AB095. P069. Identification of therapeutic genomic alterations by investigating cancer-related genes and microsatellite instability: road to precision medicine for pancreatic ductal adenocarcinoma

2018 ◽  
Vol 1 (1) ◽  
pp. AB095-AB095
Author(s):  
Ding Ding ◽  
◽  
Ammar Javed ◽  
Dea Cunningham ◽  
Jonathan Teinor ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Precision Medicine ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Genomic Alterations

scholarly journals Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications

Gut ◽  
2020 ◽  
Vol 70 (1) ◽  
pp. 148-156 ◽  
Author(s):  
Claudio Luchini ◽  
Lodewijk A A Brosens ◽  
Laura D Wood ◽  
Deyali Chatterjee ◽  
Jae Il Shin ◽  
...  
Keyword(s):  
Systematic Review ◽  
Microsatellite Instability ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Molecular Data ◽  
The Cancer Genome Atlas ◽  
Research Network ◽  
Ductal Adenocarcinoma ◽  
Precision Oncology ◽  
Dna Mismatch ◽  
Molecular Features

ObjectiveRecently, tumours with microsatellite instability (MSI)/defective DNA mismatch repair (dMMR) have gained considerable interest due to the success of immunotherapy in this molecular setting. Here, we aim to clarify clinical-pathological and/or molecular features of this tumour subgroup through a systematic review coupled with a comparative analysis with existing databases, also providing indications for a correct approach to the clinical identification of MSI/dMMR pancreatic ductal adenocarcinoma (PDAC).DesignPubMed, SCOPUS and Embase were searched for studies reporting data on MSI/dMMR in PDAC up to 30 November 2019. Histological and molecular data of MSI/dMMR PDAC were compared with non-MSI/dMMR PDAC and with PDAC reference cohorts (including SEER database and The Cancer Genome Atlas Research Network - TCGA project).ResultsOverall, 34 studies with 8323 patients with PDAC were included in the systematic review. MSI/dMMR demonstrated a very low prevalence in PDAC (around 1%–2%). Compared with conventional PDAC, MSI/dMMR PDAC resulted strongly associated with medullary and mucinous/colloid histology (p<0.01) and with a KRAS/TP53 wild-type molecular background (p<0.01), with more common JAK genes mutations. Data on survival are still unclear.ConclusionPDAC showing typical medullary or mucinous/colloid histology should be routinely examined for MSI/dMMR status using specific tests (immunohistochemistry, followed by MSI-PCR in cases with doubtful results). Next-generation sequencing (NGS) should be adopted either where there is limited tissue or as part of NGS tumour profiling in the context of precision oncology, acknowledging that conventional histology of PDAC may rarely harbour MSI/dMMR.

scholarly journals Preclinical models of pancreatic ductal adenocarcinoma: challenges and opportunities in the era of precision medicine

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Yiqi Yu ◽  
Gang Yang ◽  
Hua Huang ◽  
Ziyao Fu ◽  
Zhe Cao ◽  
...  
Keyword(s):  
Precision Medicine ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Steady Increase ◽  
Targeted Therapeutics ◽  
Preclinical Models ◽  
High Quality ◽  
Limited Efficacy ◽  
Conventional Regimen ◽  
Challenges And Opportunities

AbstractPancreatic ductal adenocarcinoma (PDAC) is an extremely lethal malignancy, with an average 5-year survival rate of 9% (Siegel RL, Miller KD, Jemal A. Ca Cancer J Clin. 2019;69(1):7-34). The steady increase in mortality rate indicates limited efficacy of the conventional regimen. The heterogeneity of PDAC calls for personalized treatment in clinical practice, which requires the construction of a preclinical system for generating patient-derived models. Currently, the lack of high-quality preclinical models results in ineffective translation of novel targeted therapeutics. This review summarizes applications of commonly used models, discusses major difficulties in PDAC model construction and provides recommendations for integrating workflows for precision medicine.

scholarly journals A Patient with Metastatic Microsatellite Instability-High Pancreatic Ductal Adenocarcinoma with a Prolonged Response to Single-Agent Pembrolizumab

2021 ◽  
pp. 1414-1417
Author(s):  
Annie A. Guedikian ◽  
Megan E. Randall ◽  
Anita Sharko ◽  
William T. Leslie
Keyword(s):  
Microsatellite Instability ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Single Agent ◽  
Ductal Adenocarcinoma ◽  
New Approach ◽  
Prolonged Response

Immunotherapy is an effective new approach in the treatment of many malignancies. However, pancreatic ductal adenocarcinoma (PDAC) does not usually respond to immunotherapy. We discuss the case of a patient with metastatic microsatellite instability-high PDAC who had a prolonged response to single-agent pembrolizumab for almost 3 years.

scholarly journals Applied precision medicine in metastatic pancreatic ductal adenocarcinoma

2020 ◽  
Vol 12 ◽  
pp. 175883592093861 ◽  
Author(s):  
Hossein Taghizadeh ◽  
Leonhard Müllauer ◽  
Robert M. Mader ◽  
Martin Schindl ◽  
Gerald W. Prager
Keyword(s):  
Precision Medicine ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Mtor Inhibitor ◽  
Ductal Adenocarcinoma ◽  
Clinical Routine ◽  
Dismal Prognosis ◽  
Frequent Mutations ◽  
Recommended Therapy ◽  
Generation Sequencing

Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) bears a dismal prognosis due to the limited activity of systemic chemotherapy. In our platform for precision medicine, we aim to offer molecular-guided treatments to patients without further standard therapy options. Methods: In this single center, real-world retrospective analysis of our platform, we describe the molecular-based therapy approaches used in all 50 patients diagnosed with therapy-refractory mPDAC. A molecular portrait of the tumor specimens was created by next-generation sequencing, immunohistochemistry (IHC), microsatellite instability (MSI) testing, and fluorescence in situ hybridization. Results: In total, we detected 123 mutations in 50 patients. The five most frequent mutations were KRAS ( n = 40; 80%), TP53 ( n = 29; 58%), CDKN2A ( n = 8; 16%), SMAD4 ( n = 4; 8%), and NOTCH1 ( n = 4; 8%), which together accounted for 40.2% of all mutations. Two patients had gene fusions, namely, TBL1XR1–PIK3CA and EIF3E–RSPO2. IHC detected expression of EGFR, phosphorylated mTOR, and PTEN in 36 (72%), 33 (66%), and 17 patients (34%), respectively. For 14 (28%) of the 50 patients, a targeted therapy was suggested based on the identified molecular targets. The recommended treatments included the mTOR inhibitor everolimus ( n = 3), pembrolizumab ( n = 3), palbociclib ( n = 2), nintedanib ( n = 2), and cetuximab, crizotinib, tamoxifen, and the combination of lapatinib and trastuzumab, in one patient each. Finally, five patients received the recommended therapy. Four patients died due to disease progression before radiological assessment. One patient was treated with nintedanib and achieved stable disease for 6 months. Conclusion: Based on our observations, precision medicine approaches are feasible and implementable in clinical routine and may provide molecular-based therapy recommendations for mPDAC.

scholarly journals Sa1707 – Using Endoscopic Fine Needle Biopsies of Pancreatic Ductal Adenocarcinoma for Immunotherapy Precision Medicine

2019 ◽  
Vol 156 (6) ◽  
pp. S-373
Author(s):  
Eileen Carpenter ◽  
Nina Steele ◽  
Veerin Sirihorachai ◽  
Samantha Kemp ◽  
Lawrence Delrosario ◽  
...  
Keyword(s):  
Precision Medicine ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Fine Needle

scholarly journals Recent advances in precision medicine for pancreatic ductal adenocarcinoma

2021 ◽  
Author(s):  
Hiromitsu Hayashi ◽  
Takaaki Higashi ◽  
Tatsunori Miyata ◽  
Yo‐ichi Yamashita ◽  
Hideo Baba
Keyword(s):  
Precision Medicine ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Recent Advances

KRAS and TP53 status as a predictor of survival in patients with resected pancreatic ductal adenocarcinoma.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 276-276
Author(s):  
Caitlin A McIntyre ◽  
Sharon Anita Lawrence ◽  
Winston Wong ◽  
Joanne F. Chou ◽  
Marinela Capanu ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Rank Test ◽  
Driver Gene ◽  
Genomic Alterations ◽  
Driver Genes ◽  
Primary Tumors ◽  
Mutational Status ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded

276 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. KRAS, TP53, CDKN2A and SMAD4 are established driver genes in PDAC. We aimed to determine if the mutational status of these 4 driver genes, and other frequently altered genes, are predictive of clinical outcomes in patients who undergo resection. Methods: Patients who underwent resection of PDAC and consented to targeted sequencing of their primary tumor using MSK-IMPACT, were included. Genomic alterations were determined based on MSK-IMPACT sequencing results of formalin-fixed, paraffin-embedded tumor. A prospectively maintained database and electronic medical record were queried for clinical and pathologic variables. Gene mutation status was compared with overall survival (OS) and recurrence free survival (RFS) using the log-rank test, and with pathologic variables using Wilcoxon rank-sum and Fisher’s exact tests. Results: Targeted genomic sequencing was performed on N = 285 primary tumors resected between 2004-2017. N = 55 (19%) patients received neoadjuvant therapy prior to sequencing and N = 220 (77%) received adjuvant therapy. Median OS was 39 months with a median follow up of 22 months. Frequency of genomic alterations and their association with OS and RFS are shown in Table 1. Alterations in both KRAS and TP53 were associated with worse OS, but not RFS, as compared to wildtype. Mutant KRAS was also associated with larger tumor size (median, 3.0 vs 2.2cm, p = 0.009). Conclusions: Alterations in KRAS and TP53 were associated with worse OS in patients with resected PDAC. Further analysis will include the association of driver gene variants, as well as other gene alterations, with clinical and pathologic outcomes. [Table: see text]

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