scholarly journals Serum-Based KRASG12/G13 Mutation Detection Using Droplet Digital PCR: Clinical Implications and Limitations in Colorectal Adenocarcinoma With Tumor Heterogeneity

2021 ◽  
Vol 10 ◽  
Author(s):  
Ju Seok Kim ◽  
Go Eun Bae ◽  
Seok-Hwan Kim ◽  
Min Kyung Choi ◽  
Min-Kyung Yeo
Keyword(s):  
Colorectal Adenocarcinoma ◽  
Digital Pcr ◽  
Wild Type ◽  
Dynamic Changes ◽  
Tissue Samples ◽  
Mutation Status ◽  
Mutational Status ◽  
Serum Testing ◽  
Serum Detection

BackgroundCell-free DNA (cfDNA) has arisen as an alternative target for evaluating somatic mutations in cancer. KRAS mutation status is critical for targeted therapy in colorectal adenocarcinoma (CRAC). We evaluated KRASG12/G13 mutations in cfDNA extracted from serum and compared the results with KRASG12/G13 mutations detected in tissue samples. We assessed the clinical significance of KRASG12/G13 mutation in serum in regard to recurrence and metastasis of CRAC.MethodsA total of 146 CRAC patients were enrolled, and KRASG12/G13 mutations were evaluated in 146 pairs of serum and tissue samples. In addition, 35 pairs of primary and metastatic CRAC tissue samples were evaluated for KRASG12/G13 mutational status.ResultsDetection of KRASG12/13 mutation from serum and tissue had a 55% concordance rate, and serum detection had a sensitivity of 39.8%. Detection of the KRASG12/13 mutation yielded a 14% discordance rate between primary and metastatic tissue. CRAC patients with mutant KRASG12/13 mutation in serum but wild-type KRASG12/13 in tissue had concurrent KRASG12/13-mutant metastatic tumors, indicating spatial genetic heterogeneity. Changes in serum KRASG12/G13 mutation status during postoperative follow-up were associated with recurrence. Conclusion: Although serum detection of the KRASG12/13 mutation cannot substitute for detection in tissue, serum testing can support the interpretation of a CRAC patient’s status in regard to concurrent metastasis. Dynamic changes in serum KRASG12/13 mutation status during follow-up indicated that cfDNA from serum represents a potential source for monitoring recurrence in CRAC patients.

scholarly journals Identification of a Clinical Cutoff Value for Multiplex KRASG12/G13 Mutation Detection in Colorectal Adenocarcinoma Patients Using Digital Droplet PCR, and Comparison with Sanger Sequencing and PNA Clamping Assay

2020 ◽  
Vol 9 (7) ◽  
pp. 2283
Author(s):  
Kyung Ha Lee ◽  
Tae Hee Lee ◽  
Min Kyung Choi ◽  
In Sun Kwon ◽  
Go Eun Bae ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Mutant Allele ◽  
Sanger Sequencing ◽  
Colorectal Adenocarcinoma ◽  
Diagnostic Sensitivity ◽  
Absolute Quantitation ◽  
Tissue Samples ◽  
Mutant Allele Frequency ◽  
Mutational Status

KRAS (Kirsten rat sarcoma 2 viral oncogene homolog) is a major predictive marker for anti-epidermal growth factor receptor treatment, and determination of KRAS mutational status is crucial for successful management of colorectal adenocarcinoma. More standardized and accurate methods for testing KRAS mutation, which is vital for therapeutic decision-making, are required. Digital droplet polymerase chain reaction (ddPCR) is an advanced digital PCR technology developed to provide absolute quantitation of target DNA. In this study, we validated the clinical performance of ddPCR in determination of KRAS mutational status, and compared ddPCR results with those obtained by Sanger sequencing and peptide nucleic acid-clamping. Of 81 colorectal adenocarcinoma tissue samples, three repeated sets of KRASG12/G13 mutation were measured by ddPCR, yielding high consistency (ICC = 0.956). Receiver operating characteristic (ROC) curves were constructed to determine KRASG12/G13 mutational status based on mutant allele frequency generated by ddPCR. Using the best threshold cutoff (mutant allele frequency of 7.9%), ddPCR had superior diagnostic sensitivity (100%) and specificity (100%) relative to the two other techniques. Thus, ddPCR is effective for detecting the KRASG12/G13 mutation in colorectal adenocarcinoma tissue samples. By allowing definition of the optimal cutoff, ddPCR represents a potentially useful diagnostic tool that could improve diagnostic sensitivity and specificity.

scholarly journals Magnetic Resonance Imaging Derived Biomarkers of IDH Mutation Status and Overall Survival in Grade III Astrocytomas

Diagnostics ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 247
Author(s):  
Paola Feraco ◽  
Antonella Bacci ◽  
Patrizia Ferrazza ◽  
Luc van den Hauwe ◽  
Riccardo Pertile ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Overall Survival ◽  
Magnetic Resonance ◽  
Idh Mutation ◽  
Wild Type ◽  
Resonance Imaging ◽  
Characteristic Analysis ◽  
Mutation Status ◽  
Mutational Status ◽  
Adc Values

The evaluation of the isocitrate dehydrogenase (IDH) mutation status in the glioma decision-making process has diagnostic, prognostic and therapeutic implications. The aim of this study was to evaluate whether conventional magnetic resonance imaging (MRI) and apparent diffusion coefficient (ADC) can noninvasively predict the most common IDH mutational status (R132H) in GIII-astrocytomas and the overall survival (OS). Hence, twenty-two patients (9-F, 13-M) with a histological diagnosis of GIII-astrocytoma and evaluation of IDH-mutation status (12-wild type, 10-mutant) were retrospectively evaluated. Imaging studies were reviewed for the morphological feature and mean ADC values (ADCm). Statistics included a Fisher’s exact test, Student’s t-test, Spearman’s Test and receiver operating characteristic analysis. A p ≤ 0.05 value was considered statistically significant for all the tests. A younger age and a frontal location were more likely related to mutational status. IDH-wild type (Wt) exhibited a slight enhancement (p = 0.039). The ADCm values in IDH-mutant (Mut) patients were higher than those of IDH-Wt patients (p < 0.0004). The value of ADC ≥ 0.99 × 10−3 mm2/s emerged as a “cut-off” to differentiate the mutation state. In the overall group, a positive relationship between the ADCm values and OS was detected (p = 0.003; r = 0.62). Adding quantitative measures of ADC values to conventional MR imaging could be used routinely as a noninvasive marker of specific molecular patterns.

Expression level of NRP1 and SMAD2 in correlation to mutational status of RAS (BRAF) in pancreatic cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15784-e15784
Author(s):  
Libor Stanek ◽  
Petra Tesarova ◽  
Robert Gurlich
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Growth ◽  
Gene Mutation ◽  
Expression Level ◽  
Wild Type ◽  
Braf Gene ◽  
Kras Gene ◽  
Mutation Status ◽  
Mutational Status ◽  
Neuropilin 1

e15784 Background: Pancreatic cancer is the second leading cause of death in tumor diseases worldwide. Neuropilin-1 (NRP1) is overexpressed in many tumors including the pancreatic cancer. The main goal is to reveal the role of NRP1 in the process of tumorigenesis. The expression of NRP1 and the presence of KRAS point mutation lead to the cell survival by lowering the SMAD2 phosphorylation. On the other hand, the NRP1 inactivation and the wild-type KRAS in tumor cells lead to the tumor growth inhibition. Our aim is to prove correlation between NRP1 level, SMAD2 and the mutational status of KRAS, NRAS in prognosis of patients with pancreatic cancer. Methods: Retrospective study is based on analysis of 50 FFPE bioptical samples (40 resections, 8 punctures, 2 thin-needle biopsies); histology verified all as adenocarcinomas. The expression level of NRP1 and SMAD2 is measured by Imunohistochemistry by mice monoclonal antibodies Anti-Neuropilin 1 and Anti-SMAD2 (Abcan) on the device BenchMark ULTRA (Ventana Medical Systems), Roche. DNA isolation is executed by QIAamp DNA Mini Kit. We used Codon Specific Mutation Detection Kit (Diatech pharmacogenetics) for detection of somatic point mutations in codons 12, 13, 61 and 146 of KRAS and NRAS genes. BRAF mutational status was revealed by direct sequencing on ABI Prism 3130. We monitor the level of expression of NRP1 and SMAD2 and correlate it to the mutational status of RAS and BRAF, and disease prognosis. Results: NRP1 expression was detected in 24 out of 50 cases, SMAD2 expression was detected in 13 of 50 cases, other cases without expression. KRAS gene mutation was detected in 8 cases out of 60, other cases of WT. Mutation in the NRAS gene was detected in 3 of 50 cases. BRAF gene mutation was detected in 1 case out of 50, other WT. NRP1 expression correlated with KRAS gene mutation status in 9 cases and a strong correlation (p = < 0.001) was recorded. One case of mutation in the BRAF gene correlated with KRAS mutation status and NRP1 expression. Due to the small number of samples tested, without statistical significance. Inactivation of NRP1 was detected in 15 cases and was confirmed by the WT status of the KRAS gene. Conclusions: Was demonstrated that causal relationship exists between inactive NRP1 and wild-type KRAS, and that these should cause decrease of the rate of tumor growth. These characteristics, which are achievable simultaneously during the histological verification, may serve as a potential prognostic marker for subsequent decision of how radical surgical resection should be.

scholarly journals Analysis of BRAF and NRAS mutation status in advanced melanoma patients treated with anti-CTLA-4 antibodies: Association with overall survival?

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9025-9025 ◽  
Author(s):  
Joanna Mangana ◽  
Simone M. Goldinger ◽  
Katja Schindler ◽  
Sima Rozati ◽  
Anna L. Frauchiger ◽  
...  
Keyword(s):  
Overall Survival ◽  
Braf Inhibitor ◽  
Mek Inhibitor ◽  
Advanced Melanoma ◽  
Braf V600e ◽  
Wild Type ◽  
Nras Mutation ◽  
Mutation Status ◽  
Mutational Status ◽  
Melanoma Patients

9025 Background: Ipilimumab and tremelimumab are human monoclonal antibodies against cytotoxic T-lymphocyte antigen-4 (CTLA-4). Ipilimumab was the first agent to show a statistically significant benefit in overall survival with durable-long-term responses for advanced melanoma patients both in first-and second-line setting. Up to date, there is no proven association between the BRAF-V600E mutation and the disease control rate (DCR) in response to Ipilimumab. Moreover, significantly shorter survival rates have been reported in patients harboring an NRAS mutation than in those without. This retrospective analysis was carried out to assess if BRAF (V600) and NRAS mutation status affects the clinical outcome of Ipilimumab-treated melanoma patients. Methods: This is a retrospective multi-center analysisof 71 patients, with confirmed BRAF and NRAS mutation status, treated with anti-CTLA-4 antibodies from December 2006 until August 2012. The cut-off for the estimation of overall survival was end of November 2012. Results: The median overall survival of BRAFV600/NRAS mutant patients (n=44) was 1,41 years compared with 2.67 years in BRAF/NRAS wild-type patients (n=27). Although this difference was not statistically significant there was a trend for improved survival in wild-type patients. Of the 71 patients analyzed, 56 received chemotherapy prior to Ipilimumab. In the BRAF/NRAS mutant cohort, 12 patients received Ipilimumab following either a BRAF- or a MEK- inhibitor. Of those 12 patients, 8 progressed and were unable to complete Ipilimumab. Of the 4 patients who completed 4 cycles of Ipilimumab, 2 were subsequently treated with a BRAF inhibitor. Furthermore out of the 71 patients, 8 patients received a BRAF or a MEK inhibitor after progression; 5 of them are still alive. Conclusions: This is the first retrospective study to evaluate the association of both BRAF and NRAS mutational status with the overall survival of Ipilimumab-treated patients. There was a trend towards an improved survival in the BRAF/NRAS wild-type subpopulation. Additional patients will be examined to foster these preliminary results.

scholarly journals Timing of Aspirin and Other Nonsteroidal Anti-Inflammatory Drug Use Among Patients With Colorectal Cancer in Relation to Tumor Markers and Survival

2017 ◽  
Vol 35 (24) ◽  
pp. 2806-2813 ◽  
Author(s):  
Xinwei Hua ◽  
Amanda I. Phipps ◽  
Andrea N. Burnett-Hartman ◽  
Scott V. Adams ◽  
Sheetal Hardikar ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Kras Mutation ◽  
Cpg Island ◽  
The United States ◽  
Wild Type ◽  
Cpg Island Methylator Phenotype ◽  
Mutation Status ◽  
Anti Inflammatory ◽  
Kras Mutation Status

Purpose Regular use of aspirin is associated with improved survival for patients with colorectal cancer (CRC). However, the timing of and the subtype of CRC that would benefit the most from using aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) in relation to survival is unclear. Patients and Methods In all, 2,419 patients age 18 to 74 years with incident invasive CRC who were diagnosed from 1997 to 2008 were identified from population-based cancer registries in the United States, Canada, and Australia. Detailed epidemiologic questionnaires were administered at study enrollment and at 5-year follow-up. Survival outcomes were completed through linkage to national death registries. BRAF- and KRAS-mutation status, microsatellite instability, and CpG island methylator phenotype were also evaluated. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for overall survival (OS) and CRC-specific survival. Results After a median of 10.8 years of follow-up since diagnosis, 381 deaths (100 as a result of CRC) were observed. Compared with nonusers, postdiagnostic aspirin-only users had more favorable OS (HR, 0.75; 95% CI, 0.59 to 0.95) and CRC-specific survival (HR, 0.44; 95% CI, 0.25 to 0.71), especially among those who initiated aspirin use (OS: HR, 0.64; 95% CI, 0.47 to 0.86; CRC-specific survival: HR, 0.40; 95% CI, 0.20 to 0.80). The association between any NSAID use after diagnosis and OS differed significantly by KRAS-mutation status ( Pinteraction = .01). Use of any NSAID after diagnosis was associated with improved OS only among participants with KRAS wild-type tumors (HR, 0.60; 95% CI, 0.46 to 0.80) but not among those with KRAS-mutant tumors (HR, 1.24; 95% CI, 0.78 to 1.96). Conclusion Among long-term CRC survivors, regular use of NSAIDs after CRC diagnosis was significantly associated with improved survival in individuals with KRAS wild-type tumors.

BRAF V600 Mutational Status in Melanoma Correlates with Cytologic Features in Fine-Needle Aspirate Specimens

2018 ◽  
Vol 63 (1) ◽  
pp. 10-16 ◽  
Author(s):  
Paul J. Lee ◽  
Katie Dennis ◽  
Rashna Madan ◽  
Fang Fan
Keyword(s):  
Cell Morphology ◽  
Spindle Cell ◽  
Primary Melanoma ◽  
Braf Inhibitors ◽  
Wild Type ◽  
Nuclear Pleomorphism ◽  
Mutation Status ◽  
Fine Needle ◽  
Cytoplasmic Vacuolization ◽  
Mutational Status

Melanomas are known as the great mimicker and must be considered in the differential diagnosis of any fine-needle aspirations (FNA). Despite recent advancements in understanding of the mutational landscape of melanomas, there still exists a divide between the genetic and morphologic correlates. A consecutive cohort of 39 FNA of clinically verified metastatic melanomas with concurrent BRAF V600 assessment were selected [positive (n = 18) and wild-type (n = 21)]. The melanoma cytology specimens were evaluated blinded to the BRAF mutation status in a dichotomized fashion for the presence of 8 selected morphologic classifiers. When comparing the BRAF-mutated vs. BRAF-wild type cohorts, the percentage of cases were, respectively: macronucleoli (56 and 52%), intranuclear inclusions (50 and 33%), pigment (44 and 24%), binucleation/multinucleation (78 and 57%), nuclear pleomorphism (72 and 67%), cytoplasmic vacuolization (22 and 29%), spindle cell morphology (61 and 29%), and necrosis (11 and 10%). The average age of the BRAF-mutated cohort was 52.2 years, compared to the BRAF wild-type cohort at 65.2 years. The prevalence of sex ratio and the location of the primary melanoma were matched between cohorts. Spindle cell morphology was more correlated with BRAF V600-mutated melanomas. Clinicians utilized the BRAF status to alter clinical decisions with use of BRAF inhibitors.

scholarly journals More Than 10% of NPM1-Mutated AML Relapses Occur after 5 Years from Complete Remission

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2802-2802
Author(s):  
Sarah Bertoli ◽  
Suzanne Tavitian ◽  
Emilie Berard ◽  
Noemie Gadaud ◽  
Audrey Sarry ◽  
...  
Keyword(s):  
Complete Remission ◽  
Conflicts Of Interest ◽  
University Hospital ◽  
First Year ◽  
Wild Type ◽  
The Third ◽  
Mutational Status ◽  
Second Year ◽  
Wbc Count

Abstract The majority of relapses in acute myeloid leukemia (AML) patients occur in the first or second year following complete remission. In routine, AML patients are followed during five years because few relapses can occur after three or five years. These late or very late relapses remain poorly described, particularly at the molecular level, with only few consistent series in the literature. (Medeiros B et al., Leuk Lymphoma 2007; Verma D et al., Leuk Lymphoma 2010; Watts J et al., Leuk Res 2014). We retrospectively studied all AML relapses occurring after complete remission (CR) obtained with one or two induction cycles between 2000 and 2012 in Toulouse University Hospital, France. Our analyses focused on late relapses (LR, >3 years from CR) and very late relapses (VLR, >5 years from CR) in comparison to early relapses (ER, ≤3 years from CR). Between 2000 and 2012, out of 636 CR patients, 346 had morphological relapses (54.4%). The median time to relapse was 0.9 years (range, 0.1-11.9 years; interquartile range [IQR], 0.5-1.5 years). There were 198 relapses during the first year (57.2%), 82 during the second year (23.7%), 24 during the third year (6.9%) whereas 42 relapses occurred after 3 years (12.1%) and 16 after 5 years (4.6%). Characteristics at diagnosis, i.e., age, AML status, WBC count, karyotype, FLT3-ITD mutation, CEBPA mutation and induction regimen did not differ between ER and LR or VLR. However, NPM1 mutations were more frequent in LR (NPM1m at diagnosis in relapses >3 years: 46% vs. 28% in relapses <3 years, P=.0532), and in VLR (NPM1m at diagnosis in relapses >5 years: 67% vs. 27% % in relapses <5 years, P=.0070). Allogeneic stem cell transplantation (alloSCT) was more frequently performed in the LR group (24% vs. 14%, P=.0369) and in VLR group (31% vs. 14%, P=.0748). Second CR (CR2) rate and median overall survival from relapse date (OS2) were better in LR and VLR than in ER (CR2ER: 26%, CR2LR: 43%, CR2VLR: 50%; P=.0154; OS2ER: 4.6 months, OS2LR: 10.8 months, OS2VLR: 11.6 months; P=.0024). Among the 142 CR1 patients with NPM1m, 67 relapsed (47.2%). In patients with NPM1m, relapses occurred during the first year in 39 (58.2% of NPM1m relapses), during the second year in 14 (20.9%) and during the third year in 2 (3%) whereas 12 relapses occurred after 3 years (17.9%), 8 occurred after 5 years (11.9%) and 3 after 8 years (4.5%). In NPM1-wild type patients, LR and VLR were significantly less frequent (<3 years: 91.9%; >3 years: 8.1%; >5 years: 2.5%; >8 years: 0.6%; P=.0317, .0037 and .0783 respectively). NPM1m relapses represented one half of LR (48%) and two thirds of VLR (67%). Among them, genotype was NPM1m/FLT3-wild type in most patients (75% in LR and 88% in VLR patients). In LR and VLR, NPM1 mutational status had no impact on CR2 and OS2: CR2LR/NPM1m: 42% vs. CR2LR/NPM1-WT: 38% (P=.8702); CR2VLR/NPM1m: 50%vs. CR2LR/NPM1-WT: 50% (P=1.0000); OS2LR/NPM1m: 7.4 months vs. OS2LR/NPM1-WT: 19.4 months (P=.2019); OS2VLR/NPM1m: 7.8 months vs. OS2VLR/NPM1-WT: 29.8 months (P=.0917). Our data show that LR and VLR are not infrequent in AML patients with NPM1 mutations. Although this finding needs to be validated in updated multicentric cohorts with a very long follow-up, it strongly suggests that AML patients with NPM1 mutations should benefit from a prolonged follow-up beyond 5 years from CR. Table Table. Disclosures No relevant conflicts of interest to declare.

Retrospective cohort study on the safety and efficacy of bevacizumab for metastatic colorectal cancer patients: The HGCSG0801 study—Efficacy of KRAS mutational status.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 680-680 ◽  
Author(s):  
Susumu Sogabe ◽  
Satoshi Yuki ◽  
Hideyuki Hayashi ◽  
Hirohito Naruse ◽  
Michio Nakamura ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Kras Mutation ◽  
Statistical Tests ◽  
Progression Free Survival ◽  
Wild Type ◽  
Mutation Status ◽  
Free Survival ◽  
Mutational Status ◽  
Kras Mutation Status

680 Background: Mutations of the KRAS gene were identified as a prognostic marker in metastatic colorectal cancer(mCRC). Previously reported data suggests that the longer overall survival (OS) observed with bevacizumab(BV) treatment in mCRC is independent of alterations in the KRAS mutation status. So we analyzed efficacy of bevacizumab combined chemotherapy in mCRC relative to KRAS mutation status. Methods: In the retrospective analysis(n=212) of patients treated with BV(HGCSG0801), additional statistical analyses were done with data from KRAS mutation analyses. The Response Evaluation in Solid Tumors (RECIST) criteria version 1.0 was used to assess tumor response. The Kaplan–Meier method was used to determine Progression-free survival(PFS) and OS. Log-rank test was used to compare with mutant or wild-type KRAS in terms of PFS and OS. All statistical tests were performed using SPSS. Results: KRAS status was assessed in 88 patients (41.5%). Response rate was 58.9% with wild-type and 62.5% with mutant KRAS, that was not significant(p=0.823). The median Progression-free survival was 11.5 months with wild-type and 11.5 months with mutant KRAS, that was not significant(p=0.222). And median OS was 31.8 months with wild-type and 27.5 months with mutant KRAS, that was not significant(p=0.760) as well. Similar results were seen among patients with first-line therapy. Conclusions: Bevacizumab provides clinical benefit in patients with mCRC expressing either mutant or wild-type KRAS.

Expression of PD-L1 in colorectal cancer that lack mutations in RAS or TP53 genes.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14500-e14500 ◽  
Author(s):  
Maher Albitar ◽  
Sucha Sudarsanam ◽  
Wanlong Ma ◽  
Shiping Jiang ◽  
Wayne Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cells ◽  
Tp53 Mutation ◽  
Continuous Variable ◽  
Colorectal Cancers ◽  
Wild Type ◽  
Tissue Samples ◽  
Mutation Status ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

e14500 Background: PD-L1 expression as detected by immunohistochemistry (IHC) is significantly lower in colorectal cancers (CRC) when compared with lung cancer or other types of cancer. We explored if mutations in the RAS/RAF gene family, TP53 or PIK3CA can define a subgroup of CRC that express PD-L1. Methods: Tissue samples collected from 107 patients with CRC were studied for the expression of PD-L1 using clone SP142. The same samples were also tested for mutations in NRAS, KRAS, HRAS, BRAF, TP53, and PIK3CA using Next Generation Sequencing (NGS). Results: Of the 107 CRC samples only 15 (14%) showed PD-L1 positive tumor cells (≥1%) and 8 of the 15 (7.5% of total) had PD-L1 in ≤5% of tumor cells. Detected mutations in these samples were as follows: TP53 65%, KRAS 49.5%, PI3KCA 22.5%, NRAS 5%, HRAS 1%, and BRAF 17%. There was no correlation between PD-L1 expression and mutation status in any of the RAS/RAF genes. There was also no correlation between TP53 mutation and PD-L1 expression. This was true irrespective if PD-L1 expression is considered as a continuous variable or when cut-off points of 5%, 20%, or 50% were used. However, patients without any mutation in RAS or TP53 had significantly (P = 0.005) more expression of PD-L1 when cut-off point of 5% is used. This remained true if PD-L1 expression is considered as a continuous variable (P = 0.04). There was no correlation between PIK3CA and PD-L1 expression. Conclusions: PD-L1 expression is significantly more common in CRC that lack mutations in RAS or TP53. PD-L1 expression is detected in 31% of patients with wild-type RAS/TP53 as compared with 12% in patients with RAS/TP53 mutations (P = 0.04). If a cut-off point of 5% is used, 31% of RAS/TP53-wild-type CRC were positive for PD-L1, while only 6% of RAS/TP53- mutant CRC were positive for PD-L1 (P = 0.005). This suggests that in CRC without RAS/TP53 mutation, the PD-L1 may play a more important role in oncogenesis. Exploring immunotherapy in this group of CRC patients might be justified.

scholarly journals Clinical Presentation and Outcome of Patients with Myeloid Differentiation Factor 88 Gene (MYD88) Wild-Type Waldenstrom Macroglobulinemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2960-2960
Author(s):  
Jithma P Abeykoon ◽  
Jonas Paludo ◽  
Prashant Kapoor ◽  
Wilson I Gonsalves ◽  
Morie A. Gertz ◽  
...  
Keyword(s):  
Research Funding ◽  
External Validation ◽  
Immunoglobulin M ◽  
Al Amyloidosis ◽  
Wild Type ◽  
Assay Sensitivity ◽  
Mutation Status ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia

Abstract Background Waldenström macroglobulinemia (WM) is a rare, indolent immunoglobulin M- associated lymphoplasmacytic lymphoma characterized by the alternation in the MYD88 locus in 90-95% of the cases. MYD88L265P is the most common alteration in WM patients and is considered a key molecular signature with a pathophysiological role in WM. Because of extremely low prevalence of WM with MYD88 wild type (WT) genotype there is a paucity of clinical and outcome data in this unique patient population. A recent study (Treon et al, Blood May, 2014), in an analysis based on the patients' MYD88 status, reported on the clinical features including older age at presentation and an unexpectedly higher mortality (38%) in the MYD88WTcohort compared to MYD88L265P patients (mortality 6%, P < .0001). However, the sample size of the MYD88WT WM cohort was small (n=15), with a few events during the short follow-up (median 4.84 years). Herein, we report on larger cohort of WM patients with this rare genotype. Methods This study included patients evaluated at Mayo Clinic, Rochester in whom the diagnosis of WM was established based on their clinicopathologic features and the MYD88 mutation status was determined through AS-PCR (assay sensitivity 1% mutant allele) performed on archived bone marrow samples obtained between 2007-2014. Patients with MYD88WT status were the focus of this study. Clinical data were collected from the patients' medical records. The Kaplan-Meir method was utilized for the survival analysis calculated from the time of diagnosis of WM. Outcomes of MYD88WT patients were compared with those harboring the MYD88L265Pmutation. Results Our cohort of 171 patients with an established diagnosis of WM and known MYD88 mutation status was found to be enriched for MYD88WT (n=40) patients. All patients required therapy. At diagnosis, the median age of the patients with MYD88 WT was 63 years (range 37.5-83.5 years; comparable to that of the MYD88L265P cohort, median 65 years, range: 32-92 years, p=0.16). Familial WM was identified in 10% of patients. Sixty four percent of patients presented with constitutional symptoms at diagnosis. These symptoms included fatigue (45%), weight loss (17%), night sweats (8%) dizziness (10%), dyspnea (23%), bleeding (10%), headache (10%) and hyper viscosity syndrome (5%). Splenomegaly and lymphadenopathy was observed in 20% and 27% of patients, respectively. Thirteen percent of patients had concomitant AL amyloidosis. Additional baseline characteristics are reported in Table 1. Transformation to a higher grade lymphoma was noted in 9 (23%) of patients, four of whom had received a purine analog and /or chlorambucil previously. The estimated median follow of MYD88WT patients was 8.1years (95% CI: 6.4-8.9) and their median overall survival (OS) was 8.5 years (95% CI: 6.4-29.4). No OS difference was evident between this cohort and the remainder of the patients with the MYD88L265Pmutation (n=131, median OS 11.7 years, 95% CI: 10-18, p=0.7; median follow-up 7.7 years 95% CI: 6.4-9.1, Figure 1). Conclusion In this relatively large cohort of WM MYD88WT patients with a prolonged follow-up, the MYD88mutation status was not found to be a determinant of patients' outcomes. Our findings contradict the results of a seminal previous study and require external validation, preferably through prospective studies. Disclosures Kapoor: Amgen: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Kumar:Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Glycomimetics: Consultancy; Onyx: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Millennium: Consultancy, Research Funding; AbbVie: Research Funding; Kesios: Consultancy.

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