Correlation of SMAD4 mutational status and local or metastatic progression in patients with pancreatic cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14730-e14730
Author(s):  
Olfa Derbel ◽  
Arnaud de la Fouchardière ◽  
Julien Peron ◽  
Michel Rivoire ◽  
Françoise Desseigne ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Metastatic Disease ◽  
Expression Profiles ◽  
Locally Advanced ◽  
Chemotherapeutic Agents ◽  
Clinicopathological Parameters ◽  
Molecular Heterogeneity ◽  
Metastatic Progression ◽  
Molecular Features ◽  
Mutational Status

e14730 Background: Pancreatic cancer remains resistant to many key cytotoxic chemotherapeutic agents and novel targeted therapies. The molecular heterogeneity of this cancer may account for therapy failures to date, although the growing arsenal of novel targeted agents could translate into patient survival. A better understanding of the cellular and molecular features of advanced disease will afford new opportunities for investigation, therapeutic intervention and clinical management of patients afflicted with pancreatic cancer. Methods: This study examined the expression profiles of Smad4 in 45 samples of surgically resected pancreatic cancer. Of these 45 patients, 32 underwent pancreaticoduodenectomy. The clinicopathological parameters, the histologic features were determined and correlated to the stage at initial diagnosis, patterns of failure (locally advanced v metastatic disease) and the status SMAD4 genes. Results: Among the 45 patients, 40% of patients died with metastatic disease and 15 % died with locally advanced evolution. SMAD4 genetic status was determined in 25 patients and seems to be correlated with a high grade histologic features and progression to metastasis. Complementary data about correlation between the mutational status of SMAD4 and survival will be presented during congress. Conclusions: SMAD4 gene inactivation seems to be associated with poorer prognosis and disease progression. Prospective validation of SMAD4 as a predictive biomarker may personalize treatment strategies for patients with pancreatic cancer.

SMAD4 gene mutation and prognosis of pancreatic adenocarcinoma.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 180-180
Author(s):  
Olfa Derbel ◽  
Arnaud de la Fouchardière ◽  
Julien Peron ◽  
Francoise Desseigne ◽  
Pierre Heudel ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Adenocarcinoma ◽  
Metastatic Disease ◽  
Locally Advanced ◽  
Chemotherapeutic Agents ◽  
Clinicopathological Parameters ◽  
Molecular Heterogeneity ◽  
Smad4 Gene ◽  
Mutational Status ◽  
Smad4 Expression

180 Background: Pancreatic adenocarcinoma remains resistant to many key cytotoxic chemotherapeutic agents and novel targeted therapies. The molecular heterogeneity of this cancer may account for therapy failures to date, although the growing arsenal of novel targeted agents could translate into patient survival. A better understanding of the cellular and molecular features of advanced disease will afford new opportunities for investigation, therapeutic intervention and clinical management of patients afflicted with pancreatic cancer. Methods: Data of 46 patients with pancreatic adenocarcinoma were analyzed. The clinicopathological parameters, the histologic features were determined and correlated to the stage at initial diagnosis and patterns of failure (locally advanced v metastatic disease). Using tissue microarray, we assessed the relationship of SMAD4 expression with the overall survival of patients. Results: Among the 46 treated patients, 32 underwent pancreaticoduodenectomy. 40% of patients died with metastatic disease and 15 % died with locally advance evolution. Loss of SMAD4 expression was found in 22% of patients and seems to be correlated with a high grade histologic features and progression to metastasis disease. Complementary data about correlation between the mutational status of SMAD4 and survival will be presented during congress. Conclusions: SMAD4 gene inactivation seems to be associated with poorer prognosis and disease progression. Prospective validation of SMAD4 as a predictive biomarker may personalize treatment strategies for patients with pancreatic cancer.

scholarly journals Mitochondrial DNA and MitomiR Variations in Pancreatic Cancer: Potential Diagnostic and Prognostic Biomarkers

2021 ◽  
Vol 22 (18) ◽  
pp. 9692
Author(s):  
Loredana Moro
Keyword(s):  
Pancreatic Cancer ◽  
Current Knowledge ◽  
Locally Advanced ◽  
Prognostic Biomarkers ◽  
Mitochondrial Proteins ◽  
Ductal Adenocarcinoma ◽  
Metastatic Progression ◽  
Response To Chemotherapy ◽  
Personalized Cancer Therapy ◽  
Personalized Cancer

Pancreatic cancer is an aggressive disease with poor prognosis. Only about 15–20% of patients diagnosed with pancreatic cancer can undergo surgical resection, while the remaining 80% are diagnosed with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). In these cases, chemotherapy and radiotherapy only confer marginal survival benefit. Recent progress has been made in understanding the pathobiology of pancreatic cancer, with a particular effort in discovering new diagnostic and prognostic biomarkers, novel therapeutic targets, and biomarkers that can predict response to chemo- and/or radiotherapy. Mitochondria have become a focus in pancreatic cancer research due to their roles as powerhouses of the cell, important subcellular biosynthetic factories, and crucial determinants of cell survival and response to chemotherapy. Changes in the mitochondrial genome (mtDNA) have been implicated in chemoresistance and metastatic progression in some cancer types. There is also growing evidence that changes in microRNAs that regulate the expression of mtDNA-encoded mitochondrial proteins (mitomiRs) or nuclear-encoded mitochondrial proteins (mitochondria-related miRs) could serve as diagnostic and prognostic cancer biomarkers. This review discusses the current knowledge on the clinical significance of changes of mtDNA, mitomiRs, and mitochondria-related miRs in pancreatic cancer and their potential role as predictors of cancer risk, as diagnostic and prognostic biomarkers, and as molecular targets for personalized cancer therapy.

PANOVA: A phase II study of TTFields (150 kHz) concomitant with standard chemotherapy for front-line therapy of advanced pancreatic adenocarcinoma—Updated efficacy results.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15790-e15790 ◽  
Author(s):  
Manuel Benavides ◽  
Carmen Guillen ◽  
Fernando Rivera ◽  
Javier Gallego ◽  
Jose A. Lopez-Martin ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Patients ◽  
Metastatic Disease ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Skin Toxicity ◽  
Distant Metastases ◽  
Phase Iii ◽  
Prior Therapy ◽  
Grade 3

e15790 Background: TTFields are a non-invasive, regional antimitotic treatment modality, which has been approved for the treatment of glioblastoma by the FDA. TTFields predominantly act by disrupting the formation of the mitotic spindle during metaphase. TTFields were effective in multiple preclinical models of pancreatic cancer. PANOVA was the first trial testing TTFields in pancreatic cancer patients. Results from the first arm of the study, testing TTFields in combination with gemcitabine, have demonstrated superiority in efficacy compared to historical controls (Rivera F. et al, J Clin Oncol 34, 2016 (suppl 4S; abstr 269). Methods: Twenty advanced pancreatic cancer patients were enrolled in the second arm of PANOVA and treated with TTFields in combination with gemcitabine concomitant to nab-paclitaxel. All patients had unresectable tumors, an ECOG performance score of 0-1 and no prior therapy. The primary endpoint was the incidence and severity of adverse events. Results: The median age was 68.2 (range – 58-81) and most patients (65%) had an ECOG score of 1. Twelve patients (60%) had distant metastases. Ten patients (50%) had serious AEs during the study period. Eleven patients (55%) had treatment-related skin toxicity, of which 5 had grade 3 toxicity. No TTFields-related serious AEs were reported. The median PFS was 12.7 months (95% CI 5.4, NA): 9.3 months in patients with metastatic disease, and not reached in locally-advanced patients. PFS rate at 6 months was 65%: 50% in metastatic disease and 87.5% in locally advanced patients. Of the evaluable tumors, 40% had partial response and another 47% stable disease. The median OS was not reached, and the 1-year survival rate was 72% (62.5% in metastatic disease and 87.5% in locally advanced disease). Conclusions: TTFields concomitant to gemcitabine and nab-paclitaxel are safe for advanced pancreatic cancer patients, with promising clinical outcome which doubled historical data. A phase III trial is planned, testing the efficacy of TTFields combined with gemcitabine and nab-paclitaxel in locally-advanced pancreatic cancer patients. Clinical trial information: NCT01971281.

Germline ATM mutations on survival in metastatic pancreatic cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16746-e16746
Author(s):  
Arjan Gower ◽  
Gillian Gresham ◽  
Nanor Haladjian ◽  
John Lee ◽  
Camille Ng ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Metastatic Disease ◽  
Cox Regression ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Underlying Mechanism ◽  
First Line ◽  
Increased Risk ◽  
Atm Protein ◽  
The Impact

e16746 Background: Ataxia telangiectasia mutated (ATM) protein is a DNA damage repair enzyme and regulates normal cell-cycle mechanisms. Germline ATM mutations are associated with increased risk for developing pancreatic cancer (PC), occurring in approximately 2% of PC patients (pts). The role of germline ATM mutations in PC is not well defined. The objective of this study was to compare survival outcomes in patients with germline ATM mutations compared to somatic ATM mutations in PC. Methods: Tumor genomic profiling was completed in 144 PC patients at a single institution in the US, where pts were included in the analysis if they had either germline ATM mutations or somatic ATM mutations. Clinical outcomes were compared between pts with germline ATM mutations and pts with somatic ATM mutations only. Adjusted Cox regression models were fit to evaluate the impact of ATM mutation on overall survival (OS), calculated from treatment (tx) initiation to death, and progression free survival (PFS) calculated from tx initiation to first progression. Results: From 144 PC pts evaluated, 7 pts (4.9%) had germline ATM mutations, all of whom presented with metastatic disease, and 14 pts (9.7%) with somatic ATM mutations only, of whom 10 presented with metastatic disease and 4 who initially presented with locally advanced PC. The majority of pts (15/21), including all 7 pts with germline ATM mutations and 8 with somatic ATM mutations, were treated with first line gemcitabine and abraxane. Median OS was not reached in patients with germline mutations, and 11 months for patients with somatic mutations. Pts with germline ATM mutations had significantly higher OS (HR: 0.12, 95% CI 0.03-0.62, p = 0.01) and PFS (HR:0.26, 95%CI 0.07-0.91, p = 0.04) compared to patients with somatic ATM mutations only after adjusting for age, sex, and first-line tx. Conclusions: Pts with germline ATM mutations may experience greater survival benefit from tx compared to those with only somatic ATM mutations. Further research into the underlying mechanism is warranted.

Number of nonsynonymous genomic variants may correlate with prognosis in advanced pancreatic cancer.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 432-432
Author(s):  
Suneel Deepak Kamath ◽  
Joanna Roopkumar ◽  
Ying Ni ◽  
Minqian Shen ◽  
Pablo Bejarano ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Metastatic Disease ◽  
Locally Advanced ◽  
Cleveland Clinic ◽  
Advanced Pancreatic Cancer ◽  
Small Sample ◽  
Term Survival ◽  
Pancreatic Tail ◽  
Synonymous Mutations ◽  
Number Of Patients

432 Background: Pancreatic cancer is associated with poor outcomes at any stage. A very small number of patients - approximately 3% of those with metastatic disease - experience long-term survival through 5 years but the biologic mechanisms underlying the benefit observed with these “exceptional responders” are incompletely understood. We explored potential genomic differences between exceptional responders and typical responders to treatment for advanced pancreatic cancer that could confer a more favorable biology. Methods: We included consecutive exceptional responders and matched controls (MCs) with advanced pancreatic cancer in a 1:3 ratio from the Cleveland Clinic from April, 2013 – August, 2017. ERs were defined as patients with overall survival (OS) > 18 months for metastatic disease and > 24 months for locally advanced disease. Controls were matched by age, gender, stage and type of chemotherapy given and experienced OS at or below median survival for their stages. Clinical variables including demographics, comorbidities, stage, histology and treatment history were collected. Next generation sequencing (NGS) was performed for DNA sequencing of 648 genes and tumor mutation burden (TMB) on available tissue. The study population initially comprised of 14 exceptional responders and 42 MCs. However, only 4 exceptional responders and 6 MCs were included for analysis due to insufficient tissue for NGS for the remaining patients. Descriptive statistics were used for statistical analysis. Differences in survival outcomes were assessed using the Kaplan-Meier method and log-rank test. Results: The median ages for the exceptional responders and MCs were 69 and 67.5 years, respectively. Both groups were at least 75% male and white. Of the exceptional responders, 50% had pancreatic tail primaries compared to 0% of the MCs. There were no differences between groups in first-line chemotherapy used. Exceptional responders had significantly fewer non-synonymous mutations compared to MCs (2.25 vs. 5.17, p = 0.014). Mutation count < 3 was associated with significantly better progression-free survival (PFS) and OS as shown in the Table. TMB did not differ between exceptional responders and MCs (4.88 vs. 5.70 Muts/Mb, p = 0.39). Of the exceptional responders, 50% had alterations in BAGE2 versus 0% of MCs. Conversely, 50% of MCs had alterations in LRP1B, CUL4B or APC vs. 0% of exceptional responders. Conclusions: Having a lower number of non-synonymous mutations may correlate with exceptional response to systemic therapy and therefore with improved survival in pancreatic cancer. Pancreatic tail primary may also be associated with improved outcomes. These findings, though limited by small sample size, should encourage future study into genomic signatures of exceptional response. [Table: see text]

scholarly journals An update on treatment options for pancreatic adenocarcinoma

2019 ◽  
Vol 11 ◽  
pp. 175883591987556 ◽  
Author(s):  
Aurélien Lambert ◽  
Lilian Schwarz ◽  
Ivan Borbath ◽  
Aline Henry ◽  
Jean-Luc Van Laethem ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Metastatic Disease ◽  
Treatment Options ◽  
Multidisciplinary Treatment ◽  
Locally Advanced ◽  
Solid Organ ◽  
Therapeutic Vaccines ◽  
Rising Incidence ◽  
Number Of Treatment ◽  
T Cell Transfer

Pancreatic cancer is one of the most lethal solid organ tumors. Due to the rising incidence, late diagnosis, and limited treatment options, it is expected to be the second leading cause of cancer deaths in high income countries in the next decade. The multidisciplinary treatment of this disease depends on the stage of cancer at diagnosis (resectable, borderline, locally advanced, and metastatic disease), and combines surgery, chemotherapy, chemoradiotherapy, and supportive care. The landscape of multidisciplinary pancreatic cancer treatment is changing rapidly, especially in locally advanced disease, and the number of treatment options in metastatic disease, including personalized medicine, innovative targets, immunotherapy, therapeutic vaccines, adoptive T-cell transfer, or stemness inhibitors, will probably expand in the near future. This review summarizes the current literature and provides an overview of how new therapies or new therapeutic strategies (neoadjuvant therapies, conversion surgery) will guide multidisciplinary disease management, future clinical trials, and, hopefully, will increase overall survival.

Phase II Study of Gemcitabine, Cisplatin, and Infusional Fluorouracil in Advanced Pancreatic Cancer

2003 ◽  
Vol 21 (15) ◽  
pp. 2920-2925 ◽  
Author(s):  
B.F. El-Rayes ◽  
M.M. Zalupski ◽  
A.F. Shields ◽  
U. Vaishampayan ◽  
L.K. Heilbrun ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase Ii ◽  
Metastatic Disease ◽  
Phase Ii Study ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
World Health ◽  
Significant Activity ◽  
Eligibility Criteria ◽  
Probability Of Survival

Purpose: This phase II study was undertaken to determine the efficacy of adding infusional fluorouracil (FU) to the chemotherapy doublet of gemcitabine and cisplatin in patients with advanced pancreatic cancer. Patients and Methods: The eligibility criteria included histologically or cytologically confirmed adenocarcinoma of the pancreas that was either unresectable or metastatic. No prior gemcitabine therapy was allowed. Patients received a combination of gemcitabine 1,000 mg/m2 intravenously (IV) on days 1, 8, and 15; cisplatin 50 mg/m2 IV on days 1 and 15; and FU 175 mg/m2/d from days 1 to 15 by continuous IV infusion. Cycles were repeated every 28 days. Objective tumor response and toxicity were evaluated according to the World Health Organization criteria. Results: A total of 47 patients (median age, 57 years; males, 59%) were enrolled. Sixteen patients had locally advanced (LA) disease, and 31 patients had metastatic disease. A total of 183 cycles of chemotherapy were administered. In patients with metastatic disease (n = 31), the probability of survival at 6 and 12 months was 66% and 34%, respectively. Objective partial response or stable disease was observed in 26% (90% confidence interval [CI], 0.14 to 0.41) and 61% (90% CI, 0.45 to 0.74) of patients, respectively. In patients with LA disease (n = 16), there were three partial responses (19%; 90 CI, 0.07 to 0.39). One patient in this group was successfully resected after FU-based radiotherapy. The most common grade 3 to 4 toxicities were neutropenia (60%), thrombocytopenia (42%), and anemia (26%). Thirteen patients were hospitalized for treatment-related complications. Conclusion: The combination of gemcitabine, cisplatin, and infusional FU has significant activity in patients with advanced pancreatic cancer.

Clinical and molecular features of adenosquamous pancreatic cancer (ASQ): A distinct histological subtype.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 426-426
Author(s):  
Christopher Jakubowski ◽  
Su Jin Lim ◽  
Andrew Pellatt ◽  
Hao Wang ◽  
Richard A. Burkhart ◽  
...  
Keyword(s):  
Metastatic Disease ◽  
De Novo ◽  
Advanced Disease ◽  
Locally Advanced ◽  
Palliative Therapy ◽  
First Line ◽  
Similar Frequency ◽  
Molecular Features ◽  
Pancreatic Cancers ◽  
Line Therapy

426 Background: Adenosquamous pancreatic cancers (ASQ) constitute 1-5% of all pancreatic cancers. The clinical and molecular understanding of this aggressive variant, along with potential differential response to systemic therapies, is an understudied yet important topic. Methods: After obtaining Institutional Review Board approvals, the Johns Hopkins cancer registry and electronic medical record was interrogated for histopathological and clinical characteristics of ASQ. Archived pathological slides were re-examined to quantify the squamous component, response to neoadjuvant therapy and immune infiltrate. Results: Of 8,908 patients from 2003 to 2018, a total of 155 had histology consistent with ASQ. 52% presented with resectable disease, 12% with borderline resectable, 12% with locally advanced, 17% with metastatic, and 8% of cases had an unknown presentation status. Primary FNA diagnosis was available for 103 patients and 57% (n = 59) reported squamous findings on FNA. 53 patients received radiation therapy (19 neoadjuvant, 22 adjuvant, 15 palliative). Systemic therapy was received by 104 patients (32 neoadjuvant, 52 adjuvant, 67 palliative therapy for advanced/metastatic disease). The most common neoadjuvant regimens used were FOLFIRINOX (n = 9) and gemcitabine/nab-paclitaxel (n = 7). Reported responses in the neoadjuvant setting (n = 26) included 10 with stable disease (SD), 11 partial response (PR) and 5 progressive disease (PD). The most common regimens used in the first line advanced setting were FOLFIRINOX (n = 18), gemcitabine/nab-paclitaxel (n = 9), and gemcitabine (n = 8). Of 55 responses recorded there were 13 SD, 15 PR, 25 PD and 2 complete responses (CR). Of the patients who received first line therapy, 54% (n = 36), 15% (n = 10) and 6% (n = 4) went on to receive second, third or fourth line therapy, respectively. 118 patients (76.13%) had a reported date of death. Of the 98 patients who received definitive surgical resection the median recurrence free survival (mRFS) and overall survival (mOS) was 7.36 and 14.17 months, respectively. Of the 44 patients that presented with de novo unresectable or metastatic disease, mOS was 7.53 months. The mOS of advanced disease patients from the time of receipt of first line palliative chemotherapy was 8.45 months. Molecular panels revealed mutation frequencies of common somatic and DNA repair genes in similar frequency to pancreatic adenocarcinoma. The mean tumor mutation burden of 18 patients was 4.7 with a max of 27. Of 27 patients who received MMR/MSI testing 100% were pMMR/MSS. Conclusions: This is one of the largest single center series of ASQ patients reported and describes unique findings related to neoadjuvant and advanced disease treatment experience. Overall this study confirms the continued poor survival and poor response to standard regimens in this disease suggesting we should consider alternative treatment paradigms.

Local and systemic recurrence following total neoadjuvant therapy (TNT) and resection for borderline resectable and locally advanced pancreatic adenocarcinoma: Long-term follow up from two phase II studies.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4133-4133
Author(s):  
Grace E. Ryan ◽  
Janet E. Murphy ◽  
Christine A. Ulysse ◽  
Beow Y. Yeap ◽  
Jennifer Yon-Li Wo ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Neoadjuvant Therapy ◽  
Metastatic Disease ◽  
Locally Advanced ◽  
Vascular Involvement ◽  
R0 Resection ◽  
Borderline Resectable ◽  
Metastatic Recurrence ◽  
Total Neoadjuvant Therapy

4133 Background: With the advent of FOLFIRINOX, the management of pancreatic cancer has undergone a profound change. There has been a shift to TNT with FOLFIRINOX followed by radiation and an attempt at surgical resection. Recent trials of TNT have demonstrated an ability to resect locally advanced (LA) and borderline resectable disease. There is a lack of prospective data demonstrating local and systemic recurrence rates after TNT. Methods: Two previously reported prospective clinical trials (Murphy JE, et al, JAMA Oncol 2018, 2019) of total neoadjuvant therapy were conducted between 2012 and 2018 for borderline and LA disease (NCT01591733, NCT01821729). Patients received FOLFIRINOX for 8 cycles. Upon restaging, patients with resolution of vascular involvement received short-course chemoradiotherapy (5 Gy x 5 with protons or 3 Gy x 10 w photons) with capecitabine (N=34). Patients with persistent vascular involvement received long-course chemoradiotherapy with capecitabine (N=56). All patients were considered for resection after TNT except for those patients with metastatic or unresectable disease. Results: 97 eligible patients were enrolled and started treatment on the borderline resectable (n = 48) and locally advanced (n= 49) study. 90 patients completed therapy. 80 patients were taken to the operating room. 61 patients had R0 resection and 5 patients had R1 resection. The table shows the distribution of local recurrences, local recurrences and metastatic disease, and metastatic disease alone. With a median follow-up of 5.2 years (range: 2.4-6.0), of the 61 R0 patients, 22 patients remained alive and free of disease, 7 patients had a local recurrence, 4 patients had locoregional and metastatic recurrence, and 24 patients had a metastatic recurrence. 3 patients who underwent R0 resection died of unrelated causes. Median survival for patients undergoing R0 resection is 43.8 months. Conclusions: Total neoadjuvant therapy for locally advanced and borderline resectable pancreatic cancer is potentially curable and may change the pattern of spread.[Table: see text]

Sign in / Sign up

Export Citation Format

Share Document