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2.
Nat Med ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31768066

RESUMO

Accurate identification of tumor-derived somatic variants in plasma circulating cell-free DNA (cfDNA) requires understanding of the various biological compartments contributing to the cfDNA pool. We sought to define the technical feasibility of a high-intensity sequencing assay of cfDNA and matched white blood cell DNA covering a large genomic region (508 genes; 2 megabases; >60,000× raw depth) in a prospective study of 124 patients with metastatic cancer, with contemporaneous matched tumor tissue biopsies, and 47 controls without cancer. The assay displayed high sensitivity and specificity, allowing for de novo detection of tumor-derived mutations and inference of tumor mutational burden, microsatellite instability, mutational signatures and sources of somatic mutations identified in cfDNA. The vast majority of cfDNA mutations (81.6% in controls and 53.2% in patients with cancer) had features consistent with clonal hematopoiesis. This cfDNA sequencing approach revealed that clonal hematopoiesis constitutes a pervasive biological phenomenon, emphasizing the importance of matched cfDNA-white blood cell sequencing for accurate variant interpretation.

3.
Arch Pathol Lab Med ; 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31647316

RESUMO

CONTEXT.­: The American Society of Clinical Oncology/College of American Pathologists HER2 testing guideline in breast cancer was updated in 2018 to address issues on interpretation of uncommon results using dual-probe in situ hybridization according to the 2013 guideline. OBJECTIVE.­: To assess impact of the 2018 guideline on breast cancer with equivocal HER2 immunohistochemistry results. DESIGN.­: We retrospectively reviewed HER2 fluorescence in situ hybridization (FISH) data (HER2/CEP17 ratio and average HER2 copy number per cell) of HER2 immunohistochemistry-equivocal (2+ or 1+ to 2+) breast cancers at our center between January 2014 and May 2018 and compared HER2 FISH results according to 2013 and 2018 guidelines. RESULTS.­: A total of 1666 HER2 FISH results from 1421 patients with equivocal HER2 immunohistochemistry were reviewed. Based on the 2013 guideline, HER2 FISH results were amplified in 346 cases (20.8%), equivocal in 242 (14.5%), and nonamplified in 1078 (64.7%). Using the 2018 guideline, 258 cases (16%) were reclassified, including 242 previously equivocal test results (15%) and 16 previously positive results (1%) reclassified as negative. The subset of 2013 HER2-equivocal and 2018 HER2-nonamplified cases with HER2/CEP17 ratio lower than 2.0 and average HER2 copy number 4.0 or higher and lower than 6.0 showed higher incidence of micropapillary morphology compared with HER2-amplified cases. Despite most patients in this group not receiving HER2-targeted treatment, 96% had no evidence of disease at follow-up. CONCLUSIONS.­: The 2018 guideline eliminated HER2 FISH-equivocal cases by reclassifying HER2-equivocal cases and cases with nonclassical amplification without HER2 overexpression as HER2 negative. As a consequence, we observed a considerable increase in HER2 FISH-negative cases and a slight decrease in HER2 FISH-positive cases.

4.
BMJ Open ; 9(10): e031092, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31594892

RESUMO

INTRODUCTION: Genomic sequencing has rapidly transitioned into clinical practice, improving diagnosis and treatment options for patients with hereditary disorders. However, large-scale implementation of genomic sequencing faces challenges, especially with regard to the return of incidental results, which refer to genetic variants uncovered during testing that are unrelated to the primary disease under investigation, but of potential clinical significance. High-quality evidence evaluating health outcomes and costs of receiving incidental results is critical for the adoption of genomic sequencing into clinical care and to understand the unintended consequences of adoption of genomic sequencing. We aim to evaluate the health outcomes and costs of receiving incidental results for patients undergoing genomic sequencing. METHODS AND ANALYSIS: We will compare health outcomes and costs of receiving, versus not receiving, incidental results for adult patients with cancer undergoing genomic sequencing in a mixed-methods randomised controlled trial. Two hundred and sixty patients who have previously undergone first or second-tier genetic testing for cancer and received uninformative results will be recruited from familial cancer clinics in Toronto, Ontario. Participants in both arms will receive cancer-related results. Participants in the intervention arm have the option to receive incidental results. Our primary outcome is psychological distress at 2 weeks following return of results. Secondary outcomes include behavioural consequences, clinical and personal utility assessed over the 12 months after results are returned and health service use and costs at 12 months and 5 years. A subset of participants and providers will complete qualitative interviews about utility of incidental results. ETHICS AND DISSEMINATION: This study has been approved by Clinical Trials Ontario Streamlined Research Ethics Review System that provides ethical review and oversight for multiple sites participating in the same clinical trial in Ontario.Results from the trial will be shared through stakeholder workshops, national and international conferences, and peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03597165.

6.
JAMA Netw Open ; 2(9): e1912259, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31560388

RESUMO

Importance: Radiation therapy for breast cancer is associated with increased risk of a second primary contralateral breast cancer, but the genetic factors modifying this association are not well understood. Objective: To determine whether a genetic risk score comprising single nucleotide polymorphisms in the nonhomologous end-joining DNA repair pathway is associated with radiation-associated contralateral breast cancer. Design, Setting, and Participants: This case-control study included a case group of women with contralateral breast cancer that was diagnosed at least 1 year after a first primary breast cancer who were individually matched to a control group of women with unilateral breast cancer. Inclusion criteria were receiving a first invasive breast cancer diagnosis prior to age 55 years between 1985 and 2008. Women were recruited through 8 population-based cancer registries in the United States, Canada, and Denmark as part of the Women's Environment, Cancer, and Radiation Epidemiology Studies I (November 2000 to August 2004) and II (March 2010 to December 2012). Data analysis was conducted from July 2017 to August 2019. Exposures: Stray radiation dose to the contralateral breast during radiation therapy for the first breast cancer. A novel genetic risk score comprised of genetic variants in the nonhomologous end-joining DNA repair pathway was considered the potential effect modifier, dichotomized as high risk if the score was above the median of 74 and low risk if the score was at or below the median. Main Outcomes and Measures: The main outcome was risk of contralateral breast cancer associated with stray radiation dose stratified by genetic risk score, age, and latency. Results: A total of 5953 women were approached for study participation, and 3732 women (62.7%) agreed to participate. The median (range) age at first diagnosis was 46 (23-54) years. After 5 years of latency or more, among women who received the first diagnosis when they were younger than 40 years, exposure to 1.0 Gy (to convert to rad, multiply by 100) or more of stray radiation was associated with a 2-fold increased risk of contralateral breast cancer compared with women who were not exposed (rate ratio, 2.0 [95% CI, 1.1-3.6]). The risk was higher among women with a genetic risk score above the median (rate ratio, 3.0 [95% CI, 1.1-8.1]), and there was no association among women with a genetic risk score below the median (rate ratio, 1.3 [95% CI, 0.5-3.7]). Among younger women with a high genetic risk score, the attributable increased risk for contralateral breast cancer associated with stray radiation dose was 28%. Conclusions and Relevance: This study found an increased risk of contralateral breast cancer that was attributable to stray radiation exposure among women with a high genetic risk score and who received a first breast cancer diagnosis when they were younger than 40 years after 5 years or more of latency. This genetic risk score may help guide treatment and surveillance for women with breast cancer.

8.
J Clin Oncol ; 37(27): 2501-2509, 2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31403865
9.
Hum Mutat ; 2019 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-31444830

RESUMO

Fumarate hydratase (FH) mutations underpin the autosomal recessive syndrome. FH deficiency and the autosomal dominant syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC). The FH c.1431_1433dupAAA (p.Lys477dup) genomic alteration has been conclusively shown to contribute to FH deficiency when occurring with another FH germline alteration. However, a sufficiently large dataset has been lacking to conclusively determine its clinical significance to cancer predisposition in the heterozygous state. We reviewed a series of 7,571 patients with cancer who received germline results through MSK-IMPACT testing at the Memorial Sloan Kettering Cancer Center. The FH c.1431_1433dupAAA (p.Lys477dup) variant was detected in 24 individuals, none of whom was affected with renal cancer. Eleven of the 372 patients with renal cancer were identified to carried pathogenic FH variants associated with HLRCC. None of these 372 patients with renal cancer carried the FH c.1431_1433dupAAA variant. Our data indicate the FH c.1431_1433dupAAA is not associated with cancer including renal cell carcinoma.

10.
Eur J Cancer ; 120: 20-30, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31446213

RESUMO

BACKGROUND: The phase III OlympiAD study (NCT02000622) showed a statistically significant progression-free survival benefit with olaparib versus chemotherapy treatment of physician's choice (TPC) in patients with a germline BRCA mutation and human epidermal growth factor receptor 2-negative metastatic breast cancer. From this study, we report the effect of olaparib on health-related quality of life (HRQoL). METHODS: Patients were randomised 2:1 to olaparib monotherapy (300 mg twice daily) or single-agent TPC. The primary HRQoL end-point was mean change from baseline in the two-item global health status/QoL score determined from patient-completed European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item module (EORTC QLQ-C30) questionnaires and assessed using a mixed model for repeated measures. Symptoms and functioning domains, best overall response and time to deterioration of QoL were also evaluated. RESULTS: Overall questionnaire compliance rates were 93.2% for olaparib and 76.3% for TPC. Between-treatment global health status/QoL comparison showed a significant improvement in the olaparib arm versus the TPC arm, with mean change of 3.9 (standard deviation 1.2) versus -3.6 (2.2), a difference of 7.5 points (95% confidence interval [CI]: 2.48, 12.44; P = 0.0035). A higher proportion of patients in the olaparib arm showed a best overall response of 'improvement' in global health status/QoL (33.7% vs 13.4%). Median time to global health status/QoL deterioration was not reached in olaparib patients and was 15.3 months for TPC patients (hazard ratio: 0.44 [95% CI: 0.25, 0.77]; P = 0.004). For EORTC QLQ-C30 symptoms and functioning subscales, only nausea/vomiting symptom score was worse in the olaparib arm than in the TPC arm (across all visits compared with baseline). CONCLUSION: HRQoL was consistently improved for patients treated with olaparib, compared with chemotherapy TPC.

11.
Hastings Cent Rep ; 49 Suppl 1: S44-S52, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31268573

RESUMO

In recent years, with both the development of next-generation sequencing approaches and the Supreme Court decision invalidating gene patents, declining costs have contributed to the emergence of a new model of hereditary cancer genetic testing. Multigene panel testing (or multiplex testing) involves using next-generation sequencing technology to determine the sequence of multiple cancer-susceptibility genes. In addition to high-penetrance cancer-susceptibility genes, multigene panels frequently include genes that are less robustly associated with cancer predisposition. Scientific understanding about associations between many specific moderate-penetrance gene variants and cancer risks is incomplete. The emergence of multigene panel tests has created unique challenges that may have meaningful psychosocial implications. Contrasted with the serial testing process, wherein patients consider the personal and clinical implications of each evaluated gene, with multigene panel testing, patients provide broad consent to whichever genes are included in a particular panel and then, after the test, receive in-depth genetic counseling to clarify the distinct implications of their specific results. Consequently, patients undergoing multigene panel testing may have a less nuanced understanding of the test and its implications, and they may have fewer opportunities to self-select against the receipt of particular types of genetic-risk information. Evidence is conflicting regarding the emotional effects of this testing.

12.
J Thorac Oncol ; 14(11): 1989-1994, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31323388

RESUMO

INTRODUCTION: Inherited mutations are easily detected factors that influence the disease courses and optimal treatment strategies of some cancers. Germline mutations in BRCA1 associated protein 1 (BAP1) are associated with unique disease profiles in mesothelioma, atypical spitz nevi, and uveal melanoma, but the patient characteristics of an unselected population of BAP1 carriers identified by an ascertainment prevalence study are unknown. METHODS: We collected blood samples, cancer histories, and occupational exposures from 183 unselected patients with BAP1-related diseases. Clinical information for each patient was obtained from medical records. Germline DNA was extracted from blood samples and sequenced using a next-generation sequencing assay. We tested screening criteria developed to identify patients with a possible germline BAP1 mutation. RESULTS: Pathogenic or likely pathogenic germline BAP1 mutations were observed in 5 of 180 sequenced specimens and were exclusively found in patients identified by our screening criteria. Several patients with characteristics suspicious for a heritable deleterious mutation did not have a germline BAP1 mutation. The prevalence of pathogenic germline BAP1 mutations in patients with mesothelioma was 4.4% (95% confidence interval 1.1-11.1). CONCLUSIONS: Results from the first unselected prevalence ascertainment study of germline BAP1 alterations suggest that the frequency of this mutation is low among patients with mesothelioma. The proposed screening criteria successfully identified all patients with germline BAP1-mutant mesothelioma. These screening guidelines may assist physicians in selecting patients who would benefit from genetic testing. Future efforts should validate and refine these criteria and search for other germline mutations associated with mesothelioma and related diseases.

13.
Nature ; 571(7766): 576-579, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31292550

RESUMO

Mutations in BRCA1 and BRCA2 predispose individuals to certain cancers1-3, and disease-specific screening and preventative strategies have reduced cancer mortality in affected patients4,5. These classical tumour-suppressor genes have tumorigenic effects associated with somatic biallelic inactivation, although haploinsufficiency may also promote the formation and progression of tumours6,7. Moreover, BRCA1/2-mutant tumours are often deficient in the repair of double-stranded DNA breaks by homologous recombination8-13, and consequently exhibit increased therapeutic sensitivity to platinum-containing therapy and inhibitors of poly-(ADP-ribose)-polymerase (PARP)14,15. However, the phenotypic and therapeutic relevance of mutations in BRCA1 or BRCA2 remains poorly defined in most cancer types. Here we show that in the 2.7% and 1.8% of patients with advanced-stage cancer and germline pathogenic or somatic loss-of-function alterations in BRCA1/2, respectively, selective pressure for biallelic inactivation, zygosity-dependent phenotype penetrance, and sensitivity to PARP inhibition were observed only in tumour types associated with increased heritable cancer risk in BRCA1/2 carriers (BRCA-associated cancer types). Conversely, among patients with non-BRCA-associated cancer types, most carriers of these BRCA1/2 mutation types had evidence for tumour pathogenesis that was independent of mutant BRCA1/2. Overall, mutant BRCA is an indispensable founding event for some tumours, but in a considerable proportion of other cancers, it appears to be biologically neutral-a difference predominantly conditioned by tumour lineage-with implications for disease pathogenesis, screening, design of clinical trials and therapeutic decision-making.

14.
Breast Cancer Res Treat ; 177(1): 61-66, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31144151

RESUMO

PURPOSE: Human epidermal growth factor receptor 2 (HER2)-positive breast cancers are known to have significant clinical and pathological response to neoadjuvant systemic therapy (NST). The aim of this study was to identify factors associated with pathological complete response (pCR), defined as no residual invasive carcinoma in the breast and axillary lymph nodes (ypT0/is ypN0), among patients with HER2-positive breast cancer and to compare pCR rates between breast cancers with HER2 protein overexpression by immunohistochemistry (IHC) versus HER2 gene amplification by fluorescence in situ hybridization (FISH) in the absence of protein overexpression by IHC. METHODS: We conducted a retrospective review of HER2-positive breast cancer patients treated with NST and surgery at Memorial Sloan Kettering Cancer Center between January 2013 and May 2018. Estrogen receptor (ER), progesterone receptor (PR), and HER2 status were assessed according to the 2018 ASCO/CAP guidelines. RESULTS: During the study period, 560 patients were identified. Of 531 patients with IHC results available, 455 patients had HER2 IHC 3+, and 76 had IHC < 3+ but HER2 amplification detected by FISH. The overall pCR rate was 59% (330/560). The pCR rate among patients with HER2 protein overexpression (IHC 3+) was 67%, compared to 17% among patients with HER2 amplification by FISH (IHC < 3+). On univariate and multivariate analyses, HER2 protein overexpression by IHC (IHC 3+) was a significant predictor of pCR, along with grade 3 histology, PR-negative status, and dual anti-HER2 therapy. CONCLUSION: Although both HER2 IHC and FISH are standard HER2 testing methods in breast cancer, achievement of pCR is associated with HER2 IHC expression level, among other factors.

15.
Eur J Cancer ; 114: 128-136, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31060925

RESUMO

Academic, industry, regulatory leaders and patient advocates in cancer clinical research met in November 2018 at the Innovation and Biomarkers in Cancer Drug Development meeting in Brussels to address the existing dichotomy between increasing calls for personalised oncology approaches based on individual molecular profiles and the need to make resource and regulatory decisions at the societal level in differing health-care delivery systems around the globe. Novel clinical trial designs, the utility and limitations of real-world evidence (RWE) and emerging technologies for profiling patient tumours and tumour-derived DNA in plasma were discussed. While randomised clinical trials remain the gold standard approach to defining clinical utility of local and systemic therapeutic interventions, the broader adoption of comprehensive tumour profiling and novel trial designs coupled with RWE may allow patient and physician autonomy to be appropriately balanced with broader assessments of safety and overall societal benefit.

16.
J Med Genet ; 56(6): 347-357, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30962250

RESUMO

The vocabulary currently used to describe genetic variants and their consequences reflects many years of studying and discovering monogenic disease with high penetrance. With the recent rapid expansion of genetic testing brought about by wide availability of high-throughput massively parallel sequencing platforms, accurate variant interpretation has become a major issue. The vocabulary used to describe single genetic variants in silico, in vitro, in vivo and as a contributor to human disease uses terms in common, but the meaning is not necessarily shared across all these contexts. In the setting of cancer genetic tests, the added dimension of using data from genetic sequencing of tumour DNA to direct treatment is an additional source of confusion to those who are not experienced in cancer genetics. The language used to describe variants identified in cancer susceptibility genetic testing typically still reflects an outdated paradigm of Mendelian inheritance with dichotomous outcomes. Cancer is a common disease with complex genetic architecture; an improved lexicon is required to better communicate among scientists, clinicians and patients, the risks and implications of genetic variants detected. This review arises from a recognition of, and discussion about, inconsistencies in vocabulary usage by members of the ENIGMA international multidisciplinary consortium focused on variant classification in breast-ovarian cancer susceptibility genes. It sets out the vocabulary commonly used in genetic variant interpretation and reporting, and suggests a framework for a common vocabulary that may facilitate understanding and clarity in clinical reporting of germline genetic tests for cancer susceptibility.

17.
Genet Med ; 21(7): 1668, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30894706

RESUMO

An update to the original published conflict of interest for author Liying Zhang, PhD. L.Z. received compensation from Future Technology Research LLC (seminar on precision medicine), Roche Diagnostics Asia Pacific, BGI, Illumina (speaking activities at conferences/workshop). L.Z.'s family member has a leadership position and ownership interest of Shanghai Genome Center. This correction has been made.

19.
Genet Med ; 21(9): 2116-2125, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30787465

RESUMO

PURPOSE: Cancer care professionals are confronted with interpreting results from multiplexed gene sequencing of patients at hereditary risk for cancer. Assessments for variant classification now require orthogonal data searches and aggregation of multiple lines of evidence from diverse resources. The clinical genetics community needs a fast algorithm that automates American College of Medical Genetics and Genomics (ACMG) based variant classification and provides uniform results. METHODS: Pathogenicity of Mutation Analyzer (PathoMAN) automates germline genomic variant curation from clinical sequencing based on ACMG guidelines. PathoMAN aggregates multiple tracks of genomic, protein, and disease specific information from public sources. We compared expertly curated variant data from clinical laboratories to assess performance. RESULTS: PathoMAN achieved a high overall concordance of 94.4% for pathogenic and 81.1% for benign variants. We observed negligible discordance (0.3% pathogenic, 0% benign) when contrasted against expert curated variants. Some loss of resolution (5.3% pathogenic, 18.9% benign) and gain of resolution (1.6% pathogenic, 3.8% benign) were also observed. CONCLUSION: Automation of variant curation enables unbiased, fast, efficient delivery of results in both clinical and laboratory research. We highlight the advantages and weaknesses related to the programmable automation of variant classification. PathoMAN will aid in rapid variant classification by generating robust models using a knowledgebase of diverse genetic data ( https://pathoman.mskcc.org).

20.
Breast Cancer Res Treat ; 175(1): 141-148, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30673971

RESUMO

BACKGROUND: BRCA mutation carriers have an elevated lifetime breast cancer risk and remain at risk for interval cancer development. We sought to compare BRCA mutation carriers with screen-detected versus interval breast cancers. METHODS: Women with a known BRCA mutation prior to a breast cancer diagnosis were identified. Clinical and pathologic factors, and imaging within 18 months of diagnosis were compared among screen-detected versus interval cancers. Interval cancers were those detected by physical exam among women undergoing regular screening. RESULTS: Of 124 breast cancers, 92 were screen and 22 clinically detected, of which 11 were interval cancers among regular screeners, and 10 were incidentally found on prophylactic mastectomy. Women with interval cancers were younger, had lower body mass indexes, and were more likely to be Black than those with screen-detected cancers (p < 0.05). Interval cancers were all invasive, larger, more likely to be node positive, and more likely to require axillary lymph node dissection and chemotherapy (p < 0.05). No significant differences were seen by BRCA mutation, mammographic density, MRI background parenchymal enhancement, tumor grade, or receptor status between cohorts. Women screened with both mammogram and MRI had significantly lower proportions of interval cancers compared to women screened with only mammogram or MRI alone (p < 0.05). CONCLUSIONS: Interval breast cancers among BRCA mutation carriers have worse clinicopathologic features than screen-detected tumors, and require more-aggressive medical and surgical therapy. Imaging with mammogram and MRI is associated with lower interval cancer development and should be utilized among this high-risk population.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Heterozigoto , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Detecção Precoce de Câncer , Feminino , Testes Genéticos , Humanos , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias
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