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1.
N Engl J Med ; 384(5): 440-451, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33471974

RESUMO

BACKGROUND: Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants. METHODS: In a population-based case-control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed. RESULTS: Pathogenic variants in 12 established breast cancer-predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of estrogen receptor-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of estrogen receptor-positive breast cancer. Pathogenic variants in 16 candidate breast cancer-predisposition genes, including the c.657_661del5 founder pathogenic variant in NBN, were not associated with an increased risk of breast cancer. CONCLUSIONS: This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer-predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.).


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Variação Genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Razão de Chances , Risco , Análise de Sequência de DNA , Adulto Jovem
2.
J Natl Cancer Inst ; 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33146377

RESUMO

To evaluate the racial/ethnic differences in prevalence of germline pathogenic variants (PVs) and the effect of race/ethnicity on breast cancer (BC) risk among carriers, results of multigene testing of 77,900 women with BC (Non-Hispanic White [NHW] = 57,003; Ashkenazi-Jewish = 4,798; Black = 6,722; Hispanic = 5,194; and Asian = 4,183) were analyzed and the frequency of PVs in each gene were compared between BC cases and race/ethnicity-matched gnomAD reference controls. Compared to NHWs, BRCA1 PVs were enriched in Ashkenazi-Jews and Hispanics while CHEK2 PVs were statistically significantly lower in Blacks, Hispanics, and Asians (all two-sided P< 0.05). In case-control studies BARD1 PVs were associated with high risks (Odds Ratio>4.00) of BC in Blacks, Hispanics and Asians; ATM PVs were associated with increased risk of BC among all races/ethnicities except Asians; whereas CHEK2 and BRIP1 PVs were associated with increased risk of BC among NHWs and Hispanics only. These findings suggest a need for personalized management of BC risk in PV carriers based on race/ethnicity.

3.
Cancer ; 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33146899

RESUMO

Approximately 5% to 10% of women diagnosed with breast cancer will have a pathogenic variant (PV) in a hereditary cancer susceptibility gene, and this has significant implications for the management of these patients and their relatives. Despite the benefits of genetic testing, many eligible patients with breast cancer never undergo testing because of various barriers, including complicated testing criteria such as those from the National Comprehensive Cancer Network (NCCN). In 2019, the American Society of Breast Surgeons (ASBrS) proposed germline genetic testing for all patients with breast cancer to increase the identification of PV carriers. In 2020, a Mayo Clinic study highlighted the limitations of these 2 genetic testing guidelines (NCCN and ASBrS) and proposed a hybrid approach of testing all women diagnosed with breast cancer by the age of 65 years and using NCCN criteria for older patients. This commentary presents an updated analysis of the Mayo Clinic data and discusses the rationale for using the age of 60 years rather than 65 years as the cutoff for this hybrid approach. Using an age at diagnosis of ≤60 or ≤65 years for the universal testing of patients with breast cancer detected more PVs (11.9% [16 of 134] and 15.7% [21 of 134], respectively) in comparison with using the NCCN criteria. Lowering the age for universal testing from 65 to 60 years maintained the sensitivity of detecting a PV at >90% while sparing testing for an additional 10% of women. Compared with the testing of all patients, the hybrid approach would allow 31% of all women with breast cancer to forgo testing and result in fewer variants of uncertain significance identified and, therefore, would decrease the chance of harm from misinterpretation of these variants.

4.
Clin Cancer Res ; 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028596

RESUMO

PURPOSE: To compare the clinical characteristics and overall survival (OS) of germline mutation carriers in homologous recombination repair (HRR) genes and noncarriers with pancreatic ductal adenocarcinoma (PDAC). METHODS: Germline DNA from 3,078 patients with PDAC enrolled in a prospective registry at Mayo Clinic between 2000 and 2017 was analyzed for mutations in 37 cancer predisposition genes. Characteristics and OS of patients with mutations in eight genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, PALB2, RAD51C, and RAD51D) involved in HRR were compared with patients testing negative for mutations in all 37 genes. RESULTS: The 175 HRR mutation carriers and 2,730 noncarriers in the study had a median duration of follow-up of 9.9 years. HRR mutation carriers were younger (median age at diagnosis: 63 vs. 66 years, P < 0.001) and more likely to have metastatic disease at diagnosis (46% vs. 36%, P = 0.004). In a multivariable model adjusting for sex, age at diagnosis, and tumor staging, patients with germline HRR mutations had a significantly longer OS compared with noncarriers [HR, 0.83; 95% confidence interval (CI), 0.70-0.97; P = 0.02]. Further gene-level analysis demonstrated that germline ATM mutation carriers had longer OS compared with patients without germline mutations in any of the 37 genes (HR, 0.72; 95% CI, 0.55-0.94; P = 0.01). CONCLUSIONS: This study demonstrates that germline mutation carrier status in PDAC is associated with longer OS compared with noncarriers. Further research into tumor biology and response to platinum-based chemotherapy in germline mutation carriers with PDAC are needed to better understand the association with longer OS.

5.
JCO Precis Oncol ; 4: 32-43, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32832836

RESUMO

PURPOSE: In studies of men of European ancestry, rare pathogenic variants in DNA repair pathway genes have been shown to be associated with risk of aggressive prostate cancer. The contribution of rare coding variation to prostate cancer risk in men of African ancestry has not been established. METHODS: We sequenced a panel of 19 DNA repair and cancer predisposition genes in 2,453 African American and 1,151 Ugandan prostate cancer cases and controls. Rare variants were classified as pathogenic or putatively functionally disruptive and examined in association with prostate cancer risk and disease aggressiveness in gene and pathway-level association analyses. RESULTS: Pathogenic variants were found in 75 out of 2,098 cases (3.6%) and 31 out of 1,481 controls (2.1%) (OR=1.82, 95% CI=1.19 to 2.79, P=0.0044) with the association being stronger for more aggressive disease phenotypes (OR=3.10, 95% CI=1.54 to 6.23, P=0.0022). The highest risks for aggressive disease were observed with pathogenic variants in the ATM, BRCA2, PALB2 and NBN genes, with odds ratios ranging from ~4 to 15 in the combined study sample of African American and Ugandan men. Rare, non-pathogenic, non-synonymous variants did not have a major impact on risk of overall prostate cancer or disease aggressiveness. CONCLUSIONS: Rare pathogenic variants in DNA repair genes have appreciable effects on risk of aggressive prostate cancer in men of African ancestry. These findings have potential implications for panel testing and risk stratification in this high-risk population.

7.
NPJ Breast Cancer ; 6: 13, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32377563

RESUMO

In silico predictions of missense variants is an important consideration when interpreting variants of uncertain significance (VUS) in the BRCA1 and BRCA2 genes. We trained and evaluated hundreds of machine learning algorithms based on results from validated functional assays to better predict missense variants in these genes as damaging or neutral. This new optimal "BRCA-ML" model yielded a substantially more accurate method than current algorithms for interpreting the functional impact of variants in these genes, making BRCA-ML a valuable addition to data sources for VUS classification.

8.
Hum Mutat ; 41(8): e1-e6, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32442341

RESUMO

Multigene panel testing for cancer predisposition mutations is becoming routine in clinical care. However, the gene content of panels offered by testing laboratories vary significantly, and data on mutation detection rates by gene and by the panel is limited, causing confusion among clinicians on which test to order. Using results from 147,994 multigene panel tests conducted at Ambry Genetics, we built an interactive prevalence tool to explore how differences in ethnicity, age of onset, and personal and family history of different cancers affect the prevalence of pathogenic mutations in 31 cancer predisposition genes, across various clinically available hereditary cancer gene panels. Over 13,000 mutation carriers were identified in this high-risk population. Most were non-Hispanic white (74%, n = 109,537), but also Black (n = 10,875), Ashkenazi Jewish (n = 10,464), Hispanic (n = 10,028), and Asian (n = 7,090). The most prevalent cancer types were breast (50%), ovarian (6.6%), and colorectal (4.7%), which is expected based on genetic testing guidelines and clinician referral for testing. The Hereditary Cancer Multi-Gene Panel Prevalence Tool presented here can be used to provide insight into the prevalence of mutations on a per-gene and per-multigene panel basis, while conditioning on multiple custom phenotypic variables to include race and cancer type.

9.
J Natl Cancer Inst ; 2020 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-32427313

RESUMO

BACKGROUND: The risks of breast cancer in African American (AA) women associated with inherited mutations in breast cancer predisposition genes are not well defined. Thus, whether multigene germline hereditary cancer testing panels are applicable to this population is unknown. We assessed associations between mutations in panel-based genes and breast cancer risk in 5054 AA women with breast cancer and 4993 unaffected AA women drawn from 10 epidemiologic studies. METHODS: Germline DNA samples were sequenced for mutations in 23 cancer predisposition genes using a QIAseq multiplex amplicon panel. Prevalence of mutations and odds ratios (ORs) for associations with breast cancer risk were estimated with adjustment for study design, age, and family history of breast cancer. RESULTS: Pathogenic mutations were identified in 10.3% of women with estrogen receptor (ER)-negative breast cancer, 5.2% of women with ER-positive breast cancer, and 2.3% of unaffected women. Mutations in BRCA1, BRCA2, and PALB2 were associated with high risks of breast cancer (OR = 47.55, 95% confidence interval [CI] = 10.43 to >100; OR = 7.25, 95% CI = 4.07 to 14.12; OR = 8.54, 95% CI = 3.67 to 24.95, respectively). RAD51D mutations were associated with high risk of ER-negative disease (OR = 7.82, 95% CI = 1.61 to 57.42). Moderate risks were observed for CHEK2, ATM, ERCC3, and FANCC mutations with ER-positive cancer, and RECQL mutations with all breast cancer. CONCLUSIONS: The study identifies genes that predispose to breast cancer in the AA population, demonstrates the validity of current breast cancer testing panels for use in AA women, and provides a basis for increased referral of AA patients for cancer genetic testing.

10.
EBioMedicine ; 54: 102728, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32268276

RESUMO

BACKGROUND: Metastatic prostate cancer is a clonally heterogeneous disease state characterized by progressive somatic perturbations. The aim of this study was to identify cell free DNA- (cfDNA-) based alterations and their associations with outcomes in progressive metastatic prostate cancer. METHODS: In this longitudinal prospective cohort study plasma cfDNA/circulating tumor DNA (ctDNA) was analyzed before, during, and after androgen deprivation therapy (ADT) in 4 independent patient groups ranging from untreated metastatic hormone sensitive prostate cancer (mHSPC) to metastatic castrate resistant prostate cancer (mCRPC). Next generation sequencing was performed on ctDNA and germline DNA to characterize alterations and associations with clinical outcomes were determined for each group. FINDINGS: cfDNA yields were different in progressive mHSPC and mCRPC states (P < .001). In mHSPC, a higher than median ctDNA fraction was predictive of shorter time to ADT failure (HR, 2.29 [95% CI, 1.13-4.65]; Log-Rank P = .02). cfDNA, ctDNA taken with volume of metastatic disease in mHSPC and with alkaline phosphatase levels prognosticated survival better than clinical factors alone in mHSPC and mCRPC states (Log Rank P = 0.03). ctDNA-based AR, APC mutations were increased in mCRPC compared to mHSPC (P < ·05).TP53 mutations, RB1 loss, and AR gene amplifications correlated with poorer survival in mCRPC. Mutations in multiple DNA repair genes (ATM, BRCA1, BRCA2, CHEK2) were associated with time to ADT treatment failure and survival in mHSPC. INTERPRETATION: ctDNA fraction can further refine clinical prognostic factors in metastatic prostate cancer. Somatic ctDNA alterations have potential prognostic, predictive, and therapeutic implications in metastatic prostate cancer management. FUNDING: Several funding sources have supported this study. A full list is provided in the Acknowledgments. No funding was received from Predicine, Inc. during the conduct of the study.

11.
Eur J Surg Oncol ; 46(6): 1111-1117, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32201124

RESUMO

BACKGROUND: Squamous cell carcinoma (SCC) of the rectum is a rare form of gastrointestinal malignancy. The current knowledge on the natural history is primarily derived from case series. METHODS: Using the National Cancer Data Base (NCDB), we determined the prognostic factors and overall survival (OS) outcomes of rectal SCC reported to NCDB between 2004 and 2015. Kaplan-Meier method and log-rank test were used to perform OS analysis. Propensity matched analysis was undertaken to compare the OS outcomes between rectal and anal SCC. RESULTS: Of the 3405 cases included in our analysis, 67% were female. Median age at diagnosis was 61 years and did not differ by sex. In stages I-III, patients who received definitive chemoradiation only (108 months) had a better median OS as compared to surgery alone (76 months) (p = 0.012). On multivariate analysis, age <60 years, female sex, and receipt of chemoradiation with or without surgery were independent predictors of better OS in stage I-III disease. Administration of chemoradiation was associated with better OS in stage IV disease. On propensity matched analysis comparing outcomes to anal SCC, OS of rectal SCC was inferior (79 months) to anal SCC (113 months) (p < 0.001), no such difference in OS was noted in the cohorts that received surgery plus post-surgical chemoradiation (p = 0.12). CONCLUSION: Outcomes of rectal SCC were dependent upon age, sex, comorbidity score, and therapy received. Chemoradiation alone or in combination with surgery was associated with a better median OS in patients with stages I-III.

12.
HPB (Oxford) ; 22(10): 1490-1495, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32122786

RESUMO

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) has been used as an inflammation based prognostic marker for various malignancies. This study evaluated the association between NLR and overall survival (OS) in patients with metastatic gallbladder cancer (GBC) METHODS: An optimal cut off point for NLR was identified by plotting spline-based hazard ratio curves to identify a threshold effect and patients were divided into two groups, ≥5 or <5. Kaplan-Meier curves were plotted for NLR≥5 and NLR<5 and OS between the two groups. RESULTS: Of the 231 patients included, 138 (60%) had NLR <5 and 93 (40%) had NLR ≥5. There were no significant differences noted in gender, race, and administration of chemotherapy between the two groups. On univariable analysis, patients with NLR ≥5 had a significantly poor OS compared to those with NLR <5 (Median OS: 3.6 vs 8.7 months, p < 0.001). On multivariable analysis, adjusting for age, performance status, albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, platelet count and no administration of chemotherapy, NLR of ≥5 was associated with a worse OS compared to NLR <5 (HR: 1.70, 95%CI:1.20-2.39, p < 0.05). CONCLUSION: The current study demonstrates that NLR ≥5 is an independent predictor of poor prognosis in patients with metastatic GBC.

13.
J Clin Oncol ; 38(13): 1409-1418, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32125938

RESUMO

PURPOSE: To determine the sensitivity and specificity of genetic testing criteria for the detection of germline pathogenic variants in women with breast cancer. MATERIALS AND METHODS: Women with breast cancer enrolled in a breast cancer registry at a tertiary cancer center between 2000 and 2016 were evaluated for germline pathogenic variants in 9 breast cancer predisposition genes (ATM, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, and TP53). The performance of the National Comprehensive Cancer Network (NCCN) hereditary cancer testing criteria was evaluated relative to testing of all women as recommended by the American Society of Breast Surgeons. RESULTS: Of 3,907 women, 1,872 (47.9%) meeting NCCN criteria were more likely to carry a pathogenic variant in 9 predisposition genes compared with women not meeting criteria (9.0% v 3.5%; P < .001). Of those not meeting criteria (n = 2,035), 14 (0.7%) had pathogenic variants in BRCA1 or BRCA2. The sensitivity of NCCN criteria was 70% for 9 predisposition genes and 87% for BRCA1 and BRCA2, with a specificity of 53%. Expansion of the NCCN criteria to include all women diagnosed with breast cancer at ≤ 65 years of age achieved > 90% sensitivity for the 9 predisposition genes and > 98% sensitivity for BRCA1 and BRCA2. CONCLUSION: A substantial proportion of women with breast cancer carrying germline pathogenic variants in predisposition genes do not qualify for testing by NCCN criteria. Expansion of NCCN criteria to include all women diagnosed at ≤ 65 years of age improves the sensitivity of the selection criteria without requiring testing of all women with breast cancer.

15.
J Natl Compr Canc Netw ; 18(2): 151-159, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32023527

RESUMO

BACKGROUND: Current staging systems for gallbladder cancer (GBC) are primarily based on surgical pathology and therefore are not relevant for unresectable patients and those undergoing neoadjuvant chemotherapy. METHODS: Patients with a confirmed diagnosis of GBC managed at a tertiary referral center (2000-2016) were included. Independent predictors of overall survival (OS) were identified using multivariable analysis (MVA). A combination of these variables was then assessed to identify a set of factors that provided maximal accuracy in predicting OS, and a nomogram and a new staging system were created based on these factors. Harrell's C-statistic was calculated to evaluate the predictive accuracy of the nomogram and staging system. RESULTS: A total of 528 patients were included in the final analysis. On MVA, factors predictive of poor OS were older age, ECOG performance status, hemoglobin level <9 g/dL, presence of metastases, and alkaline phosphatase (ALP) level >200 U/L. A nomogram and a 4-tier staging system predictive of OS were created using age at diagnosis, ECOG status, tumor size, presence or absence of metastasis, and ALP level. The C-statistic for this novel staging system was 0.71 compared with 0.69 for the TNM staging system (P=.08). In patients who did not undergo surgery, the C-statistics of the novel and TNM staging systems were 0.60 and 0.51, respectively (P<.001). CONCLUSIONS: We created a novel, clinically based staging system for GBC based on nonoperative information at the time of diagnosis that was superior to the TNM staging system in predicting OS in patients who did not undergo surgery, and that performed on par with TNM staging in surgical patients.

16.
JCO Oncol Pract ; 16(7): e573-e580, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32048920

RESUMO

PURPOSE: There is a concern that influenza vaccination could increase the incidence of immune-related adverse events (irAEs) in patients with cancer receiving immune checkpoint inhibitors. The aim of our study was to determine the safety of influenza vaccination in this patient population. PATIENTS AND METHODS: We retrospectively identified patients who received at least 1 dose of pembrolizumab during any influenza season from September 2014 to August 2017 and reviewed medical records for irAEs. The primary endpoint was the incidence of irAEs. We used multivariable logistic regression and cumulative incidence curve with competing risks for comparison. RESULTS: Among 162 patients with cancer included in this study, 70 patients (43.2%) received at least 1 influenza vaccination. The vaccinated group was significantly older (P = .002) and received more cycles of pembrolizumab (P = .006). The incidence of any grade irAEs in the vaccinated group trended toward being lower (25.7% v 40.2%; P = .07) compared with the nonvaccinated group. Influenza vaccination was independently associated with fewer irAEs, with an odds ratio of 0.4 (95% CI, 0.2 to 0.9; P = .03) in multivariable analyses. The vaccinated group was less likely to have irAEs compared with the nonvaccinated group (24.7% v 34.4% at 12 months; P = .05), with death as a competing risk. The median irAE-free duration in the vaccinated group was longer than the nonvaccinated group (not reached v 28 months; P = .037). CONCLUSION: Influenza vaccination in patients with cancer receiving immune checkpoint inhibitor therapy was not associated with increased irAEs. This supports the safety of influenza vaccination in this patient population.

17.
J Natl Cancer Inst ; 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32091585

RESUMO

BACKGROUND: The germline cancer predisposition genes associated with increased risk of each clinical subtype of breast cancer, defined by estrogen receptor (ER), progesterone receptor (PR), and HER2, are not well defined. METHODS: A total of 54,555 invasive breast cancer patients with 56,480 breast tumors were subjected to clinical hereditary cancer multigene panel testing. Heterogeneity for predisposition genes across clinical breast cancer subtypes was assessed by comparing mutation frequencies by gene among tumor subtypes and by association studies between each tumor subtype and reference controls. RESULTS: Mutations in 15 cancer predisposition genes were detected in 8.6% of patients with ER+/HER2-; 8.9% with ER+/HER2+; 7.7% with ER-/HER2+; and 14.4% of ER-/PR-/HER2- tumors. BRCA1, BRCA2, BARD1 and PALB2 mutations were enriched in ER- and HER2- tumors, RAD51C and RAD51D mutations were enriched in ER- tumors only, TP53 mutations were enriched in HER2+ tumors, and ATM and CHEK2 mutations were enriched in both ER+ and/or HER2+ tumors. All genes were associated with moderate (odds ratio (OR)>2.00) or strong (OR > 5.00) risks of at least one subtype of breast cancer in case-control analyses. Mutations in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53 had predicted lifetime absolute risks of ≥ 20.0% for breast cancer. CONCLUSIONS: Germline mutations in hereditary cancer panel genes confer subtype-specific risks of breast cancer. Combined tumor subtype, age at breast cancer diagnosis, and family history of breast and/or ovarian cancer information provides refined categorical estimates of mutation prevalence for women considering genetic testing.

18.
Eur J Surg Oncol ; 46(5): 789-795, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31954549

RESUMO

BACKGROUND: CA19-9 elevation has shown to be associated with poor prognosis in extrahepatic cholangiocarcinoma (ECCA). However, the role of CA19-9 in staging of ECCA has not been evaluated. We hypothesized that CA19-9 elevation is a marker of aggressive biology in ECCA and that inclusion of CA19-9 in the staging system may improve overall survival (OS) discrimination. METHODS: Patients with ECCA whose CA19-9 levels, irrespective of surgical status, were reported to the National Cancer Database (2004-2015) were included. The patients were classified based on their CA19-9 levels and a new staging system was proposed. Net reclassification improvement (NRI) model was used to assess the predictive improvement in the proposed survival model as compared to AJCC-TNM staging. RESULTS: Of the 2100 patients included in the study, 626 (32%) and 1474 (68%) had normal and elevated CA19-9 levels (>38 U/ml), respectively. Median OS was lower among patients with elevated CA19-9 level compared to those with CA19-9 level ≤38 U/ml (8.5 vs 16 months, p < 0.01). On multivariate analysis, CA19-9 elevation independently predicted poor prognosis [HR:1.72 (1.46-2.02); p < 0.01] with similar impact as node-positivity, positive resection margins and non-receipt of chemotherapy. We developed a new staging system by incorporating CA19-9 into the 7th edition AJCC TNM staging system. NRI of 46% (95%CI: 39-57%) indicates that the new staging system is substantially effective at re-classifying events at 12 months as compared to AJCC 7th edition. CONCLUSION: Elevated CA19-9 was found to be an independent risk factor for mortality in ECCA and its inclusion in the proposed staging system improved OS discrimination.

19.
Neuroendocrinology ; 110(3-4): 234-245, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31121586

RESUMO

BACKGROUND: The role of perioperative systemic therapy (PST) in the management of localized pancreatic neuroendocrine neoplasms (PanNEN) is unclear. OBJECTIVES: We aimed to evaluate the benefit of PST compared to surgery alone (SA) in patients with localized PanNEN. METHOD: We selected patients with stages I-III PanNEN who underwent curative-intent surgical resection in National Cancer Database from 2006 to 2014. Patients who had both PST and surgical resection were matched with patients who received SA by propensity score at 1-to-1 ratio with nearest neighbor method. RESULTS: Four thousand eight hundred and ninety-two patients were included in this study with median age of 60 years. Factors associated with significant more use of PST compared to SA included age <65 years, community medical facilities, grade 3 tumor, tumor in the pancreatic head, T34 tumor, and N1 tumor. Three hundred and one PST patients were matched with 301 SA patients. In the matched cohort, the PST group had significantly shorter overall survival (OS) compared to the SA group (median overall both not reached, p = 0.037). This finding was confirmed by multivariable Cox proportional hazards regression in the original cohort (hazard ratio [HR] 1.45, 95% CI 1.11-1.89, p = 0.006). Subgroup analyses showed that adjuvant therapy was not associated with improved OS in grades 1-2 PanNEN (HR 2.03, 95% CI 1.31-3.16, p = 0.002). CONCLUSIONS: PST stratified by grade and neoadjuvant or adjuvant therapy compared to SA was not associated with improved OS in patients with localized PanNEN. PST for localized PanNEN should be used with caution until prospective data are available.

20.
Genet Med ; 22(2): 407-415, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31406321

RESUMO

PURPOSE: Despite the rapid uptake of multigene panel testing (MGPT) for hereditary cancer predisposition, there is limited guidance surrounding indications for testing and genes to include. METHODS: To inform the clinical approach to hereditary cancer MGPT, we comprehensively evaluated 32 cancer predisposition genes by assessing phenotype-specific pathogenic variant (PV) frequencies, cancer risk associations, and performance of genetic testing criteria in a cohort of 165,000 patients referred for MGPT. RESULTS: We identified extensive genetic heterogeneity surrounding predisposition to cancer types commonly referred for germline testing (breast, ovarian, colorectal, uterine/endometrial, pancreatic, and melanoma). PV frequencies were highest among patients with ovarian cancer (13.8%) and lowest among patients with melanoma (8.1%). Fewer than half of PVs identified in patients meeting testing criteria for only BRCA1/2 or only Lynch syndrome occurred in the respective genes (33.1% and 46.2%). In addition, 5.8% of patients with PVs in BRCA1/2 and 26.9% of patients with PVs in Lynch syndrome genes did not meet respective testing criteria. CONCLUSION: Opportunities to improve upon identification of patients at risk for hereditary cancer predisposition include revising BRCA1/2 and Lynch syndrome testing criteria to include additional clinically actionable genes with overlapping phenotypes and relaxing testing criteria for associated cancers.

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