Publications by authors named "Lauren K Brais"

32 Publications

Phase II study of pembrolizumab in refractory esophageal cancer with correlates of response and survival.

J Immunother Cancer 2021 09;9(9)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

Background: Immune checkpoint inhibitors have revolutionized cancer treatment, but the benefits in refractory patients with esophageal cancer have been modest. Predictors of response as well as new targets for novel therapeutic combinations are needed. In this phase 2 clinical trial, we tested single-agent pembrolizumab in patients with advanced esophageal cancer, who received at least one prior line of therapy.

Methods: Pembrolizumab 200 mg every 3 weeks was tested in 49 patients with refractory esophageal cancer: 39 with adenocarcinoma and 10 with esophageal squamous cell carcinoma. Major endpoints were radiological response by Immune-related Response Evaluation Criteria In Solid Tumors and survival. Tumor samples were evaluated for programmed cell death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), and immune contexture by both NanoString mRNA expression analysis and flow cytometry. Peripheral blood mononuclear cells and a panel of circulating chemokines were also analyzed.

Results: The overall response rate (ORR) was 8% (4 of 49 patients; 95% CI 2.3% to 19.6%). Median overall survival (OS) was 5.8 months (95% CI 4.0 to 9.5). ORR and OS were not associated with histology. For PD-L1-positive patients, ORR was 13.3% (95% CI 1.7% to 40.5%) and median OS was 7.9 months (95% CI 4.7 to 15.5). A trend toward improved OS was observed in seven patients with a TMB ≥10 mut/Mb (p=0.086). Tumors with a PD-L1 Combined Positive Score ≥1 showed enrichment of LAG3 (p=0.005) and IDO1 (p=0.04) gene expression. Baseline levels of circulating CXCL10, interleukin 2 (IL2) receptor α (IL2RA) and IL6 were associated with survival: CXCL10 favorably, (HR 0.37, p=0.002 (progression-free survival); HR 0.55, p=0.018 (OS)); IL2RA and IL6 unfavorably (HR 1.57, p=0.020 for IL6 (OS); HR 2.36, p=0.025 for IL2RA (OS)).

Conclusions: Pembrolizumab monotherapy was modestly effective in refractory esophageal cancer. Circulating CXCL10 at baseline appeared to be a robust predictor of response. Other T cell exhaustion markers are upregulated in PD-L1-positive patients, suggesting that immunotherapy combinations such as anti-LAG3/programmed cell death protein 1 (PD-1) or anti-IDO1/PD-1 may be of promise in refractory esophageal cancer.
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http://dx.doi.org/10.1136/jitc-2021-002472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487210PMC
September 2021

Spatially organized multicellular immune hubs in human colorectal cancer.

Cell 2021 Sep 26;184(18):4734-4752.e20. Epub 2021 Aug 26.

Department of Immunology, HMS, Boston, MA, USA.

Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.
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http://dx.doi.org/10.1016/j.cell.2021.08.003DOI Listing
September 2021

Trifluridine/Tipiracil and Regorafenib in Patients with Metastatic Colorectal Cancer: A Retrospective Study at a Tertiary Oncology Center.

Oncologist 2021 Aug 18. Epub 2021 Aug 18.

Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Background: Trifluridine/tipiracil (FTD/TPI) and regorafenib prolong survival for patients with refractory metastatic colorectal cancer (mCRC); limited comparative effectiveness data exist.

Materials And Methods: A retrospective, longitudinal cohort study of patients with mCRC who initiated FTD/TPI or regorafenib (index therapy) between 2012 and 2017 at a U.S. tertiary oncology center, Dana-Farber Cancer Institute, was conducted. Using best tumor response assessments, real-world overall response rates (rwORR) and disease control rates (rwDCR) were described and analyzed using logistic regression. Survival rate was examined for each month after index therapy using Kaplan-Meier. Overall survival (OS) was assessed using Cox proportional hazards models. Subgroup analyses among patients with index therapy as second- or third-line were performed.

Results: One hundred twenty-six and 95 patients were treated with FTD/TPI or regorafenib as index therapy, respectively. Patients treated with FTD/TPI versus regorafenib had a better response (rwORR 52.5% vs. 34.2%; adjusted odds ratio [OR] = 2.6; all p value <.05; rwDCR 64.2% vs. 46.1%; adjusted OR = 2.5; all p value <.05). Similar findings were observed for FTD/TPI versus regorafenib as second- or third-line therapy (rwORR 54.8% vs. 25.9%; adjusted OR = 4.1; all p value <.05; rwDCR 69.0% vs. 37.0%; adjusted OR = 4.9; all p value <.05). A greater proportion of patients treated with FTD/TPI versus regorafenib survived at 3 months (86.2% vs. 73.4%; p value = .016) and 4 months (79.6% vs. 65.8%; p value = .017). Adjusted OS hazard ratio for FTD/TPI versus regorafenib was 0.80, p value = .157.

Conclusion: Patients treated with FTD/TPI had better tumor response and disease control than patients treated with regorafenib. Subgroup analysis in second- or third-line suggests that early use of FTD/TPI may have clinical benefits.

Implications For Practice: In this retrospective cohort study, patients with refractory metastatic colorectal cancer treated with trifluridine/tipiracil (FTD/TPI) were significantly less likely than those treated with regorafenib to have dose modifications and more likely to have higher real-world objective response rate (rwORR) and real-world disease control rate (rwDCR) while treated. Patients treated with FTD/TPI versus regorafenib had significantly higher odds of having rwORR or rwDCR in adjusted analyses. Monthly survival rates were higher overall in patients treated with FTD/TPI versus regorafenib in the first 6 months of follow-up, particularly at months 3 and 4. This study offers insight into patients' treatment experience in real-world clinical settings.
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http://dx.doi.org/10.1002/onco.13942DOI Listing
August 2021

Hepcidin-regulating iron metabolism genes and pancreatic ductal adenocarcinoma: a pathway analysis of genome-wide association studies.

Am J Clin Nutr 2021 10;114(4):1408-1417

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Background: Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis.

Objectives: The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC.

Methods: We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs.

Results: The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association.

Conclusions: Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association.
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http://dx.doi.org/10.1093/ajcn/nqab217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488877PMC
October 2021

Extracellular Domain In-Frame Deletions Are Therapeutically Targetable Genomic Alterations That Function as Oncogenic Drivers in Cholangiocarcinoma.

Cancer Discov 2021 Oct 29;11(10):2488-2505. Epub 2021 Apr 29.

Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

We conducted next-generation DNA sequencing on 335 biliary tract cancers and characterized the genomic landscape by anatomic site within the biliary tree. In addition to frequent fusions among patients with intrahepatic cholangiocarcinoma (IHCC), we identified extracellular domain in-frame deletions (EID) in 5 of 178 (2.8%) patients with IHCC, including two patients with p.H167_N173del. Expression of this EID in NIH3T3 cells resulted in constitutive FGFR2 activation, oncogenic transformation, and sensitivity to FGFR inhibitors. Three patients with EIDs were treated with Debio 1347, an oral FGFR1/2/3 inhibitor, and all showed partial responses. One patient developed an acquired L618F kinase domain mutation at disease progression and experienced a further partial response for 17 months to an irreversible FGFR2 inhibitor, futibatinib. Together, these findings reveal EIDs as an alternative mechanism of FGFR2 activation in IHCC that predicts sensitivity to FGFR inhibitors in the clinic. SIGNIFICANCE: EIDs are transforming genomic alterations that occur predominantly in patients with IHCC. These EIDs are sensitive to FGFR inhibition , and patients with these alterations benefited from treatment with FGFR inhibitors in the clinic..
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http://dx.doi.org/10.1158/2159-8290.CD-20-1669DOI Listing
October 2021

Implementing Systematic Genetic Counseling and Multigene Germline Testing for Individuals With Pancreatic Cancer.

JCO Oncol Pract 2021 02 13;17(2):e236-e247. Epub 2021 Jan 13.

Dana-Farber Cancer Institute, Boston, MA.

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% 38.0%, < .001), including those undergoing multigene germline testing (MGT) ≤ 7 days of initial oncology evaluation (14.7% 60.3%, < .001), with preserved pathogenic variant detection rates (10.0% 11.2%, = 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.
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http://dx.doi.org/10.1200/OP.20.00678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257923PMC
February 2021

Molecular Characterization and Therapeutic Targeting of Colorectal Cancers Harboring Receptor Tyrosine Kinase Fusions.

Clin Cancer Res 2021 03 7;27(6):1695-1705. Epub 2021 Jan 7.

Division of Gastrointestinal Cancers, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

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 and 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 promoter hypermethylation and one was associated with a sessile serrated polyp. Molecular profiles of MMR-D colorectal cancer with RTK fusions largely resembled 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 fusion and received sequential crizotinib and alectinib therapy for a total of 7.5 months until developing an L1196Q gatekeeper mutation. The second patient, whose tumor contained an 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 and wild-type tumors. Despite enrichment in acquired MMR-D tumors, RTK fusions also occur in MSS colorectal cancer and provide an important therapeutic target.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4073DOI Listing
March 2021

Population-Scale CT-based Body Composition Analysis of a Large Outpatient Population Using Deep Learning to Derive Age-, Sex-, and Race-specific Reference Curves.

Radiology 2021 02 24;298(2):319-329. Epub 2020 Nov 24.

From the Department of Radiology, Brigham and Women's Hospital, Boston, Mass (K.M., C.P. Bay, N.M., W.C.W., M.H.R.); MGH & BWH Center for Clinical Data Science, Boston, Mass (C.P. Bridge, K.P.A.); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Mass (A.B., L.K.B., B.M.W.); and Department of Radiology, Massachusetts General Hospital, Boston, Mass (F.J.F., F.M.T.).

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 scores derived from these curves were compared with sex-specific thresholds for sarcopenia by using χ 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 ( = 0.99) and equivalency ( < .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 ( < .001 except for subcutaneous fat area vs age [ = .003]). Sex-specific thresholds for sarcopenia demonstrated that age and race bias were not present if scores derived from the reference curves were used ( < .001). Skeletal muscle area scores were significantly predictive of 2-year survival ( = .04) in combined models that included BMI. Conclusion Fully automated body composition (BC) metrics vary significantly by age, race, and sex. The 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 See also the editorial by Summers in this issue.
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http://dx.doi.org/10.1148/radiol.2020201640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128280PMC
February 2021

Mendelian Randomization Analysis of n-6 Polyunsaturated Fatty Acid Levels and Pancreatic Cancer Risk.

Cancer Epidemiol Biomarkers Prev 2020 12 23;29(12):2735-2739. Epub 2020 Sep 23.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

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.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710600PMC
December 2020

Diabetes, Weight Change, and Pancreatic Cancer Risk.

JAMA Oncol 2020 10 8;6(10):e202948. Epub 2020 Oct 8.

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

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.
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http://dx.doi.org/10.1001/jamaoncol.2020.2948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426876PMC
October 2020

Insulin-Like Growth Factor-1 Receptor Expression and Disease Recurrence and Survival in Patients with Resected Pancreatic Ductal Adenocarcinoma.

Cancer Epidemiol Biomarkers Prev 2020 08 28;29(8):1586-1595. Epub 2020 May 28.

Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.

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 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; = 0.002] and worse OS (median OS, 17.4 vs. 25.8 months; HR, 1.39; 95% CI, 1.00-1.92; = 0.046). The association between high IGF1R expression and reduced DFS was identified primarily among patients with a preoperative body mass index ≥25 kg/m (HR, 4.27; 95% CI, 2.03-8.96, comparing extreme tertiles; = 0.032). -mutant tumors had greater IGF1R expression, and IGF1R expression in tumor epithelium was inversely correlated with that in stromal cells. Mutations in 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, < 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.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415636PMC
August 2020

Genetic and Circulating Biomarker Data Improve Risk Prediction for Pancreatic Cancer in the General Population.

Cancer Epidemiol Biomarkers Prev 2020 05 22;29(5):999-1008. Epub 2020 Apr 22.

Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

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.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020898PMC
May 2020

Predictors of Recurrence and Survival in Patients With Surgically Resected Pancreatic Neuroendocrine Tumors.

Pancreas 2020 02;49(2):249-254

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.

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.
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http://dx.doi.org/10.1097/MPA.0000000000001477DOI Listing
February 2020

Treatment Patterns and Health Resource Use Among Patients with Metastatic Gastroenteropancreatic Neuroendocrine Tumors Treated at a Tertiary Referral Center.

Oncologist 2020 04 30;25(4):e644-e650. Epub 2020 Jan 30.

Dana Faber Cancer Institute, Boston, Massachusetts, USA.

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.
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http://dx.doi.org/10.1634/theoncologist.2019-0691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160404PMC
April 2020

Postdiagnosis Loss of Skeletal Muscle, but Not Adipose Tissue, Is Associated with Shorter Survival of Patients with Advanced Pancreatic Cancer.

Cancer Epidemiol Biomarkers Prev 2019 12 18;28(12):2062-2069. Epub 2019 Sep 18.

Dana-Farber Cancer Institute, Boston, Massachusetts.

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 cm), those in the top quartile (average loss of 12.9 ± 4.9 cm) 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; = 0.004) and lower monocyte chemoattractant protein-1 (MCP-1; = 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.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891169PMC
December 2019

Intrinsic Resistance to Immune Checkpoint Blockade in a Mismatch Repair-Deficient Colorectal Cancer.

Cancer Immunol Res 2019 08 19;7(8):1230-1236. Epub 2019 Jun 19.

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

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 β-microglobulin (), 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.
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679789PMC
August 2019

Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer.

Genet Med 2019 01 2;21(1):213-223. Epub 2018 Jul 2.

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

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.
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http://dx.doi.org/10.1038/s41436-018-0009-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6666401PMC
January 2019

Altered exocrine function can drive adipose wasting in early pancreatic cancer.

Nature 2018 06 20;558(7711):600-604. Epub 2018 Jun 20.

Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.

Malignancy is accompanied by changes in the metabolism of both cells and the organism. 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 cancer. Tissue wasting is a multifactorial disease and targeting specific circulating factors to reverse this syndrome has been mostly ineffective in the clinic. 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.
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http://dx.doi.org/10.1038/s41586-018-0235-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112987PMC
June 2018

Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine.

Cancer Discov 2018 09 14;8(9):1096-1111. Epub 2018 Jun 14.

Dana-Farber Cancer Institute, Boston, Massachusetts.

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 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. 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. .
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http://dx.doi.org/10.1158/2159-8290.CD-18-0275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192263PMC
September 2018

Association of Alterations in Main Driver Genes With Outcomes of Patients With Resected Pancreatic Ductal Adenocarcinoma.

JAMA Oncol 2018 Mar 8;4(3):e173420. Epub 2018 Mar 8.

Department of Pathology, University of Rochester Medical Center, Rochester, New York.

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.
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http://dx.doi.org/10.1001/jamaoncol.2017.3420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844844PMC
March 2018

Cell Cycle Protein Expression in Neuroendocrine Tumors: Association of CDK4/CDK6, CCND1, and Phosphorylated Retinoblastoma Protein With Proliferative Index.

Pancreas 2017 Nov/Dec;46(10):1347-1353

From the *Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; †Medical Oncology Department 2, Chinese PLA General Hospital, Beijing, China; ‡Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA; §Collaborative Innovation Center of Tianjin for Medical Epigenetic, Key Laboratory of Hormone and Development (Ministry of Health), Metabolic Disease Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin; ∥College of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China; ¶Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA; #Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Huazhong University of Science and Technology, Wuhan, China; **Department of Epidemiology, Harvard T.H. Chan School of Public Health; ††Department of Biostatistics, Harvard T.H. Chan School of Public Health; ‡‡Division of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School; §§Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; ∥∥Yale Cancer Center; ¶¶Department of Medicine, Yale University School of Medicine; and ##Smilow Cancer Hospital, New Haven, CT.

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.
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http://dx.doi.org/10.1097/MPA.0000000000000944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645256PMC
June 2018

Lymph node metastases in resected pancreatic ductal adenocarcinoma: predictors of disease recurrence and survival.

Br J Cancer 2017 Dec 5;117(12):1874-1882. Epub 2017 Oct 5.

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA.

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 P<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 P<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.
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http://dx.doi.org/10.1038/bjc.2017.349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729468PMC
December 2017

Management of Neuroendocrine Tumor Liver Metastases: Long-Term Outcomes and Prognostic Factors from a Large Prospective Database.

Ann Surg Oncol 2017 Aug 16;24(8):2319-2325. Epub 2017 Mar 16.

Department of Surgery, Division of Surgical Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, MA, USA.

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.
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http://dx.doi.org/10.1245/s10434-017-5839-xDOI Listing
August 2017

Retrospective review of serotonergic medication tolerability in patients with neuroendocrine tumors with biochemically proven carcinoid syndrome.

Cancer 2017 Jul 7;123(14):2735-2742. Epub 2017 Mar 7.

Harvard Medical School, Boston, Massachusetts.

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.
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http://dx.doi.org/10.1002/cncr.30633DOI Listing
July 2017

Association Between Tumor Progression Endpoints and Overall Survival in Patients with Advanced Neuroendocrine Tumors.

Oncologist 2017 02 8;22(2):165-172. Epub 2017 Feb 8.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

Endpoints related to tumor progression are commonly used in clinical trials of novel therapeutic agents for neuroendocrine tumors (NETs). Whether improved tumor control translates into improved overall survival (OS), however, is uncertain. We assessed associations between tumor progression endpoints and OS in observational cohorts of patients with advanced neuroendocrine tumors treated with somatostatin analogs or with everolimus. We identified 440 patients with advanced NET who had received treatment with single-agent somatostatin analogs and 109 patients treated with everolimus, all of whom were treated at our institution and were evaluable for both tumor progression and survival. We assessed associations between progression-free survival (PFS) and OS by using the Kendall tau test, and we assessed associations between tumor progression and OS by using a landmark analysis. In the 440 patients treated with somatostatin analogs, we observed a significant correlation between PFS and OS by using the Kendall tau test (0.31;  < .0001). Additionally, the development of progressive disease was associated with OS in a landmark analysis, at landmark times of 6, 12, 18, and 24 months. In the 109 patients treated with everolimus, we similarly observed a significant correlation between PFS and OS by using the Kendall tau test (0.44;  < .0001) and associations between progressive disease and OS by using a landmark analysis at 3, 6, and 12 months. In these observational cohorts of patients with metastatic NET treated with single-agent somatostatin analogs or everolimus, longer times to disease progression and longer PFS were both associated with improved OS. Our findings support the continued use of disease progression endpoints in NET clinical trials. 2017;22:165-172 Clinical trials in patients with advanced neuroendocrine tumors have used progression-free survival as a primary endpoint. While there is a general assumption that slowing or halting tumor growth is beneficial, little direct evidence links improvements in progression endpoints to improvements in overall survival. This study assessed associations between tumor progression endpoints and overall survival in observational cohorts of patients with advanced neuroendocrine tumor treated with somatostatin analogs or everolimus. Longer times to disease progression and improved progression-free survival were both associated with improved overall survival. The findings support the continued use of tumor progression endpoints in clinical trials for neuroendocrine tumors.
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http://dx.doi.org/10.1634/theoncologist.2016-0175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330705PMC
February 2017

Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer.

J Clin Oncol 2017 Apr 30;35(10):1086-1095. Epub 2017 Jan 30.

Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Chinedu I. Ukaegbu, Lauren K. Brais, Philip G. McNamara, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Dana-Farber Cancer Institute; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Hajime Uno, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Harvard Medical School; Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Jason L. Hornick, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, and Sapna Syngal, Brigham and Women's Hospital, Boston, MA; and Brian A. Allen, John Kidd, Nanda Singh, Anne-Renee Hartman, and Richard J. Wenstrup, Myriad Genetics, Salt Lake City, UT.

Purpose Hereditary factors play an important role in colorectal cancer (CRC) risk, yet the prevalence of germline cancer susceptibility gene mutations in patients with CRC unselected for high-risk features (eg, early age at diagnosis, personal/family history of cancer or polyps, tumor microsatellite instability [MSI], mismatch repair [MMR] deficiency) is unknown. Patients and Methods We recruited 1,058 participants who received CRC care in a clinic-based setting without preselection for age at diagnosis, personal/family history, or MSI/MMR results. All participants underwent germline testing for mutations in 25 genes associated with inherited cancer risk. Each gene was categorized as high penetrance or moderate penetrance on the basis of published estimates of the lifetime cancer risks conferred by pathogenic germline mutations in that gene. Results One hundred five (9.9%; 95% CI, 8.2% to 11.9%) of 1,058 participants carried one or more pathogenic mutations, including 33 (3.1%) with Lynch syndrome (LS). Twenty-eight (96.6%) of 29 available LS CRCs demonstrated abnormal MSI/MMR results. Seventy-four (7.0%) of 1,058 participants carried non-LS gene mutations, including 23 (2.2%) with mutations in high-penetrance genes (five APC, three biallelic MUTYH, 11 BRCA1/2, two PALB2, one CDKN2A, and one TP53), 15 of whom lacked clinical histories suggestive of their underlying mutation. Thirty-eight (3.6%) participants had moderate-penetrance CRC risk gene mutations (19 monoallelic MUTYH, 17 APC*I1307K, two CHEK2). Neither proband age at CRC diagnosis, family history of CRC, nor personal history of other cancers significantly predicted the presence of pathogenic mutations in non-LS genes. Conclusion Germline cancer susceptibility gene mutations are carried by 9.9% of patients with CRC. MSI/MMR testing reliably identifies LS probands, although 7.0% of patients with CRC carry non-LS mutations, including 1.0% with BRCA1/2 mutations.
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http://dx.doi.org/10.1200/JCO.2016.71.0012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455355PMC
April 2017

Association Between Somatostatin Receptor Expression and Clinical Outcomes in Neuroendocrine Tumors.

Pancreas 2016 11;45(10):1386-1393

From the *Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; †Department of Geriatric Gastroenterology, Chinese PLA General Hospital, Beijing, China; ‡Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA; §Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormone and Development (Ministry of Health), Metabolic Disease Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China; ∥IPSEN Bioscience Inc, Global Drug Discovery Department, Cambridge, MA; ¶IPSEN Innovation, Global Drug Discovery Department, Les Ulis, France; Departments of #Biostatistics, and **Epidemiology, Harvard T.H. Chan School of Public Health, ††Massachusetts General Hospital, ‡‡Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, §§Department of Radiology, Massachusetts General Hospital, and ∥∥Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Objective: Somatostatin receptors (SSTRs), products of gene superfamily SSTR1-5, are commonly expressed in neuroendocrine tumors (NETs). Somatostatin analogs (SSAs) bind to SSTRs and are used as therapeutic agents in patients with advanced NETs. We hypothesized that tumor SSTR expression status would be associated with clinical outcomes in NET.

Methods: Expression of the 5 SSTRs was evaluated by immunohistochemistry, using tissue microarrays comprising 173 primary NETs, 24 matched metastases, and 22 metastatic NETs from 195 patients. Cox proportional hazards regression analysis was used to assess the association of SSTR expression status (high vs low) with clinical outcomes, adjusting for potential confounders.

Results: High expression of SSTR2 was associated with longer overall survival (OS) in the cohort overall (multivariate hazard ratio, 0.42; 95% confidence interval, 0.21-0.84; P = 0.013). In a subgroup of patients with metastatic small intestine NET treated with SSAs and evaluable for progression, SSTR2 expression was associated with both longer progression-free survival (PFS) and OS. No associations with PFS or OS were observed with expression of other SSTRs.

Conclusions: Our study demonstrated that expression of SSTR2, but not other SSTRs, is associated with longer OS. In patients treated with SSAs, expression of SSTR2 is associated with longer PFS survival.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067972PMC
http://dx.doi.org/10.1097/MPA.0000000000000700DOI Listing
November 2016

Drug-related pneumonitis during mammalian target of rapamycin inhibitor therapy in patients with neuroendocrine tumors: a radiographic pattern-based approach.

Eur J Cancer 2016 Jan 4;53:163-70. Epub 2016 Jan 4.

Department of Radiology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA.

Purpose: The purpose of this study was to investigate the incidence of drug-related pneumonitis during mammalian target of rapamycin (mTOR) inhibitor therapy in patients with neuroendocrine tumours (NET) and characterise radiographic patterns of pneumonitis.

Methods: Sixty-six patients (39 males, 27 females, age: 22-79 years) with advanced NET treated with mTOR inhibitor, everolimus, were retrospectively studied. Chest computed tomography scans during therapy were reviewed for abnormalities suspicious for drug-related pneumonitis by an independent review of two radiologists. Extent, distributions, and specific findings were evaluated in cases positive for pneumonitis. Radiographic patterns of pneumonitis were classified using the American Thoracic Society/European Respiratory Society classification of interstitial pneumonia.

Results: Drug-related pneumonitis was radiographically detected in 14 patients (21%). Time from the initiation of therapy to pneumonitis was within 6 months of therapy in 10 patients (71%), while it ranged from 1.0 to 27.7 months. Pneumonitis was more common in patients who had never smoked (p=0.03). Lower lungs were more extensively involved than upper and middle lungs. Peripheral and lower distributions were most common (n=8), followed by peripheral and multifocal distributions (n=3). Ground glass and reticular opacities were present in all cases, with consolidation in eight cases. The radiographic pattern of pneumonitis was classified as cryptogenic organising pneumonia (COP) pattern in eight patients, non-specific interstitial pneumonia (NSIP) pattern in five, and hypersensitivity pneumonitis pattern in one patient.

Conclusion: Drug-related pneumonitis was noted in 21% of the advanced NET patients treated with everolimus. Radiographic pattern of pneumonitis was most commonly COP pattern, followed by NSIP pattern.
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http://dx.doi.org/10.1016/j.ejca.2015.10.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724503PMC
January 2016

Survival among patients with pancreatic cancer and long-standing or recent-onset diabetes mellitus.

J Clin Oncol 2015 Jan 17;33(1):29-35. Epub 2014 Nov 17.

Chen Yuan, Douglas A. Rubinson, Zhi Rong Qian, Shuji Ogino, Kimmie Ng, Megan J. Gorman, Lauren K. Brais, Tingting Li, Matthew H. Kulke, Charles S. Fuchs, and Brian M. Wolpin, Dana-Farber Cancer Institute; Chen Wu, Peter Kraft, Shuji Ogino, Meir J. Stampfer, Frank B. Hu, and Edward L. Giovannucci, Harvard School of Public Health; and Ying Bao, Shuji Ogino, Kimmie Ng, Thomas E. Clancy, Richard S. Swanson, Meir J. Stampfer, Frank B. Hu, Edward L. Giovannucci, Matthew H. Kulke, Charles S. Fuchs, and Brian M. Wolpin, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Purpose: Long-standing diabetes is a risk factor for pancreatic cancer, and recent-onset diabetes in the several years before diagnosis is a consequence of subclinical pancreatic malignancy. However, the impact of diabetes on survival is largely unknown.

Patients And Methods: We analyzed survival by diabetes status among 1,006 patients diagnosed from 1986 to 2010 from two prospective cohort studies: the Nurses' Health Study (NHS) and Health Professionals Follow-Up Study (HPFS). We validated our results among 386 patients diagnosed from 2004 to 2013 from a clinic-based case series at Dana-Farber Cancer Institute (DFCI). We estimated hazard ratios (HRs) for death using Cox proportional hazards models, with adjustment for age, sex, race/ethnicity, smoking, diagnosis year, and cancer stage.

Results: In NHS and HPFS, HR for death was 1.40 (95% CI, 1.15 to 1.69) for patients with long-term diabetes (> 4 years) compared with those without diabetes (P < .001), with median survival times of 3 months for long-term diabetics and 5 months for nondiabetics. Adjustment for a propensity score to reduce confounding by comorbidities did not change the results. Among DFCI patient cases, HR for death was 1.53 (95% CI, 1.07 to 2.20) for those with long-term diabetes compared with those without diabetes (P = .02), with median survival times of 9 months for long-term diabetics and 13 months for nondiabetics. Compared with nondiabetics, survival times were shorter for long-term diabetics who used oral hypoglycemics or insulin. We observed no statistically significant association of recent-onset diabetes (< 4 years) with survival.

Conclusion: Long-standing diabetes was associated with statistically significantly decreased survival among patients with pancreatic cancer enrolled onto three longitudinal studies.
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http://dx.doi.org/10.1200/JCO.2014.57.5688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268250PMC
January 2015

Somatic mutation of CDKN1B in small intestine neuroendocrine tumors.

Nat Genet 2013 Dec 3;45(12):1483-6. Epub 2013 Nov 3.

1] Broad Institute, Cambridge, Massachusetts, USA. [2] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [3].

The diagnosed incidence of small intestine neuroendocrine tumors (SI-NETs) is increasing, and the underlying genomic mechanisms have not yet been defined. Using exome- and genome-sequence analysis of SI-NETs, we identified recurrent somatic mutations and deletions in CDKN1B, the cyclin-dependent kinase inhibitor gene, which encodes p27. We observed frameshift mutations of CDKN1B in 14 of 180 SI-NETs, and we detected hemizygous deletions encompassing CDKN1B in 7 out of 50 SI-NETs, nominating p27 as a tumor suppressor and implicating cell cycle dysregulation in the etiology of SI-NETs.
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http://dx.doi.org/10.1038/ng.2821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239432PMC
December 2013
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