Preliminary observations of blood-based (BB) molecular testing in a subset of patients with pancreatic cancer (PDA) participating in the Know Your Tumor (KYT) initiative.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 268-268 ◽  
Author(s):  
Michael J. Pishvaian ◽  
Lynn Matrisian ◽  
Andrew Eugene Hendifar ◽  
Anitra Engebretson ◽  
Lola Rahib ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Internal Control ◽  
Kras Mutation ◽  
Tumor Tissue ◽  
Tissue Sample ◽  
Therapeutic Option ◽  
Circulating Tumor Cell ◽  
Molecular Profiling ◽  
Molecular Testing ◽  
Kras Mutations

268 Background: Obtaining an adequate tissue sample for molecular profiling to guide therapy selection for patients with advanced cancers can be clinically difficult, and/or patients may not want to undergo a biopsy. There has been a growing interest in the use of BB tests, including cell free DNA (cfDNA) and exosome/circulating tumor cell based-analyses as surrogates for tumor tissue (TT) testing. Validation of BB tests in PDA is possible because > 90% of PDAs harbor KRAS mutations – thus providing a reliable “internal control.” Methods: The Pancreatic Cancer Action Network (PanCAN) and Perthera initiated an IRB-approved registry trial for patients with pancreatic cancer wherein we facilitated commercially available, CLIA certified multi-Omic profiling including next generation DNA sequencing (NGS), immunohistochemistry, and phosphoproteomics on patient tumor samples. In a subset of these patients, we incorporated BB testing. Results: A KRAS mutation has been identified in 87% of KYT patients based on TT NGS in general. As of this report, 17 BB test results (cfDNA NGS) were available. In 8 patients we were able to compare the cfDNA NGS directly with TT NGS. BB testing identified a KRAS mutation in 1/8 compared to 8/8 from the tumor tissue. Of the 9/17 patients who did not have corresponding TT NGS, a KRAS mutation was found on BB testing in 3/9 samples. 4/17 BB cases overall revealed KRAS mutations, but when cases were filtered for patients with extensive metastatic disease and progressive disease at the time of blood sampling, the KRAS mutation rate increased to 2/5 overall. Actionable findings (i.e. linked to a specific therapeutic option) were identified in 6/17 cases, of which 3/17 had both an actionable mutation and a KRAS mutation. Conclusions: Although we are aware of the limitations of this study, we recommend that for patients who have biopsiable disease, a TT test should still be the gold standard for molecular profiling. For those without biopsiable disease, the KYT program presents an opportunity to determine the parameters that influence the probability of obtaining reliable molecular profiling information from a BB sample.

Comparative circulating tumor DNA levels for KRAS mutations in patients with nonresectable pancreatic cancer.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 288-288 ◽  
Author(s):  
Julia S. Johansen ◽  
Cecile Rose T. Vibat ◽  
Dan Calatayud ◽  
Benny Vittrup Jensen ◽  
Jane Preuss Hasselby ◽  
...  
Keyword(s):  
Patient Outcome ◽  
Pancreatic Cancer ◽  
Cancer Patients ◽  
Kras Mutation ◽  
Circulating Tumor Dna ◽  
Resectable Pancreatic Cancer ◽  
Kras Mutations ◽  
Study Objective ◽  
Wide Range ◽  
Tumor Dna

288 Background: Non-resectable pancreatic cancer patients have a wide range of median time for overall survival (OS). Currently there is a lack of diagnostic tools to predict patient outcome at diagnosis. KRAS mutations are present in the vast majority of pancreatic tumors. The study objective was to determine if quantitative baseline and longitudinal monitoring of KRAS mutations from plasma circulating tumor DNA (ctDNA) could be used to stratify patients for predicting outcome. Methods: Plasma was prospectively collected from the Danish BIOPAC study for non-resectable pancreatic cancer patients undergoing treatment with gemcitabine or FOLFIRINOX. Feasibility of monitoring ctDNA KRAS mutations was assessed in 10 patients with long OS (median 493 days; range 360-1031) and 10 patients with short OS (median 66 days; range 21-136). KRAS G12A/C/D/R/S/V, and G13D mutations were PCR enriched, sequenced by massively parallel deep sequencing, quantitated and standardized by reporting number of copies detected per 105 genome equivalents (GE). Results: In a pilot study of 20 patients, all 18 patients with evaluable DNA had detectable KRAS mutations. Of 18 patients, 12 had baseline plus longitudinal time points (7 short, 5 long OS). Mutant KRAS copies were higher for short OS (median=994; range 0-34305 copies/105 GE) vs. with long OS (median 196; range, 34-278 copies/105 GE). Longitudinally, KRAS mutation levels remained mostly low with long OS (last time point median 204; range 8-873 copies/105 GE) vs. short OS where levels increased or remained high (median 2363; range 71-47919 copies/105 GE). Identical KRAS mutations were consistently detected for a given patient with short OS. However, long OS patients had variable KRAS mutations in longitudinal analysis. Conclusions: High levels of ctDNA KRAS mutations at diagnosis and post-treatment elevation of KRAS mutations were more associated with short OS. Different levels of KRAS mutation at diagnosis may predict patient outcome and could reflect distinct underlying tumor biology. Expansion of this prospective-retrospective biomarker cohort will be reported.

Quantitating pathologic response to neoadjuvant chemotherapy in KRAS-mutated versus nonmutated lung cancers.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7014-7014
Author(s):  
Jamie E. Chaft ◽  
Paul K. Paik ◽  
Camelia S. Sima ◽  
Mark G. Kris ◽  
Lee M. Krug ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Treatment Effect ◽  
Kras Mutation ◽  
Disease Free Survival ◽  
Pathologic Response ◽  
Pathological Response ◽  
Molecular Testing ◽  
Kras Mutations ◽  
Lung Cancers ◽  
The Impact

7014 Background: Trials of neoadjuvant chemotherapy in non-small cell lung cancers (NSCLC) have demonstrated that pathologic response correlates with downstaging and survival. There is controversy as to whether KRAS mutated patients (pts) have the same benefit with adjuvant chemotherapy as non-mutated pts however the impact of KRAS mutations on response to neoadjuvant therapy has not been reported. Methods: Pts with resectable stage I-III non-squamous NSCLCs were treated with 4 cycles of cisplatin, docetaxel, and bevacizumab, followed by surgical resection. Tumors were tested for KRAS mutations. Percent treatment effect (necrosis, inflammation, fibrosis) was quantified histologically. Pts were followed until disease recurrence and/or death. Binary variables were compared using the Fisher’s Exact Test. Survival was assessed by pathological response based on the literature (≥90 vs <90%) using the Kaplan-Meier method, stratified by stage (IB-IIB vs. III) and by KRAS mutation. Results: We accrued 51 pts. 34/51 (67%) had clinical stage IIIA disease. 48 had molecular testing: 14/48 (29%) had KRAS mutations and 4/48 (8%) had EGFR mutations. The median follow-up was 2 years (yr) (range, 3-63 months). 41 pts had resection and analysis for pathological response. The 2 yr disease free survival (DFS) and overall survival (OS) were superior in the 11/41 (27%) with ≥90% versus those with <90% treatment effect: DFS 91% vs. 56%, p=0.029 and OS 100% vs. 60%, p=0.013. These outcomes remained significant when adjusted for stage. For pts with KRAS mutations, 0 of 10 tumors analyzed had ≥90% treatment effect whereas 11 of 31 (35%) pts with wild-type KRAS had ≥90%, p=0.039. There was an inferior median OS for KRAS mutated pts (22 months) compared to pts without a known KRAS mutation, (Not Reached, p=0.03). Conclusions: Following neoadjuvant chemotherapy, pts with tumors having ≥90% necrosis had improved survival. There were no patients with KRAS mutation that achieved ≥90% treatment effect in response to cisplatin, docetaxel, and bevacizumab. Adaptive adjuvant trial strategies to improve upon outcomes of those with <90% necrosis at resection and new approaches specifically targeting KRAS-mutated NSCLCs are needed.

Association of KRAS G12D mutation with outcome in patients with pancreatic cancer after surgery.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 221-221 ◽  
Author(s):  
Yo Mikayama ◽  
Soichiro Morinaga ◽  
Takuo Watanabe ◽  
Masakatsu Numata ◽  
Hiroshi Tamagawa ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Outcome ◽  
Cancer Patients ◽  
Pancreatic Adenocarcinoma ◽  
Kras Mutation ◽  
Prognostic Significance ◽  
Disease Free Survival ◽  
Mobility Shift ◽  
Kras Gene ◽  
Kras Mutations

221 Background: The frequency of KRAS gene mutations in pancreatic adenocarcinoma is high and most mutations occur in codon 12 and 13. However, the association of KRAS mutation status with clinical outcome of pancreatic cancer patients after surgery is not clearly understood. The aim of present study was to clarify whether presence of mutation in KRAS is of prognostic significance, and to determine whether the different type of KRAS mutation have different impact on clinical outcome in pancreatic cancer. Methods: A total of 62 pancreatic adenocarcinoma tissues from patients underwent curative surgery were analyzed for KRAS mutation. DNA was extracted from the tissue microarray. The domain containing the KRAS gene codons 12 and 13 was amplified by PCR, and KRAS mutation was detected by loop hybrid mobility shift assay (LH-MSA). Results: KRAS mutation was detected in 41 of 62 tumors (66.1%). Mutations of KRAS codon 12 and codon 13 were detected in 37 of 62 tumors (59.7%) and in 4 of 62 tumors (6.5%), respectively. G12D mutation were detected in 35.5% (22/62) and G12V mutation in 19.4% (12/62) of all. The patients with KRAS mutations had a significantly shorter overall survival (OS) (log rank, p=0.0375) and disease free survival (DFS) (p=0.0175). When the type of mutation were evaluated, G12D mutation was significantly associated with both shorter OS (p=0.0410) and DFS (p=0.0214), whereas G12V mutation was associated with neither OS (p=0.6727) nor DFS (p=0.9854). Conclusions: The presence of KRAS mutation was significantly associated with poor outcome of pancreatic cancer patients after surgery. A specific mutation G12D demonstrated significant association with shorter OS and DFS in pancreatic cancer. The different type of KRAS mutation might have different impact on clinical outcome in pancreatic cancer.

Clinical significance of monitoring KRAS in tissue and serum of pancreatic cancer patients.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 286-286
Author(s):  
Fumiaki Watanabe ◽  
Koichi Suzuki ◽  
Hideki Ishikawa ◽  
Yuhei Endo ◽  
Kosuke Ichida ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Patients ◽  
Clinical Significance ◽  
Kras Mutation ◽  
Tumor Biology ◽  
Pancreatic Tumors ◽  
Curative Surgery ◽  
Kras Mutations ◽  
Tumor Tissues ◽  
Predictive And Prognostic Biomarker

286 Background: KRAS monitoring provides valuable information for early diagnosis and prediction of treatment outcome in colorectal cancer. KRAS mutation is observed in only half of colon cancer patients, whereas it is detected in 90% of pancreatic cancer patients. Therefore, investigating tumor DNA in serum by KRAS monitoring may be even more valuable in pancreatic cancer patients. In this study, we elucidated the clinical significance of KRAS monitoring in pancreatic cancer patients during treatment. Methods: KRAS in tumor tissues was analyzed for mutations by Scorpion ARMS or RASKET in 69 patients with pancreatic tumors. KRAS in serum was analyzed for mutations (G12D, G12V, G12C, G12A, G12S, G12R, G13D, Q61L, and Q61H) using droplet digital polymerase chain reaction in 58 patients who underwent the curative surgery (N = 39) or the chemotherapy (N = 19) and who had KRAS mutation in their tissues. Results: KRAS mutation in tumor tissues was detected in 62 of 69 patients (92.5%). These 62 patients showed significantly poorer prognosis (3years overall survival; 43.9%) than the seven patients without mutation (p = 0.03), who were all alive. Monitoring of KRAS in serum revealed KRAS mutation in 22 of 58 patients (37.9%). In patients who underwent the chemotherapy (N = 19), 2years OS of patients who detected KRAS mutation in serum (N = 9) was 0% and them which not detected it (N = 10) was 46.7% (p = 0.01). And in the curative resection group (N = 39), we detected KRAS mutations in serum among recurrent patients after surgery, but did not detect them among non-recurrent patients. Conclusions: KRAS mutation in serum could be a valuable predictive and prognostic biomarker in pancreatic cancer patients. Additionally, assessment of KRAS in tumor tissues may provide information about individual tumor biology. So, monitoring KRAS status of patients with pancreatic cancer may be useful of the treatment strategy.

Kirsten Rat Sarcoma Viral Oncogene Homologue (KRAS) Mutations in the Occurrence and Treatment of Pancreatic Cancer

2019 ◽  
Vol 19 (23) ◽  
pp. 2176-2186 ◽  
Author(s):  
Ziying Zhu ◽  
Saisong Xiao ◽  
Haojie Hao ◽  
Qian Hou ◽  
Xiaobing Fu
Keyword(s):  
Pancreatic Cancer ◽  
Kras Mutation ◽  
High Recurrence Rate ◽  
Kras Mutations ◽  
Effective Prevention ◽  
Downstream Signaling ◽  
Medicinal Treatment ◽  
Close Relationship ◽  
Treatment Measures ◽  
Oncogene Homologue

: Pancreatic cancer is a highly malignant tumor with a 5-year survival rate of less than 6%, and incidence increasing year by year globally. Pancreatic cancer has a poor prognosis and a high recurrence rate, almost the same as the death rate. However, the available effective prevention and treatment measures for pancreatic cancer are still limited. The genome variation is one of the main reasons for the development of pancreatic cancer. In recent years, with the development of gene sequencing technology, in-depth research on pancreatic cancer gene mutation presents that a growing number of genetic mutations are confirmed to be in a close relationship with invasion and metastasis of pancreatic cancer. Among them, KRAS mutation is a special one. Therefore, it is particularly important to understand the mechanism of the KRAS mutation in the occurrence and development of pancreatic cancer, and to explore the method of its transformation into clinical tumor molecular targeted treatment sites, to further improve the therapeutic effect on pancreatic cancer. Therefore, to better design chemical drugs, this review based on the biological functions of KRAS, summarized the types of KRAS mutations and their relationship with pancreatic cancer and included the downstream signaling pathway Raf-MEK-ERK, PI3K-AKT, RalGDS-Ral of KRAS and the current medicinal treatment methods for KRAS mutations. Moreover, drug screening and clinical treatment for KRAS mutated cell and animal models of pancreatic cancer are also reviewed along with the prospect of targeted medicinal chemistry therapy for precision treatment of pancreatic cancer in the future.

KRAS mutation analysis in patients (pts) with locally advanced pancreatic cancer (LAPC) treated with gefitinib and chemoradiation therapy (CT-RT) in a phase I trial

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4106-4106 ◽  
Author(s):  
H. Chen ◽  
D. Raben ◽  
T. Schefter ◽  
M. Kane ◽  
M. McCarter ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
Phase I ◽  
Kras Mutation ◽  
Phase I Trial ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Kras Mutations ◽  
Direct Dna Sequencing ◽  
Kras Codon

4106 Background: Correlative studies that incorporate biomarkers to rapidly analyze response to new agents are needed. Unique to pancreatic cancer is the high incidence of KRAS mutations (over 90%). This pilot study evaluated plasma KRAS mutations for disease monitoring in LAPC pts treated on a Phase I trial combining CT-RT with the EGFR inhibitor, gefitinib. Methods: DNA was extracted from plasma of 11 pts collected at 3 timepoints: pre-gefitinib, pre-CT-RT, and post-gefitinib+CT-RT. Matched tissue DNA was obtained from 4 pts with available paraffin blocks. KRAS codon 12 mutations were detected using a two-stage RFLP-PCR assay. Cell line controls: Calu-1 (mutant KRAS) and LNCaP (wild-type KRAS). Mutations were confirmed by direct DNA sequencing. Results were related to pt clinical data. Results: KRAS mutations were detected in the pre-gefitinib plasma of 5/11 pts, and in the matched tumor tissue of 3/4 pts. Of the 5 pts with plasma KRAS mutations, 2 pts with no detectable mutant KRAS in the plasma post-gefitinib+CT-RT had overall survival of 8 and 21 months, whereas 2 pts who retained mutant KRAS had overall survival of only 2 and 5 months, and one pt withdrew early. Of the 3 tumor tissues containing mutant KRAS, the mutations were also detectable in the matched plasma in 2 pts (67%). KRAS codon 12 mutations spectrum: 4 GGT→GAT, 2 GGT→GTT and 1 GGT→AGT. Conclusions: Plasma KRAS mutations are readily detectable in LAPC pts, and the clearance or persistence of plasma KRAS mutations after treatments reflected the clinical course in some cases. The use of plasma KRAS mutation as a marker of survival and response will be further assessed in a recently approved phase I trial using a proteasome inhibitor with chemoradiation at the University of Colorado. No significant financial relationships to disclose.

Highly sensitive quantitative detection of circulating tumor DNA in urine and plasma from advanced colorectal cancer patients in aid of early diagnosis of clinically relevant KRAS mutations.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 654-654 ◽  
Author(s):  
Jason C. Poole ◽  
Cecile Rose T. Vibat ◽  
Lucie Benesova ◽  
Barbora Belsanova ◽  
Saege Hancock ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
Kras Mutation ◽  
Tumor Tissue ◽  
Advanced Colorectal Cancer ◽  
Circulating Tumor Dna ◽  
Plasma Samples ◽  
Kras Mutations ◽  
Clinical Sensitivity ◽  
Colorectal Cancer Patients

654 Background: Acquisition of point mutations in KRAS gene is causally associated with the onset of development of a resistance to anti-EGFR therapy in colorectal cancer. Newly acquired KRAS mutations can be detected in blood plasma months before radiographic detection. The objective of this study was to demonstrate feasibility of an ultrasensitive non-invasive method for detection of KRAS mutations in urine and plasma of patients with advanced colorectal cancer. Methods: Archived, matched urine and plasma samples (stored between 3-5 years prior to ctDNA extraction) from 20 treatment naïve, advanced stage cancer patients with known tumor tissue KRAS mutations determined by an accredited clinical laboratory, were used in a retrospective setting for a blinded concordance study. KRAS status in urine and plasma was compared to that in tumor tissue in order to assess clinical sensitivity of the ctDNA assay. An ultrashort-amplicon (31bp) assay for KRAS mutation enrichment and detection in highly fragmented urinary and plasma ctDNA was developed. The assay detected 1 copy of KRASG12A/C/D/R/S/V or G13D mutant allele in a background of wild-type DNA with a verified analytical sensitivity of 0.007% (7 copies per ~100,000 genome equivalents). Results: In a pilot study of 20 advanced stage colorectal cancer patients, 15 of 16 evaluable archived urine samples (94%) had KRAS mutation that was concordant with tissue biopsy. Of 20 archived plasma samples evaluated, 19 (95%) displayed the KRAS mutation concordant with tumor tissue. Of 16 paired urine and plasma samples, 15 (94%) had concordant KRAS mutation calls. Conclusions: This study demonstrates high clinical sensitivity (≥94%) of concordant KRAS mutation detection between urine, plasma and tissue specimens from advanced colorectal cancer patients. Early detection and monitoring of acquired KRAS mutations in circulating tumor DNA, and in particular urinary ctDNA, opens the possibility of a new paradigm for a truly non-invasive method of individualized care for colorectal cancer patients.

scholarly journals CRISPR/Cas9-Mediated Knock-Out of KrasG12D Mutated Pancreatic Cancer Cell Lines

2019 ◽  
Vol 20 (22) ◽  
pp. 5706 ◽  
Author(s):  
Eva Lentsch ◽  
Lifei Li ◽  
Susanne Pfeffer ◽  
Arif B. Ekici ◽  
Leila Taher ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Signal Transduction ◽  
Cell Lines ◽  
Kras Mutation ◽  
Genetically Modify ◽  
Regular Growth ◽  
Ductal Adenocarcinoma ◽  
Kras Mutations ◽  
Western Blots ◽  
Knock Out

In 90% of pancreatic ductal adenocarcinoma cases, genetic alteration of the proto-oncogene Kras has occurred, leading to uncontrolled proliferation of cancerous cells. Targeting Kras has proven to be difficult and the battle against pancreatic cancer is ongoing. A promising approach to combat cancer was the discovery of the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) system, which can be used to genetically modify cells. To assess the potential of a CRISPR/CRISPR-associated protein 9 (Cas9) method to eliminate Kras mutations in cells, we aimed to knock-out the c.35G>A (p.G12D) Kras mutation. Therefore, three cell lines with a heterozygous Kras mutation (the human cell lines SUIT-2 and Panc-1 and the cell line TB32047 from a KPC mouse model) were used. After transfection, puromycin selection and single-cell cloning, proteins from two negative controls and five to seven clones were isolated to verify the knock-out and to analyze changes in key signal transduction proteins. Western blots showed a specific knock-out in the KrasG12D protein, but wildtype Kras was expressed by all of the cells. Signal transduction analysis (for Erk, Akt, Stat3, AMPKα, and c-myc) revealed expression levels similar to the wildtype. The results described herein indicate that knocking-out the KrasG12D mutation by CRISPR/Cas9 is possible. Additionally, under regular growth conditions, the knock-out clones resembled wildtype cells.

Brain metastases (BM) in pancreatic ductal adenocarcinoma (PDAC): Clinical and molecular characteristics.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15728-e15728
Author(s):  
Emmet Jordan ◽  
Thomas Joseph Kaley ◽  
Marinela Capanu ◽  
Hayley Estrella ◽  
Steven D Leach ◽  
...  
Keyword(s):  
De Novo ◽  
Stage Iv ◽  
Molecular Profiling ◽  
Impact Testing ◽  
Ductal Adenocarcinoma ◽  
Molecular Characteristics ◽  
Molecular Testing ◽  
Cancer Genes ◽  
Kras Mutations ◽  
Molecular Features

e15728 Background: BM from PDAC represents a rare clinical entity (<0.6%) of PDAC cases for which the clinical and molecular features are not well described. We reviewed detailed clinical characteristics and molecular profiling performed in a cohort of PDAC pts with BM evaluated at MSKCC. Methods: Patients (pts) with BM from PDAC diagnosed from 01/1990-08/2016 were identified from a prospectively maintained database, following IRB approval. Clinicopathological data including time to BM development, overall survival (OS) from PDAC diagnosis (dx) and OS from BM dx was recorded. Molecular profiling was performed by MSK-IMPACT testing (>340 key cancer genes) or via Seqeunom testing (8 gene panel). Results: We identified n= 24 pts with BM from PDAC. Twenty-three/24 pts had imaging for symptoms. Mean no. of systemic regimens was 3 (range 0-7). Three/24 (13%) had BM at initial dx. Median time from PDAC dx to BM development was 17 months (mths) (range 0-79). Median survival from BM was 50 days (range 7-975). BM treatment included; surgery; n=4, RT; n=13 or supportive care; n=7. Two pts had survival of 21 & 31 months post BM, both had resection. Median OS from PDAC dx was 18 mths (0-82). 10 pts had consent/pathology for molecular testing (MSK-IMPACT n=7, Sequenom n=3). Results are available for 6 pts, 3 by IMPACT. 6/6 pts had KRAS mutations (MUT); G12D (4), G12V (1), Q61K (1). 0/6 pts had ERBB2 AMP or MUT. One tumor arising from an IPMN had concurrent GNAS and KRAS MUT. By MSK-IMPACT; 2/3 pts had MYC AMP, 2/3 TP53 MUT, 1/3 ARID1A loss, 1/3 CDKN2A loss. 5/24 pts had germline testing, 3 had BRCA MUT; BRCA1 (2), BRCA2 (1). Conclusions: The presence of BM portends a poor prognosis. In general pts who develop BM are younger at initial PDAC dx and may have a better OS from dx [median OS 18 mths (all pts); OS de novo stage IV pts; 17 mths]. Somatic profiling identified KRAS MUT in all resulted pts with alterations in TP53 and MYC also detected. Although speculative, germline BRCA MUT occurred in 13% (60% of pts tested). See table. [Table: see text]

Cell-free KRAS in pancreatic cancer as a rapid prognostic marker.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15534-e15534
Author(s):  
Patricia Saiz-Lopez ◽  
Raquel Alcaraz-Ortega ◽  
Ana Maria Lopez ◽  
Beatriz Llorente ◽  
Maria Soledad Diez-Ordoñez ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Internal Control ◽  
Roc Curve ◽  
Stage Iv ◽  
Exclusion Criterion ◽  
Molecular Characteristics ◽  
Plasma Samples ◽  
Liquid Biopsies ◽  
Kras Mutations ◽  
Exon 2

e15534 Background: KRAS mutations are present over 90% of patients with pancreatic cancer (PC). Liquid biopsies provide the opportunity to genotype alterations in a less invasive way and offer a possibility to monitor the molecular characteristics of a cancer through the course of treatment. We aim to establish an association between the mutational levels of KRAS detected in plasma with patient stage and evolution. Methods: Plasma samples were collected from patients with newly diagnosed PC, before any treatment and during one year. Diagnosis of any previous cancer was an exclusion criterion. Samples were frozen (-80ºC) until analysis of KRAS mutations in cell free DNA (cfDNA) by real time PCR. Specifically, Idylla TM technology was used due to the rapid capacity to report up to 21 KRAS mutations in exon 2, 3, and 4 (LOD = < 5%), without necessity of cfDNA isolation. Mutation was considered present (categorical measurement), taking into account cycle quantification values (Cq) established by the commercial test. Cut-off values for Cq were studied by the ROC curve (receiver operating characteristic) with the Youden's J statistic. Paired tissue samples were analyzed when available. Results: A total of 23 patients were enrolled, median age 65 years old, 57% male, 100% adenocarcinoma, 18 (70%) metastatic. Sixteen patients could also be tested in tissue, being 15 (93.8%) positive for KRAS mutation. Plasma basal mutations were detected in 10 patients (43.5%), all in stage IV (p = 0.046), and interestingly, all with liver involvement (p = 0.003). Moreover, these patients also had metastasis in another organ apart from the liver. The most frequent mutation was G12V (5), followed by G12D (4) and G12R (1). Patients with basal KRAS mutations detected in plasma had a survival of 6.1 months (CI 95%, 3.7-8.5), and non-mutated 11.2 months (95% CI, 7.8-14.7) (p = 0.041). The presence of these cell-free KRAS mutations was more informative for survival than stage IV disease vs III (p = 0.054). Paying attention to KRAS wild type detection in plasma samples used as an internal control of the PCR, we could establish a Cq value cut-off of < 21 Cq for mutant samples, with a sensitivity of 100% (95% CI, 75%-100%) and specificity of 50% (95% CI, 19%-81%), area under ROC curve 0.823 (95% CI, 0.649-0.997). Conclusions: Measurement of cell-free KRAS in plasma samples at diagnosis could be used to quickly predict metastasis and survival in patients with pancreatic adenocarcinoma.

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