of patients’ family members. Most recommendations were made for moderate-to-high risk genes and were consistent with guidelines. Sixty-six percent of patients (n = 39/59) implemented recommendations. This study suggests that P/LP variants in DDR genes beyond BRCA1 and BRCA2 can change clinical management recommendations for patients and their family members, facilitate identification of new at-risk carriers, and impact treatment decisions. Additional efforts are needed to improve the implementation rates of genetic-testing-based management recommendations for patients and their family members.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers14102426
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2527080-1
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  • 5
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    Germline multigene panel testing in colorectal cancer: Precision therapy and clinical management implications.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. 3582-3582
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 3582-3582
    Abstract: 3582 Background: Recent studies suggest that the prevalence of abnormalities in homologous recombination deficiency (HRD) genes and other cancer genes not traditionally associated with colorectal cancer (CRC) may be more common in patients with CRC than previously appreciated. Herein, we investigate the efficacy of comprehensive multigene panels in patients with CRC to identify candidates for precision therapies. Methods: DNA sequencing and exon-level copy number analysis were performed in over 9000 patients (pts) referred because of personal history of colon cancer between 2013 and 2018 at a commercial diagnostic laboratory. The genes requisitioned varied but consistently included 14 genes on a hereditary CRC panel; the patient data were de-identified and further analyzed for all 83 genes on a large hereditary cancer syndrome panel under an IRB-approved protocol. Results: Pathogenic/likely pathogenic (P/LP) findings were identified in 2101 of 9669 pts (21%), 1838 (19%) pts when MUTYH heterozygotes are excluded. When restricted to five Lynch syndrome (LS) genes, only 9% of patients had a P/LP finding, which increased to 15% of patients when 19 guidelines-based CRC genes were assessed. 137 pts (1.4%) had two or more P/LP variants. P/LP variants were in MLH1, MSH2, MSH6, PMS2, CHEK2, APC, MUTYH, BRCA2, ATM, BRCA1, PALB2, RAD50, BRIP1, TP53, EPCAM, among others, of which 1.4% were BRCA1/2. When a comprehensive multigene panel was utilized P/LP variants in genes with known therapeutic implications, such as in HRD and mismatch repair deficiency (MMRD), were detected in 1408 (14%) of patients, and 1670 (17%) had P/LP variants in genes with established clinical management guidelines. Conclusions: This study suggests that 1 in 5 patients with CRC harbor actionable germline variants, up to one-half of which remain undetected when only LS genes are tested. Comprehensive panel testing identified candidates for precision treatment and established management recommendations, and have clinical implications for both pts and their at risk family members.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.3582
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 6
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    Landscape of germline mutations in hepatobiliary carcinoma: Unrealized risk, untapped clinical trial opportunities.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 4_suppl ( 2019-02-01), p. 236-236
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 4_suppl ( 2019-02-01), p. 236-236
    Abstract: 236 Background: Hepatobiliary cancer (HBC), including cholangiocarcinoma, affects over 40,000 people in the U.S. each year, and results in over 30,000 cancer deaths annually. Despite continuing advances in next-generation sequencing (NGS), the understanding of germline genetic risk as it relates to these malignancies remains limited, and guidelines for the germline testing of these patients are lacking. We report the spectrum of pathogenic/likely pathogenic (P/LP) germline genetic variants observed in patients with HBC, and the clinical utility related to germline genetic test results. Methods: We retrospectively studied a consecutive series of 267 patients referred to Invitae for germline genetic testing based on a personal history of HBC, per an IRB approved protocol. Patients were evaluated with a multigene panel of up to 135 genes chosen by the ordering providers. De-identified clinical and family history information were reviewed as provided by clinicians. Results: Among 267 HBC patients 15% (n = 41) had P/LP variants identified in genes including MUTYH, ATM, CHEK2, BAP1, BRCA1, MLH1, BRCA2, PALB2, TP53, APC, CDH1, MSH6, and PMS2 (12% excluding MUTYH heterozygotes). Amongst patients with a family history (FH) of HBC, P/LP rate was 13%; for patients with a FH of cancers other than HBC, P/LP rate was 16%; for patients with no reported FH, P/LP rate was 13%. Conclusions: In this study, 15% of HBC patients had P/LP variants in cancer-risk genes. The clinical utility of these germline P/LP variants includes 32% of patients who were eligible for ongoing clinical treatment trials based on their germline test results (NCT02286687), 60% with clinical management recommendations per current NCCN guidelines, and cascade testing of at risk family members. These data justify comprehensive germline multigene panel testing in all HBC patients, in view of the potential impact on clinical management for a substantial fraction of positive patients as well as facilitating cascade testing for risk assessment of family members.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.4_suppl.236
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 7
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    Unexpected germline mutations in a pan-cancer analysis including sarcoma, renal, and other cancers.
    American Society of Clinical Oncology (ASCO) ; 2017
    In:  Journal of Clinical Oncology Vol. 35, No. 15_suppl ( 2017-05-20), p. 1584-1584
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. 1584-1584
    Abstract: 1584 Background: Multi-gene testing for cancer predisposition is increasingly utilized in clinical care. Although the diagnostic yield and management implications of such testing in breast, ovarian and colorectal cancer are relatively well understood, data for other cancer types are still emerging. In this study we retrospectively examined 39,147 patients referred for hereditary cancer syndrome testing for pathogenic germline variants in 80 cancer risk genes, focusing on those patients with renal, sarcoma, paraganglioma, melanoma, and pancreatic cancers. Methods: Test results and personal/family history were extracted from a sequential series of de-identified clinical test reports. Data for genes not clinically ordered were analyzed under an IRB approved research protocol. Common low penetrance risk alleles were excluded. Results: Overall, 14.3% (5,589) of patients carried germline pathogenic mutations in 80 cancer risk genes. Of the 949 patients with renal cancer 20% (190) were positive, and 44% of these findings were “unexpected”, meaning they appeared in genes that are not commonly requisitioned in renal cancer patients. Of the 423 sarcoma patients, 16% (68) had positive findings, 45% of which were “unexpected”. For both cancer types, greater than 90% of these “unexpected” findings were in genes with published management recommendations. Similar results were observed in melanoma, paraganglioma and pancreatic cancer patients. A second or third pathogenic variant, many of which were also “unexpected”, were found in 3.6% of positive cases. Conclusions: In this series of patients we estimate almost 12% of pathogenic variants across cancer indications are “unexpected”. These data suggest many actionable pathogenic variants are being missed due to adherence to overly restrictive, narrowly constructed tumor-specific panels. Clinicians should expand the scope of their test panels in order to capture variants with the potential to impact patients and their family members by informing implementation of established management guidelines.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2017.35.15_suppl.1584
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
    detail.hit.zdb_id: 2005181-5
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  • 8
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    Underdiagnosis of Hereditary Breast and Ovarian Cancer in Medicare Patients: Genetic Testing Criteria Miss the Mark
    Springer Science and Business Media LLC ; 2018
    In:  Annals of Surgical Oncology Vol. 25, No. 10 ( 2018-10), p. 2925-2931
    Details
    In: Annals of Surgical Oncology, Springer Science and Business Media LLC, Vol. 25, No. 10 ( 2018-10), p. 2925-2931
    Type of Medium: Online Resource
    ISSN: 1068-9265 , 1534-4681
    URL: Article
    DOI: 10.1245/s10434-018-6621-4
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2074021-9
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  • 9
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    Determining the clinical value of germline genetic testing coupled with tumor mutation profiling.
    American Society of Clinical Oncology (ASCO) ; 2017
    In:  Journal of Clinical Oncology Vol. 35, No. 15_suppl ( 2017-05-20), p. 1577-1577
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. 1577-1577
    Abstract: 1577 Background: Somatic mutation analysis by next-generation sequencing (NGS) is an expanding clinical assessment offered to cancer patients. Studies report that 4–12% of patients have a positive tumor mutation profiling (TMP) result in a known cancer predisposition gene also identified in their germline, which has potential implications for the patient’s acute treatment, ongoing surveillance, and the screening of family members. We report a series of patients with TMP coupled with germline genetic testing and include yield of pathogenic germline mutations, discordance between germline and TMP findings, and potential clinical impact. Methods: Our study used de-identified data from 182 consecutive patients who underwent TMP followed by germline testing with an NGS-based hereditary cancer gene panel. Results: 50/182 cases (27%) had one or more likely pathogenic or pathogenic (LP/P) germline variants, which is higher than previous reports. Among these 50, 28 (56%) met guidelines for germline testing by personal or family history criteria, 10 (20%) met recently established NCCN criteria for germline testing of patients with BRCA1/2 tumor variants, and 12 (24%) had TMP results that suggested a germline mutation but did not meet any guidelines for germline testing. We identified 52 LP/P germline variants in BRCA2 (17), BRCA1 (7), PALB2 (6), MUTYH (5), CHEK2 (2), and 15 other genes, all with established guidelines that would impact the clinical management of patients and their family members. In 9/50 cases, germline testing revealed variants that were absent in TMP results and provided new information with clinical implications for patients and their families, including variants in BRCA1 and CHEK2. Conclusions: In TMP patients, 50 of 182 had a medically actionable germline mutation with established management guidelines. Among these 50, 12 (24%) met neither current personal or family criteria nor the latest NCCN guidelines for germline testing in patients with TMP. Also striking were nine patients whose germline LP/P mutations were absent in TMP results. These data suggest that indications for germline testing of cancer patients must be expanded to avoid missing important germline findings in patients undergoing TMP.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2017.35.15_suppl.1577
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
    detail.hit.zdb_id: 2005181-5
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  • 10
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    Underdiagnosis of Hereditary Colorectal Cancers Among Medicare Patients: Genetic Testing Criteria for Lynch Syndrome Miss the Mark
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  JCO Precision Oncology , No. 5 ( 2021-11), p. 1103-1111
    Details
    In: JCO Precision Oncology, American Society of Clinical Oncology (ASCO), , No. 5 ( 2021-11), p. 1103-1111
    Abstract: Strict clinical criteria used by Medicare for germline testing for Lynch syndrome (LS) could lead to missed diagnoses of hereditary cancer syndromes given variable individual and family phenotypes. The aim of this study was to compare rates and spectrum of pathogenic or likely pathogenic (P/LP) variants in LS and other hereditary cancer genes on the basis of meeting Medicare LS testing criteria. METHODS Retrospective review of Medicare beneficiaries who had multigene panel testing with an indication of personal or family history of colorectal cancer (CRC) was performed. Ordering providers determined if Medicare LS criteria were met. The results of genetic testing were compared on the basis of whether or not Medicare testing criteria were met. RESULTS Among 639 Medicare beneficiaries, 495 (77.5%) met testing criteria. Overall rates of P/LP variant identification were similar between those meeting and not meeting testing criteria (18.4% v 11.8%; P = .06). LS was diagnosed more frequently among those meeting testing criteria (10.1% v 4.9%; P = .05). No statistical differences were found in rates of P/LP variant identification for non-LS CRC genes (5.3% v 5.6%; P = .89) or non-CRC genes (4.2% v 2.1%; P = .23). PMS2, MUTYH, and ATM P/LP variants were found at higher rates among those outside of criteria. CONCLUSION Among Medicare beneficiaries undergoing genetic testing for suspected LS, rates of P/LP variants in actionable cancer genes were similar regardless of whether testing criteria were met. Current testing criteria fail to identify individuals with P/LP variants in PMS2 and other actionable cancer genes. Relaxing LS testing criteria could improve identification of individuals with hereditary cancer syndromes among Medicare beneficiaries.
    Type of Medium: Online Resource
    ISSN: 2473-4284
    URL: Article
    DOI: 10.1200/PO.21.00132
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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