Molecular characterisation of pancreatic ductal adenocarcinoma with NTRK fusions and review of the literature

AimsThe majority of pancreatic ductal adenocarcinomas (PDACs) harbour oncogenic mutations in KRAS with variants in TP53, CDKN2A and SMAD4 also prevalent. The presence of oncogenic fusions including NTRK fusions are rare but important to identify. Here we ascertain the prevalence of NTRK fusions and document their genomic characteristics in a large series of PDAC.MethodsWhole genome sequencing and RNAseq were performed on a series of patients with resected or locally advanced/metastatic PDAC collected between 2008 and 2020 at a single institution. A subset of specimens underwent immunohistochemistry (IHC) analysis. Clinical and molecular characterisation and IHC sensitivity and specificity were evaluated.Results400 patients were included (resected n=167; locally advanced/metastatic n=233). Three patients were identified as harbouring an NTRK fusion, two EML4-NTRK3 (KRAS-WT) and a single novel KANK1-NTRK3 fusion. The latter occurring in the presence of a subclonal KRAS mutation. Typical PDAC drivers were present including mutations in TP53 and CDKN2A. Substitution base signatures and tumour mutational burden were similar to typical PDAC. The prevalence of NTRK fusions was 0.8% (3/400), while in KRAS wild-type tumours, it was 6.25% (2/32). DNA prediction alone documented six false-positive cases. RNA analysis correctly identified the in-frame fusion transcripts. IHC analysis was negative in the KANK1-NTRK3 fusion but positive in a EML4-NTRK3 case, highlighting lower sensitivity of IHC.ConclusionNTRK fusions are rare; however, with emerging therapeutic options targeting these fusions, detection is vital. Reflex testing for KRAS mutations and subsequent RNA-based screening could help identify these cases in PDAC.

Download Full-text

Use of FOLFIRINOX or Nab-Paclitaxel Plus Gemcitabine for the Treatment of Locally Advanced Pancreatic Adenocarcinoma: A Single Institution Observational Study

Cancers ◽

10.3390/cancers13194939 ◽

2021 ◽

Vol 13 (19) ◽

pp. 4939

Author(s):

Alberto Servetto ◽

Antonio Santaniello ◽

Fabiana Napolitano ◽

Francesca Foschini ◽

Roberta Marciano ◽

...

Keyword(s):

Median Overall Survival ◽

Locally Advanced ◽

Distant Metastases ◽

Ductal Adenocarcinoma ◽

Controlled Clinical Trials ◽

Single Institution ◽

Locally Advanced Pancreatic Adenocarcinoma ◽

Grade 3 ◽

Advanced Pancreatic Adenocarcinoma

Patients with locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC) do not present distant metastases but are not eligible for surgery upfront. Chemotherapy regimens, such as FOLFIRINOX (FFN) or nab-paclitaxel plus gemcitabine (GemNab) in combination with loco-regional treatments are generally used in this setting. However, the best treatment choice is unknown. We retrospectively analyzed the information of 225 patients with stage II–III PDAC treated at our institution between October 2011 and December 2020. A total of 94 patients with LA PDAC who are non-eligible for surgery upfront received neoadjuvant FFN or GemNab. Of the 67 patients receiving FFN, 28 (41.8%) underwent surgery after neoadjuvant therapy. Of the 27 patients treated with GemNab, 6 (22.2%) became eligible for resection. The median overall survival (OS) was 85.1 weeks and 54.3 weeks in the FFN and GemNab groups, respectively (HR = 0.54, p = 0.0109). The median OS was 189.7 weeks and 76.4 weeks in the resected and unresected cohorts, respectively (HR = 0.25, p < 0.0001). Neutropenia (37.3%), anemia (6.0%), and diarrhea (6.0%) in the FFN group and neutropenia (22.2%) and thrombocytopenia (18.5%) in the GemNab groups were the most frequent grade 3–4 side effects. Higher rates of thrombocytosis (p < 0.0001) and peripheral edema (p < 0.0001) were observed in the GemNab group. Our results suggest that the use of FFN is associated with more favorable clinical outcomes than GemNab for patients with LA PDAC. Future randomized and controlled clinical trials are needed to further elucidate the role of these regimens and loco-regional treatments in this setting.

Download Full-text

Outcomes in treatment of locally advanced pancreatic ductal adenocarcinoma with irreversible electroporation at a single institution

HPB ◽

10.1016/j.hpb.2021.06.318 ◽

2021 ◽

Vol 23 ◽

pp. S618-S619

Author(s):

D.H. Wolbrom ◽

S.R. Abdel-Misih ◽

T. Manning-Carter ◽

A.R. Sasson ◽

G.V. Georgakis

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Locally Advanced ◽

Irreversible Electroporation ◽

Ductal Adenocarcinoma ◽

Single Institution

Download Full-text

ROBOT ASSISTED LAPAROSCOPIC TRANSPERITONEALINFRARENAL PARA-AORTIC LYMPHADENECTOMY IN PATIENTS WITH LOCALLY ADVANCED CERVICAL CANCER BY SINGLE DOCKING: SINGLE INSTITUTION EXPERIENCE

10.26226/morressier.5770e29bd462b80290b4b962 ◽

2016 ◽

Author(s):

Selim Misirlioglu

Keyword(s):

Cervical Cancer ◽

Locally Advanced ◽

Advanced Cervical Cancer ◽

Single Institution ◽

Robot Assisted ◽

Locally Advanced Cervical Cancer ◽

Single Docking

Download Full-text

Combined chemotherapy and EUS-guided intra-tumoral 32-P implantation for locally advanced pancreatic ductal adenocarcinoma: a pilot study

Endoscopy ◽

10.1055/a-1353-0941 ◽

2021 ◽

Author(s):

Jeevinesh Naidu ◽

Dylan Bartholomeusz ◽

Joshua Zobel ◽

Romina Safaeian ◽

William Hsieh ◽

...

Keyword(s):

Locally Advanced ◽

Adelaide Hospital ◽

Response To Treatment ◽

Ductal Adenocarcinoma ◽

Resection Margins ◽

R0 Resection ◽

Royal Adelaide Hospital ◽

Combined Chemotherapy ◽

Radioactive Phosphorus ◽

18Fdg Pet

Aim: This study evaluated clinical outcomes of combined chemotherapy and Endoscopic Ultrasound (EUS) guided intra-tumoral radioactive phosphorus-32 (32P OncoSil) implantation in locally advanced pancreatic adenocarcinoma (LAPC). Methods: Consecutive patients with a new histological diagnosis of LAPC were recruited over 20 months. Baseline CT and 18FDG PET-CT were performed and repeated after 12 weeks to assess response to treatment. Following 2 cycles of conventional chemotherapy, patients underwent EUS-guided 32P OncoSil implantation followed by a further six cycles of chemotherapy. Results: Twelve patients with LAPC (8M:4F; median age 69 years, IQR 61.5-73.3) completed the treatment. Technical success was 100% and no procedural complications were reported. At 12 weeks, there was a median reduction of 8.2cm3 (95% CI 4.95-10.85; p=0.003) in tumour volume, with minimal or no 18FDG uptake in 9 (75%) patients. Tumour downstaging was achieved in 6 (50%) patients, leading to successful resection in 5 (42%) patients, of which 4 patients (80%) had clear (R0) resection margins. Conclusions: EUS guided 32P OncoSil implantation is feasible and well tolerated and was associated with a 42% rate of surgical resection in our cohort. However, further evaluation in a larger randomized multicenter trial is warranted. (32P funded by OncoSil Medical Ltd, equipment and staff funded by the Royal Adelaide Hospital, ClinicalTrials.gov number, NCT03003078).

Download Full-text

Predicting Surgical Margins in Patients With Borderline Resectable and Locally Advanced Pancreatic Cancer Undergoing Resection

The American Surgeon ◽

10.1177/00031348211011129 ◽

2021 ◽

pp. 000313482110111

Author(s):

Weizheng Ren ◽

Dimitrios Xourafas ◽

Stanley W. Ashley ◽

Thomas E. Clancy

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Univariate Analysis ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Ductal Adenocarcinoma ◽

Resection Margins ◽

Borderline Resectable ◽

Stepwise Selection ◽

R1 Resection ◽

Positive Resection Margins

Background Many patients with borderline resectable/locally advanced pancreatic ductal adenocarcinoma (borderline resectable [BR]/locally advanced [LA] pancreatic ductal adenocarcinoma [PDAC]) undergoing resection will have positive resection margins (R1), which is associated with poor prognosis. It might be useful to preoperatively predict the margin (R) status. Methods Data from patients with BR/LA PDAC who underwent a pancreatectomy between 2008 and 2018 at Brigham and Women’s Hospital were retrospectively reviewed. Logistic regression analysis was used to evaluate the association between R status and relevant preoperative factors. Significant predictors of R1 resection on univariate analysis ( P < .1) were entered into a stepwise selection using the Akaike information criterion to define the final model. Results A total of 142 patients with BR/LA PDAC were included in the analysis, 60(42.3%) had R1 resections. In stepwise selection, the following factors were identified as positive predictors of an R1 resection: evidence of lymphadenopathy at diagnosis (OR = 2.06, 95% CI: 0.99-4.36, P = .056), the need for pancreaticoduodenectomy (OR = 3.81, 96% CI: 1.15-15.70, P = .040), extent of portal vein/superior mesenteric vein involvement at restaging (<180°, OR = 3.57, 95% CI: 1.00-17.00, P = .069, ≥180°, OR = 7,32, 95% CI: 1.75-39.87, P = .010), stable CA 19-9 serum levels (less than 50% decrease from diagnosis to restaging, OR = 2.27, 95% CI: 0.84-6.36 P = .107), and no preoperative FOLFIRINOX (OR = 2.17, 95% CI: 0.86-5.64, P = .103). The prognostic nomogram based on this model yielded a probability of achieving an R1 resection ranging from <5% (0 factors) to >70% (all 5 factors). Conclusions Relevant preoperative clinicopathological characteristics accurately predict positive resection margins in patients with BR/LA PDAC before resection. With further development, this model might be used to preoperatively guide surgical decision-making in patients with BR/LA PDAC.

Download Full-text

Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) in Pancreatic Ductal Adenocarcinoma (PDA): An integrative analysis of a novel therapeutic target

Scientific Reports ◽

10.1038/s41598-019-54545-9 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Ritu Pandey ◽

Muhan Zhou ◽

Shariful Islam ◽

Baowei Chen ◽

Natalie K Barker ◽

...

Keyword(s):

Cell Adhesion ◽

Pancreatic Ductal Adenocarcinoma ◽

Therapeutic Target ◽

Cell Activity ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Ductal Adenocarcinoma ◽

Wild Type ◽

Cancer Genome Atlas ◽

Novel Therapeutic

AbstractWe investigated biomarker CEACAM6, a highly abundant cell surface adhesion receptor that modulates the extracellular matrix (ECM) in pancreatic ductal adenocarcinoma (PDA). The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) RNA-Seq data from PDA patients were analyzed for CEACAM6 expression and evaluated for overall survival, association, enrichment and correlations. A CRISPR/Cas9 Knockout (KO) of CEACAM6 in PDA cell line for quantitative proteomics, mitochondrial bioenergetics and tumor growth in mice were conducted. We found CEACAM6 is over-expressed in primary and metastatic basal and classical PDA subtypes. Highest levels are in classical activated stroma subtype. CEACAM6 over-expression is universally a poor prognostic marker in KRAS mutant and wild type PDA. High CEACAM6 expression is associated with low cytolytic T-cell activity in both basal and classical PDA subtypes and correlates with low levels of T-REG markers. In HPAF-II cells knockout of CEACAM6 alters ECM-cell adhesion, catabolism, immune environment, transmembrane transport and autophagy. CEACAM6 loss increases mitochondrial basal and maximal respiratory capacity. HPAF-II CEACAM6−/− cells are growth suppressed by >65% vs. wild type in mice bearing tumors. CEACAM6, a key regulator affects several hallmarks of PDA including the fibrotic reaction, immune regulation, energy metabolism and is a novel therapeutic target in PDA.

Download Full-text

A pilot study of intraluminal brachytherapy using 125I seed strand for locally advanced pancreatic ductal adenocarcinoma with obstructive jaundice

Brachytherapy ◽

10.1016/j.brachy.2016.05.004 ◽

2016 ◽

Vol 15 (6) ◽

pp. 859-864 ◽

Cited By ~ 10

Author(s):

MinJie Yang ◽

ZhiPing Yan ◽

JianJun Luo ◽

QingXin Liu ◽

Wen Zhang ◽

...

Keyword(s):

Pilot Study ◽

Obstructive Jaundice ◽

Pancreatic Ductal Adenocarcinoma ◽

Locally Advanced ◽

Ductal Adenocarcinoma ◽

125I Seed ◽

Intraluminal Brachytherapy

Download Full-text

Lung Adenocarcinoma From East Asian Never-Smokers Is a Disease Largely Defined by Targetable Oncogenic Mutant Kinases

Journal of Clinical Oncology ◽

10.1200/jco.2010.29.6038 ◽

2010 ◽

Vol 28 (30) ◽

pp. 4616-4620 ◽

Cited By ~ 229

Author(s):

Yihua Sun ◽

Yan Ren ◽

Zhaoyuan Fang ◽

Chenguang Li ◽

Rong Fang ◽

...

Keyword(s):

East Asian ◽

Egfr Mutations ◽

Driver Mutations ◽

Single Institution ◽

Pik3ca Mutations ◽

Oncogenic Mutations ◽

Oncogenic Driver ◽

Never Smokers ◽

Lung Adenocarcinomas ◽

Concurrent Analysis

Purpose To determine the proportion of lung adenocarcinomas from East Asian never-smokers who harbor known oncogenic driver mutations. Patients and Methods In this surgical series, 52 resected lung adenocarcinomas from never-smokers (< 100 cigarettes in a lifetime) at a single institution (Fudan University, Shanghai, China) were analyzed concurrently for mutations in EGFR, KRAS, NRAS, HRAS, HER2, BRAF, ALK, PIK3CA, TP53 and LKB1. Results Forty-one tumors harbored EGFR mutations, three harbored EML4-ALK fusions, two harbored HER2 insertions, and one harbored a KRAS mutation. All mutations were mutually exclusive. Thus, 90% (47 of 52; 95% CI, 0.7896 to 0.9625) of lung adenocarcinomas from never-smokers were found to harbor well-known oncogenic mutations in just four genes. No BRAF, NRAS, HRAS, or LKB1 mutations were detected, while 15 had TP53 mutations. Four tumors contained PIK3CA mutations, always together with EGFR mutations. Conclusion To our knowledge, this study represents the first comprehensive and concurrent analysis of major recurrent oncogenic mutations found in a large cohort of lung adenocarcinomas from East Asian never-smokers. Since drugs are now available that target mutant EGFR, HER2, and ALK, respectively, this result indicates that prospective mutation testing in these patients should successfully assign a targeted therapy in the majority of cases.

Download Full-text