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1.
JCO Oncol Pract ; 17(2): e236-e247, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33439686

RESUMO

PURPOSE: National guidelines recommend genetic counseling and multigene germline testing (GC/MGT) for all patients with pancreatic ductal adenocarcinoma (PDAC). This study's aim was to assess real-world effectiveness of implementing systematic GC/MGT for all patients with PDAC at a high-volume academic institution. METHODS: An iterative process for systematizing GC/MGT was developed in which gastrointestinal oncology providers at the Dana-Farber Cancer Institute were recommended to refer all patients with PDAC for GC/MGT (clinician-directed referral). Workflows were subsequently changed such that patients with PDAC were automatically offered GC/MGT when scheduling their initial oncology consultation (automated referral). Clinical and germline data were collected on a consecutive cohort of patients with PDAC undergoing GC/MGT during a 25-month enrollment period (19-month clinician-directed referrals; 6-month automated referrals). RESULTS: One thousand two hundred fourteen patients with PDAC were seen for initial oncologic evaluation, 266 (21.9%) of whom underwent GC/MGT. Compared with baseline clinician-directed referrals, implementation of automated referrals led to a significant increase in patients with PDAC undergoing GC/MGT (16.5% v 38.0%, P < .001), including those undergoing multigene germline testing (MGT) ≤ 7 days of initial oncology evaluation (14.7% v 60.3%, P < .001), with preserved pathogenic variant detection rates (10.0% v 11.2%, P = 0.84). 16 of 28 (57.1%) pathogenic variant carriers had relatives who pursued cascade germline testing, and 13 of 26 (50.0%) carriers with incurable disease received targeted therapy based on MGT results. CONCLUSION: Implementation of systematic GC/MGT in patients with PDAC is feasible and leads to management changes for patients with PDAC and their families. GC/MGT workflows that bypass the need for clinician referral result in superior uptake and time to testing. Further investigation is needed to identify other barriers and facilitators of universal GC/MGT.

2.
Clin Cancer Res ; 27(6): 1695-1705, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33414136

RESUMO

PURPOSE: Receptor tyrosine kinase fusions in colorectal cancers are rare, but potentially therapeutically relevant. We describe clinical, molecular, and pathologic attributes of RTK fusion-associated colorectal cancer. EXPERIMENTAL DESIGN: We identified all cases with RTK fusions in patients with colorectal cancer seen at Dana-Farber Cancer Institute (Boston, MA) who underwent OncoPanel testing between 2013 and 2018. Clinical, histologic, and molecular features were extracted from the patient charts and molecular testing results. RESULTS: We identified 12 driver oncogenic fusions in various RTKs. These fusions occurred exclusively in BRAF and RAS wild-type tumors and were enriched in right-sided and mismatch repair-deficient (MMR-D) colorectal cancers. All of the MMR-D colorectal cancers with RTK fusions were found in tumors with acquired MMR-D due to MLH1 promoter hypermethylation and one was associated with a sessile serrated polyp. Molecular profiles of MMR-D colorectal cancer with RTK fusions largely resembled BRAF V600E-mutated MMR-D colorectal cancer, rather than those secondary to Lynch syndrome. We describe two patients with fusion-associated microsatellite stable (MSS) colorectal cancer who derived clinical benefit from therapeutic targeting of their translocation. The first harbored an ALK-CAD fusion and received sequential crizotinib and alectinib therapy for a total of 7.5 months until developing an ALK L1196Q gatekeeper mutation. The second patient, whose tumor contained an ROS1-GOPC fusion, continues to benefit from entrectinib after 9 months of therapy. CONCLUSIONS: RTK fusions in colorectal cancer are a rare, but important disease subgroup that occurs in RAS and BRAF wild-type tumors. Despite enrichment in acquired MMR-D tumors, RTK fusions also occur in MSS colorectal cancer and provide an important therapeutic target.

3.
Clin Cancer Res ; 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33262135

RESUMO

PURPOSE: While abundant myeloid cell populations in the pancreatic ductal adenocarcinoma (PDAC) microenvironment have been postulated to suppress anti-tumor immunity, the composition of these populations, their spatial locations, and how they relate to patient outcomes are poorly understood. EXPERIMENTAL DESIGN: To generate spatially-resolved tumor and immune cell data at single cell resolution, we developed two quantitative multiplex immunofluorescence assays to interrogate myeloid cells (CD15, CD14, ARG1, CD33, HLA-DR) and macrophages [CD68, CD163, CD86, interferon regulatory factor 5 (IRF5), MRC1 (CD206)] in the PDAC tumor microenvironment. Spatial point pattern analyses were conducted to assess the degree of co-localization between tumor cells and immune cells. Multivariable-adjusted Cox proportional hazards regression was used to assess associations with patient outcomes. RESULTS: In a multi-institutional cohort of 305 primary PDAC resection specimens, myeloid cells were abundant, enriched within stromal regions, highly heterogeneous across tumors, and differed by somatic genotype. High densities of CD15+ARG1+ immunosuppressive granulocytic cells and M2-polarized macrophages were associated with worse patient survival. Moreover, beyond cell density, closer proximity of M2-polarized macrophages to tumor cells was strongly associated with disease-free survival, revealing the clinical significance and biologic importance of immune cell localization within tumor areas. CONCLUSIONS: A diverse set of myeloid cells are present within the PDAC tumor microenvironment and are distributed heterogeneously across patient tumors. Not only the densities but also the spatial locations of myeloid immune cells are associated with patient outcomes, highlighting the potential role of spatially-resolved myeloid cell subtypes as quantitative biomarkers for PDAC prognosis and therapy.

4.
Radiology ; : 201640, 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33231527

RESUMO

Background Although CT-based body composition (BC) metrics may inform disease risk and outcomes, obtaining these metrics has been too resource intensive for large-scale use. Thus, population-wide distributions of BC remain uncertain. Purpose To demonstrate the validity of fully automated, deep learning BC analysis from abdominal CT examinations, to define demographically adjusted BC reference curves, and to illustrate the advantage of use of these curves compared with standard methods, along with their biologic significance in predicting survival. Materials and Methods After external validation and equivalency testing with manual segmentation, a fully automated deep learning BC analysis pipeline was applied to a cross-sectional population cohort that included any outpatient without a cardiovascular disease or cancer who underwent abdominal CT examination at one of three hospitals in 2012. Demographically adjusted population reference curves were generated for each BC area. The z scores derived from these curves were compared with sex-specific thresholds for sarcopenia by using χ2 tests and used to predict 2-year survival in multivariable Cox proportional hazards models that included weight and body mass index (BMI). Results External validation showed excellent correlation (R = 0.99) and equivalency (P < .001) of the fully automated deep learning BC analysis method with manual segmentation. With use of the fully automated BC data from 12 128 outpatients (mean age, 52 years; 6936 [57%] women), age-, race-, and sex-normalized BC reference curves were generated. All BC areas varied significantly with these variables (P < .001 except for subcutaneous fat area vs age [P = .003]). Sex-specific thresholds for sarcopenia demonstrated that age and race bias were not present if z scores derived from the reference curves were used (P < .001). Skeletal muscle area z scores were significantly predictive of 2-year survival (P = .04) in combined models that included BMI. Conclusion Fully automated body composition (BC) metrics vary significantly by age, race, and sex. The z scores derived from reference curves for BC parameters better capture the demographic distribution of BC compared with standard methods and can help predict survival. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Summers in this issue.

5.
Cancer Epidemiol Biomarkers Prev ; 29(12): 2735-2739, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32967863

RESUMO

BACKGROUND: Whether circulating polyunsaturated fatty acid (PUFA) levels are associated with pancreatic cancer risk is uncertain. Mendelian randomization (MR) represents a study design using genetic instruments to better characterize the relationship between exposure and outcome. METHODS: We utilized data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium, involving approximately 9,269 cases and 12,530 controls of European descent, to evaluate associations between pancreatic cancer risk and genetically predicted plasma n-6 PUFA levels. Conventional MR analyses were performed using individual-level and summary-level data. RESULTS: Using genetic instruments, we did not find evidence of associations between genetically predicted plasma n-6 PUFA levels and pancreatic cancer risk [estimates per one SD increase in each PUFA-specific weighted genetic score using summary statistics: linoleic acid odds ratio (OR) = 1.00, 95% confidence interval (CI) = 0.98-1.02; arachidonic acid OR = 1.00, 95% CI = 0.99-1.01; and dihomo-gamma-linolenic acid OR = 0.95, 95% CI = 0.87-1.02]. The OR estimates remained virtually unchanged after adjustment for covariates, using individual-level data or summary statistics, or stratification by age and sex. CONCLUSIONS: Our results suggest that variations of genetically determined plasma n-6 PUFA levels are not associated with pancreatic cancer risk. IMPACT: These results suggest that modifying n-6 PUFA levels through food sources or supplementation may not influence risk of pancreatic cancer.

6.
JAMA Oncol ; 6(10): e202948, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32789511

RESUMO

Importance: Pancreatic cancer is the third-leading cause of cancer death in the United States; however, few high-risk groups have been identified to facilitate early diagnosis strategies. Objective: To evaluate the association of diabetes duration and recent weight change with subsequent risk of pancreatic cancer in the general population. Design, Setting, and Participants: This cohort study obtained data from female participants in the Nurses' Health Study and male participants in the Health Professionals Follow-Up Study, with repeated exposure assessments over 30 years. Incident cases of pancreatic cancer were identified from self-report or during follow-up of participant deaths. Deaths were ascertained through reports from the next of kin, the US Postal Service, or the National Death Index. Data collection was conducted from October 1, 2018, to December 31, 2018. Data analysis was performed from January 1, 2019, to June 30, 2019. Exposures: Duration of physician-diagnosed diabetes and recent weight change. Main Outcome and Measures: Hazard ratios (HRs) for subsequent development of pancreatic cancer. Results: Of the 112 818 women (with a mean [SD] age of 59.4 [11.7] years) and 46 207 men (with a mean [SD] age of 64.7 [10.8] years) included in the analysis, 1116 incident cases of pancreatic cancers were identified. Compared with participants with no diabetes, those with recent-onset diabetes had an age-adjusted HR for pancreatic cancer of 2.97 (95% CI, 2.31-3.82) and those with long-standing diabetes had an age-adjusted HR of 2.16 (95% CI, 1.78-2.60). Compared with those with no weight loss, participants who reported a 1- to 4-lb weight loss had an age-adjusted HR for pancreatic cancer of 1.25 (95% CI, 1.03-1.52), those with a 5- to 8-lb weight loss had an age-adjusted HR of 1.33 (95% CI, 1.06-1.66), and those with more than an 8-lb weight loss had an age-adjusted HR of 1.92 (95% CI, 1.58-2.32). Participants with recent-onset diabetes accompanied by weight loss of 1 to 8 lb (91 incident cases per 100 000 person-years [95% CI, 55-151]; HR, 3.61 [95% CI, 2.14-6.10]) or more than 8 lb (164 incident cases per 100 000 person-years [95% CI, 114-238]; HR, 6.75 [95% CI, 4.55-10.00]) had a substantially increased risk for pancreatic cancer compared with those with neither exposure (16 incident cases per 100 000 person-years; 95% CI, 14-17). Incidence rates were even higher among participants with recent-onset diabetes and weight loss with a body mass index of less than 25 before weight loss (400 incident cases per 100 000 person-years) or whose weight loss was not intentional judging from increased physical activity or healthier dietary choices (334 incident cases per 100 000 person-years). Conclusions and Relevance: This study demonstrates that recent-onset diabetes accompanied by weight loss is associated with a substantially increased risk for developing pancreatic cancer. Older age, previous healthy weight, and no intentional weight loss further elevate this risk.

7.
Cancer Epidemiol Biomarkers Prev ; 29(8): 1586-1595, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32467349

RESUMO

BACKGROUND: Insulin-like growth factor-1 receptor (IGF1R) signaling is important in pancreatic ductal adenocarcinoma (PDAC) biology, but little is known regarding IGF1R expression and patient characteristics and outcomes. METHODS: In 365 patients with resected PDAC, we evaluated IGF1R protein expression using IHC on whole-slide sections and IGF1R genomic status using next-generation sequencing. Associations of IGF1R expression, measured by H-scores incorporating staining intensity and proportion of positive tumor cells, with disease-free survival (DFS) and overall survival (OS) were evaluated in 317 and 321 patients, respectively, using Cox regression adjusting for known prognostic factors. RESULTS: Higher IGF1R expression in tumor cells was associated with worse DFS comparing highest versus lowest expression tertiles [median DFS, 10.8 vs. 16.1 months; adjusted hazard ratio (HR), 1.73; 95% confidence interval (CI), 1.24-2.44; P trend = 0.002] and worse OS (median OS, 17.4 vs. 25.8 months; HR, 1.39; 95% CI, 1.00-1.92; P trend = 0.046). The association between high IGF1R expression and reduced DFS was identified primarily among patients with a preoperative body mass index ≥25 kg/m2 (HR, 4.27; 95% CI, 2.03-8.96, comparing extreme tertiles; P interaction = 0.032). KRAS-mutant tumors had greater IGF1R expression, and IGF1R expression in tumor epithelium was inversely correlated with that in stromal cells. Mutations in IGF1R were infrequent, and no overt loss-of-function alterations were identified. Higher IGF1R expression was modestly associated with higher gene copy number (Pearson correlation coefficient = 0.26, P < 0.001). CONCLUSIONS: Higher IGF1R protein expression was associated with worse patient outcomes in resected PDAC. IMPACT: IGF1R expression in PDAC represents a potential biomarker to guide patient selection for more aggressive, multidrug regimens in the adjuvant setting.

8.
Cancer Epidemiol Biomarkers Prev ; 29(5): 999-1008, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32321713

RESUMO

BACKGROUND: Pancreatic cancer is the third leading cause of cancer death in the United States, and 80% of patients present with advanced, incurable disease. Risk markers for pancreatic cancer have been characterized, but combined models are not used clinically to identify individuals at high risk for the disease. METHODS: Within a nested case-control study of 500 pancreatic cancer cases diagnosed after blood collection and 1,091 matched controls enrolled in four U.S. prospective cohorts, we characterized absolute risk models that included clinical factors (e.g., body mass index, history of diabetes), germline genetic polymorphisms, and circulating biomarkers. RESULTS: Model discrimination showed an area under ROC curve of 0.62 via cross-validation. Our final integrated model identified 3.7% of men and 2.6% of women who had at least 3 times greater than average risk in the ensuing 10 years. Individuals within the top risk percentile had a 4% risk of developing pancreatic cancer by age 80 years and 2% 10-year risk at age 70 years. CONCLUSIONS: Risk models that include established clinical, genetic, and circulating factors improved disease discrimination over models using clinical factors alone. IMPACT: Absolute risk models for pancreatic cancer may help identify individuals in the general population appropriate for disease interception.

9.
Pancreas ; 49(2): 249-254, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32011530

RESUMO

OBJECTIVE: Given the lack of consensus on surveillance guidelines after pancreatic neuroendocrine tumor (PanNET) resection, we assessed outcomes in a large cohort of patients with nonmetastatic, surgically resected PanNETs. METHODS: Data of patients with PanNETs resected between 1990 and 2017 were retrospectively collected using databases at 3 academic institutions. The National Death Index was queried to determine vital status. Kaplan-Meier analysis was used to estimate recurrence-free survival (RFS) and disease-specific survival (DSS) rates. Variables associated with recurrence and disease-related death were identified through Cox multivariate analyses. RESULTS: Of 307 patients with PanNET who underwent resection, recurrence occurred in 79 (26%) of patients. For stage I and II disease, 5-year RFS rates were 90% and 43%, whereas 5-year DSS rates were 98% and 86% (P < 0.0001 and P = 0.0038, respectively). For grades 1, 2, and 3 disease, 5-year RFS rates were 87%, 49%, and 18%, and 5-year DSS rates were 98%, 89%, and 51% (P < 0.0001 for both). Stage II, grade 2, and grade 3 disease were each associated with increased recurrence and disease-specific death. CONCLUSIONS: Stage and grade are important prognostic factors that should be utilized to tailor postsurgical surveillance after curative resection of PanNET.

10.
Oncologist ; 25(4): e644-e650, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31999024

RESUMO

BACKGROUND: Although an increasing number of treatments have become available for patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs), there remains little consensus on treatment sequence and its impact on health care resource use (HRU). We sought to describe treatment patterns and HRU, in a cohort of patients with metastatic GEP-NETs treated at a tertiary referral center in the U.S. MATERIALS AND METHODS: We identified patients with a well-differentiated, metastatic GEP-NET evaluated at Dana-Farber Cancer Institute between July 2003 and May 2015. For these patients, we describe the sequence of treatment regimens received for their disease, together with associated HRU. RESULTS: We identified 682 patients with advanced GEP-NETs. Of these patients, 597 (87.0%) initiated ≥1 treatment over the follow-up period. The mean age at diagnosis was 58.5 years, 50.2% were men, and 94.0% were white. A total of 83.1% initiated a somatostatin analog (SSA) as their first-line treatment, with 55% and 31% of patients continuing with second- and third-line therapies. A total of 31.2% of patients with SSAs underwent dose escalation to above standard dose. In this setting, patients with pancreatic neuroendocrine tumors were more commonly treated with cytotoxic regimens than other NET tumor types and also had higher HRU. CONCLUSION: Our study suggests that, at a tertiary referral center, patients with advanced NETs commonly received multiple courses of treatments. Our data suggest a clear preference for use of SSAs as a first-line treatment for patients with advanced NETs, with SSAs commonly escalated and continued throughout the course of treatment in combination with other regimens. IMPLICATIONS FOR PRACTICE: The current study demonstrates the common use of somatostatin analog as a first-line therapy for patients with advanced gastroenteropancreatic neuroendocrine tumors as well as the incorporation of multiple different treatment regimens in the treatment course of patients with this disease.

11.
Cancer Epidemiol Biomarkers Prev ; 28(12): 2062-2069, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31533940

RESUMO

BACKGROUND: Pancreatic cancer is associated with development of cachexia, a wasting syndrome thought to limit survival. Few studies have longitudinally quantified peripheral tissues or identified biomarkers predictive of future tissue wasting. METHODS: Adipose and muscle tissue were measured by computed tomography (CT) at diagnosis and 50 to 120 days later in 164 patients with advanced pancreatic cancer. Tissue changes and survival were evaluated by Cox proportional hazards regression. Baseline levels of circulating markers were examined in relation to future tissue wasting. RESULTS: Compared with patients in the bottom quartile of muscle change per 30 days (average gain of 0.8 ± 2.0 cm2), those in the top quartile (average loss of 12.9 ± 4.9 cm2) had a hazard ratio (HR) for death of 2.01 [95% confidence interval (CI), 1.12-3.62]. Patients in the top quartile of muscle attenuation change (average decrease of 4.9 ± 2.4 Hounsfield units) had an HR of 2.19 (95% CI, 1.18-4.04) compared with those in the bottom quartile (average increase of 2.4 ± 1.6 Hounsfield units). Changes in adipose tissue were not associated with survival. Higher plasma branched chain amino acids (BCAA; P = 0.004) and lower monocyte chemoattractant protein-1 (MCP-1; P = 0.005) at diagnosis were associated with greater future muscle loss. CONCLUSIONS: In patients with advanced pancreatic cancer, muscle loss and decrease in muscle density in 2 to 4 months after diagnosis were associated with reduced survival. BCAAs and MCP-1 levels at diagnosis were associated with subsequent muscle loss. IMPACT: BCAAs and MCP-1 levels at diagnosis could identify a high-risk group for future tissue wasting.


Assuntos
Tecido Adiposo/fisiopatologia , Composição Corporal , Músculo Esquelético/fisiopatologia , Neoplasias Pancreáticas/mortalidade , Tomografia Computadorizada por Raios X/métodos , Tecido Adiposo/diagnóstico por imagem , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
12.
Cancer Immunol Res ; 7(8): 1230-1236, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31217164

RESUMO

Immunotherapy with checkpoint inhibitors, such as the programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab, are effective in a variety of tumors, yet not all patients respond. Tumor microsatellite instability-high (MSI-H) has emerged as a biomarker of response to checkpoint blockade, leading to the tissue agnostic approval of pembrolizumab in MSI-H cancers. Here we describe a patient with MSI-H colorectal cancer that was treated with this immune checkpoint inhibitor and exhibited progression of disease. We examined this intrinsic resistance through genomic, transcriptional, and pathologic characterization of the patient's tumor and the associated immune microenvironment. The tumor had typical MSI-H molecular features, including a high neoantigen load. We also identified biallelic loss of the gene for ß2-microglobulin (B2M), whose product is critical for antigen presentation. Immune infiltration deconvolution analysis of bulk transcriptome data from this anti-PD-1-resistant tumor and hundreds of other colorectal cancer specimens revealed a high natural killer cell and M2 macrophage infiltration in the patient's cancer. This was confirmed by single-cell transcriptome analysis and multiplex immunofluorescence. Our study provides insight into resistance in MSI-H tumors and suggests immunotherapeutic strategies in additional genomic contexts of colorectal cancer.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA , Resistencia a Medicamentos Antineoplásicos/genética , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Variações do Número de Cópias de DNA , Metilação de DNA , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Mutação , Análise de Célula Única , Tomografia Computadorizada por Raios X
13.
Genet Med ; 21(1): 213-223, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29961768

RESUMO

PURPOSE: Germline variants in double-strand DNA damage repair (dsDDR) genes (e.g., BRCA1/2) predispose to pancreatic adenocarcinoma (PDAC) and may predict sensitivity to platinum-based chemotherapy and poly(ADP) ribose polymerase (PARP) inhibitors. We sought to determine the prevalence and significance of germline cancer susceptibility gene variants in PDAC with paired somatic and survival analyses. METHODS: Using a customized next-generation sequencing panel, germline/somatic DNA was analyzed from 289 patients with resected PDAC ascertained without preselection for high-risk features (e.g., young age, personal/family history). All identified variants were assessed for pathogenicity. Outcomes were analyzed using multivariable-adjusted Cox proportional hazards regression. RESULTS: We found that 28/289 (9.7%; 95% confidence interval [CI] 6.5-13.7%) patients carried pathogenic/likely pathogenic germline variants, including 21 (7.3%) dsDDR gene variants (3 BRCA1, 4 BRCA2, 14 other dsDDR genes [ATM, BRIP1, CHEK2, NBN, PALB2, RAD50, RAD51C]), 3 Lynch syndrome, and 4 other genes (APC p.I1307K, CDKN2A, TP53). Somatic sequencing and immunohistochemistry identified second hits in the tumor in 12/27 (44.4%) patients with germline variants (1 failed sequencing). Compared with noncarriers, patients with germline dsDDR gene variants had superior overall survival (hazard ratio [HR] 0.54; 95% CI 0.30-0.99; P = 0.05). CONCLUSION: Nearly 10% of PDAC patients harbor germline variants, although the majority lack somatic second hits, the therapeutic significance of which warrants further study.


Assuntos
Adenocarcinoma/genética , Predisposição Genética para Doença , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/genética , Adenocarcinoma/epidemiologia , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Quebras de DNA de Cadeia Dupla , Intervalo Livre de Doença , Grupos Étnicos/genética , Feminino , Mutação em Linhagem Germinativa/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia
14.
Cancer Discov ; 8(9): 1096-1111, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29903880

RESUMO

Clinically relevant subtypes exist for pancreatic ductal adenocarcinoma (PDAC), but molecular characterization is not yet standard in clinical care. We implemented a biopsy protocol to perform time-sensitive whole-exome sequencing and RNA sequencing for patients with advanced PDAC. Therapeutically relevant genomic alterations were identified in 48% (34/71) and pathogenic/likely pathogenic germline alterations in 18% (13/71) of patients. Overall, 30% (21/71) of enrolled patients experienced a change in clinical management as a result of genomic data. Twenty-six patients had germline and/or somatic alterations in DNA-damage repair genes, and 5 additional patients had mutational signatures of homologous recombination deficiency but no identified causal genomic alteration. Two patients had oncogenic in-frame BRAF deletions, and we report the first clinical evidence that this alteration confers sensitivity to MAPK pathway inhibition. Moreover, we identified tumor/stroma gene expression signatures with clinical relevance. Collectively, these data demonstrate the feasibility and value of real-time genomic characterization of advanced PDAC.Significance: Molecular analyses of metastatic PDAC tumors are challenging due to the heterogeneous cellular composition of biopsy specimens and rapid progression of the disease. Using an integrated multidisciplinary biopsy program, we demonstrate that real-time genomic characterization of advanced PDAC can identify clinically relevant alterations that inform management of this difficult disease. Cancer Discov; 8(9); 1096-111. ©2018 AACR.See related commentary by Collisson, p. 1062This article is highlighted in the In This Issue feature, p. 1047.


Assuntos
Carcinoma Ductal Pancreático/genética , Perfilação da Expressão Gênica/métodos , Variação Genética , Genômica/métodos , Neoplasias Pancreáticas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/tratamento farmacológico , Reparo do DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Mutação em Linhagem Germinativa , Recombinação Homóloga , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/tratamento farmacológico , Medicina de Precisão , Análise de Sequência de RNA/métodos , Sequenciamento Completo do Exoma/métodos
15.
Nature ; 558(7711): 600-604, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29925948

RESUMO

Malignancy is accompanied by changes in the metabolism of both cells and the organism1,2. Pancreatic ductal adenocarcinoma (PDAC) is associated with wasting of peripheral tissues, a metabolic syndrome that lowers quality of life and has been proposed to decrease survival of patients with cancer3,4. Tissue wasting is a multifactorial disease and targeting specific circulating factors to reverse this syndrome has been mostly ineffective in the clinic5,6. Here we show that loss of both adipose and muscle tissue occurs early in the development of pancreatic cancer. Using mouse models of PDAC, we show that tumour growth in the pancreas but not in other sites leads to adipose tissue wasting, suggesting that tumour growth within the pancreatic environment contributes to this wasting phenotype. We find that decreased exocrine pancreatic function is a driver of adipose tissue loss and that replacement of pancreatic enzymes attenuates PDAC-associated wasting of peripheral tissues. Paradoxically, reversal of adipose tissue loss impairs survival in mice with PDAC. When analysing patients with PDAC, we find that depletion of adipose and skeletal muscle tissues at the time of diagnosis is common, but is not associated with worse survival. Taken together, these results provide an explanation for wasting of adipose tissue in early PDAC and suggest that early loss of peripheral tissue associated with pancreatic cancer may not impair survival.


Assuntos
Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Insuficiência Pancreática Exócrina/etiologia , Insuficiência Pancreática Exócrina/metabolismo , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/patologia , Animais , Composição Corporal , Modelos Animais de Doenças , Progressão da Doença , Insuficiência Pancreática Exócrina/patologia , Feminino , Masculino , Camundongos , Neoplasias Pancreáticas/metabolismo
16.
JAMA Oncol ; 4(3): e173420, 2018 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-29098284

RESUMO

Importance: Although patients with resected pancreatic adenocarcinoma are at high risk for disease recurrence, few biomarkers are available to inform patient outcomes. Objective: To evaluate the alterations of the 4 main driver genes in pancreatic adenocarcinoma and patient outcomes after cancer resection. Design, Setting, and Participants: This study analyzed protein expression and DNA alterations for the KRAS, CDKN2A, SMAD4, and TP53 genes by immunohistochemistry and next-generation sequencing in formalin-fixed, paraffin-embedded tumors in 356 patients with resected pancreatic adenocarcinoma who were treated at the Dana-Farber/Brigham and Women's Cancer Center (October 26, 2002, to May 21, 2012), University of Rochester Medical Center (March 1, 2006, to November 1, 2013), or Stanford Cancer Institute (September 26, 1995, to May 22, 2013). Associations of driver gene alterations with disease-free survival (DFS) and overall survival (OS) were evaluated using Cox proportional hazards regression with estimation of hazard ratios (HRs) and 95% CIs and adjustment for age, sex, tumor characteristics, institution, and perioperative treatment. Data were collected September 9, 2012, to June 28, 2016, and analyzed December 17, 2016, to March 14, 2017. Main Outcomes and Measures: The DFS and OS among patients with resected pancreatic adenocarcinoma. Results: Of the 356 patients studied, 191 (53.7%) were men and 165 (46.3%) were women, with a median (interquartile range [IQR]) age of 67 (59.0-73.5) years. Patients with KRAS mutant tumors had worse DFS (median [IQR], 12.3 [6.7 -27.2] months) and OS (20.3 [11.3-38.3] months) compared with patients with KRAS wild-type tumors (DFS, 16.2 [8.9-30.5] months; OS, 38.6 [16.6-63.1] months) and had 5-year OS of 13.0% vs 30.2%. Particularly poor outcomes were identified in patients with KRAS G12D-mutant tumors, who had a median (IQR) OS of 15.3 (9.8-32.7) months. Patients whose tumors lacked CDKN2A expression had worse DFS (median, 11.5 [IQR, 6.2-24.5] months) and OS (19.7 [10.9-37.1] months) compared with patients who had intact CDKN2A (DFS, 14.8 [8.2-30.5] months; OS, 24.6 [14.1-44.6] months). The molecular status of SMAD4 was not associated with DFS or OS, whereas TP53 status was associated only with shorter DFS (HR, 1.33; 95% CI, 1.02-1.75; P = .04). Patients had worse DFS and OS if they had a greater number of altered driver genes. Compared with patients with 0 to 2 altered genes, those with 4 altered genes had worse DFS (HR, 1.79 [95% CI, 1.24-2.59; P = .002]) and OS (HR, 1.38 [95% CI, 0.98-1.94; P = .06]). Five-year OS was 18.4% for patients with 0 to 2 gene alterations, 14.1% for those with 3 alterations, and 8.2% for those with 4 alterations. Conclusions and Relevance: Patient outcomes are associated with alterations of the 4 main driver genes in resected pancreatic adenocarcinoma.


Assuntos
Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/cirurgia , Mutação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/cirurgia , Proteínas Proto-Oncogênicas/genética , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Análise Mutacional de DNA/métodos , Feminino , Seguimentos , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Pancreatectomia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Prognóstico , Proteínas Proto-Oncogênicas/metabolismo , Análise de Sobrevida , Resultado do Tratamento
17.
Pancreas ; 46(10): 1347-1353, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28991877

RESUMO

OBJECTIVES: Dysregulation of the cell cycle has been observed and implicated as an etiologic factor in a range of human malignancies, but remains relatively unstudied in neuroendocrine tumors (NETs). We evaluated expression of key proteins involved in cell cycle regulation in a large cohort of NETs. METHODS: We evaluated immunohistochemical expression of CDKN1B, CDKN1A, CDKN2A, CDK2, CDK4, CDK6, cyclin D1, cyclin E1, and phosphorylated retinoblastoma protein (phospho-RB1) in a cohort of 267 patients with NETs. We then explored associations between cell cycle protein expression, mutational status, histologic features, and overall survival. RESULTS: We found that high expression of CDK4, CDK6, CCND1, and phospho-RB1 was associated with higher proliferative index, as defined by MKI67. We additionally observed a trend toward shorter overall survival associated with low expression of CDKN1B. This association seemed strongest in SINETs (multivariate hazards ratio, 2.04; 95% confidence interval, 1.06-3.93; P = 0.03). We found no clear association between CDKN1B mutation and protein expression. CONCLUSIONS: Our results suggest that dysregulation and activation of the CDK4/CDK6-CCND1-phospho-RB1 axis is associated with higher proliferative index in NETs. Investigation of the therapeutic potential of CDK4/CDK6 inhibitors in higher grade NETs is warranted.


Assuntos
Proteínas de Ciclo Celular/biossíntese , Ciclina D1/biossíntese , Quinase 4 Dependente de Ciclina/biossíntese , Quinase 6 Dependente de Ciclina/biossíntese , Tumores Neuroendócrinos/metabolismo , Proteína do Retinoblastoma/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Índice Mitótico , Tumores Neuroendócrinos/patologia , Fosforilação , Proteína do Retinoblastoma/metabolismo , Adulto Jovem
18.
Br J Cancer ; 117(12): 1874-1882, 2017 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-28982112

RESUMO

BACKGROUND: Few studies have simultaneously assessed the prognostic value of the multiple classification systems for lymph node (LN) metastases in resected pancreatic ductal adenocarcinoma (PDAC). METHODS: In 600 patients with resected PDAC, we examined the association of LN parameters (AJCC 7th and 8th editions, LN ratio (LNR), and log odds of metastatic LN (LODDS)) with pattern of recurrence and patient survival using logistic regression and Cox proportional hazards regression, respectively. Regression models adjusted for age, sex, margin status, tumour grade, and perioperative therapy. RESULTS: Lymph node metastases classified by AJCC 7th and 8th editions, LNR, and LODDS were associated with worse disease free-survival (DFS) and overall survival (OS) (all Ptrend<0.01). American Joint Committee on Cancer 8th edition effectively predicted DFS and OS, while minimising model complexity. Lymph node metastases had weaker prognostic value in patients with positive margins and distal resections (both Pinteraction<0.03). Lymph node metastases by AJCC 7th and 8th editions did not predict the likelihood of local disease as the first site of recurrence. CONCLUSIONS: American Joint Committee on Cancer 8th edition LN classification is an effective and practical tool to predict outcomes in patients with resected PDAC. However, the prognostic value of LN metastases is attenuated in patients with positive resection margins and distal pancreatectomies.


Assuntos
Carcinoma Ductal Pancreático/secundário , Excisão de Linfonodo , Linfonodos/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias Pancreáticas/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/cirurgia , Intervalo Livre de Doença , Feminino , Humanos , Linfonodos/cirurgia , Metástase Linfática , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Neoplasia Residual , Pancreatectomia/métodos , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia/métodos , Modelos de Riscos Proporcionais , Taxa de Sobrevida
19.
Cancer ; 123(14): 2735-2742, 2017 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-28267211

RESUMO

BACKGROUND: Patients with carcinoid tumors frequently could benefit from the pharmacologic treatment of depression and anxiety. However, many prescribers avoid serotonergic medications due to the theoretical risk of exacerbating carcinoid syndrome. METHODS: The authors conducted a retrospective chart review of patients with carcinoid tumors and elevated serotonin levels (as measured by 24-hour urine 5-hydroxyindoleacetic acid [5-HIAA]) at Dana-Farber/Brigham and Women's Cancer Center who initiated treatment with serotonergic antidepressants after a carcinoid diagnosis from 2003 to 2016. Each medication regimen was categorized based on the presence of adverse interactions as defined by clinical worsening of symptoms of carcinoid syndrome in the absence of progressive disease that temporally correlated with a serotonergic medication trial. RESULTS: A total of 73 serotonergic regimens received by 52 patients were included in the primary analysis. Among these medication trials, 8.2% of the regimens (6 regimens) were categorized as being associated with a likely adverse interaction, 61.6% of the regimens (45 regimens) were categorized as having no adverse reaction, 9.6% of the regimens (7 regimens) were categorized as an unlikely adverse reaction, and 20.6% of the regimens (15 regimens) were categorized as unknown. It is interesting to note that none of the 73 trials resulted in a carcinoid crisis requiring emergency care or hospitalization. Only 3 patients discontinued serotonergic medications due to worsening carcinoid syndrome. CONCLUSIONS: Serotonergic medications appear to be a safe option for the treatment of depressive and anxiety symptoms in the majority of patients with neuroendocrine tumors and carcinoid syndrome. In the current study, <10% of patients developed a combination of flushing, diarrhea, and bloating after the initiation of serotonergic medications. Clinicians can begin with low doses, monitor these symptoms, and reduce the dose or discontinue the medication if necessary. Cancer 2017;123:2735-42. © 2017 American Cancer Society.


Assuntos
Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Síndrome do Carcinoide Maligno/metabolismo , Inibidores de Captação de Serotonina/uso terapêutico , Ansiedade/complicações , Tumor Carcinoide/complicações , Tumor Carcinoide/metabolismo , Depressão/complicações , Diarreia/induzido quimicamente , Diarreia/etiologia , Feminino , Rubor/induzido quimicamente , Rubor/etiologia , Humanos , Ácido Hidroxi-Indolacético/urina , Masculino , Síndrome do Carcinoide Maligno/complicações , Estudos Retrospectivos
20.
Ann Surg Oncol ; 24(8): 2319-2325, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28303430

RESUMO

BACKGROUND: Liver-directed therapies have been used to treat neuroendocrine liver metastases (NELM) for both symptomatic improvement and tumor growth control. We reviewed our experience with NELM to investigate the outcomes of available treatment modalities and to identify prognostic factors for survival. METHODS: We identified all patients with NELM, who were managed at our institution, from a prospectively collected institutional database. Overall survival (OS) was determined for each treatment modality. RESULTS: Between 2003 and 2010, we identified 939 patients with neuroendocrine tumors, of whom 649 patients had NELM. The primary tumor site was the small intestine in 245 patients (38%) and pancreas in 194 patients (30%). With a median follow-up of 44 months, the median, 5 and 10 year OS for each treatment group was as follows: hepatic resection (n = 58, 9%), 160 months, 90%, 70%; radiofrequency ablation (n = 28, 4%), 123 months, 84%, 55%; chemoembolization (n = 130, 20%), 66 months, 55%, 28%; systemic therapy (n = 316, 49%), 70 months, 58%, 31%; and observation (n = 117, 18%), 38 months, 38%, 20%. Age [hazard ratio (HR) 1.0, p < 0.001), small bowel primary site (HR 0.5, p < 0.001), hepatic resection (HR 0.3, p = 0.001), well-differentiated tumors (HR 0.3, p < 0.001), alkaline phosphatase within normal limit (WNL) (HR 0.4, p < 0.001), and chromogranin A WNL (HR 0.5, p < 0.001) were significant independent prognosticators for OS. CONCLUSIONS: This series represents one of the largest single-institution studies of NELM reported. We found that hepatic resection was associated with highly favorable OS. Our observations support hepatic resection in appropriately selected patients.


Assuntos
Ablação por Cateter/mortalidade , Terapia Combinada/mortalidade , Hepatectomia/mortalidade , Neoplasias Hepáticas/mortalidade , Tumores Neuroendócrinos/mortalidade , Gerenciamento Clínico , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/terapia , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida
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