scholarly journals Analysis of Mutational Spectra in Metastatic Colorectal Carcinoma: KRAS as an Indicator of Oxaliplatin-Based Chemotherapy

2019 ◽  
Vol 103 (1-2) ◽  
pp. 27-35 ◽  
Author(s):  
Chu-Cheng Chang ◽  
Jen-Kou Lin ◽  
Tzu-Chen Lin ◽  
Wei-Shone Chen ◽  
Jeng-Kai Jiang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Gene Mutations ◽  
Cytotoxic Agents ◽  
Chemotherapy Response ◽  
Wild Type ◽  
Primary Tumors ◽  
Chemotherapeutic Regimen ◽  
Mutational Spectra ◽  
Response To Chemotherapy ◽  
Mutation Spectra

Objective: Mutation spectra in colorectal cancer with metastasis and its response to chemotherapy. Summary of Background Data: No molecular markers are available for selecting the optimal chemotherapeutic regimen (irinotecan or oxaliplatin) for metastatic colorectal cancer (mCRC). Methods: We enrolled 161 mCRC patients who underwent surgery for their primary tumors at Taipei Veterans General Hospital from 2004 to 2010. The prevalence of gene mutations was measured and correlated with responses to different cytotoxic agents. Results: We detected 1,836 mutations in 12 genes. KRAS mutants affected 44.3% of the tumors. The rate of good response was insignificantly higher for patients with KRAS mutant tumors who received oxaliplatin-based chemotherapy compared with patients with KRAS wild-type tumors (65.6% versus 47.0%; P = 0.15). For patients who received irinotecan-based chemotherapy, the rate of good response was similar in patients with wild-type (55.0%; n = 11) and those with KRAS mutant tumors (54.5%; n = 12; P = 1). In patients with KRAS mutant tumors treated with an oxaliplatin-based regimen, the overall survival was 38.5 months (95% CI: 26.6–50.5 months), which was insignificantly better than that for patients treated with an irinotecan-based regimen (30.4 months; 95% CI: 15.8–45.1 months; P = 0.206). Conclusions: Our data could not come to the conclusion that patient with KRAS mutation mCRC may have better response with oxaliplatin-based first-line chemotherapy. Further study is needed to confirm the relationship between gene mutation and chemotherapy response.

scholarly journals Clinicopathological and Molecular Profiles of Sporadic Microsatellite Unstable Colorectal Cancer with or without the CpG Island Methylator Phenotype (CIMP)

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3487
Author(s):  
Shih-Ching Chang ◽  
Anna Fen-Yau Li ◽  
Pei-Ching Lin ◽  
Chun-Chi Lin ◽  
Hung-Hsin Lin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cpg Island ◽  
Gene Mutations ◽  
Proximal Colon ◽  
Tnm Stage ◽  
Cpg Island Methylator Phenotype ◽  
Kras Mutations ◽  
Methylator Phenotype ◽  
Next Generation Sequencing Ngs ◽  
Mutation Spectra

Background: The 5’-C-phosphate-G-3’ island methylator phenotype (CIMP) is a specific phenotype of colorectal cancer (CRC) associated with microsatellite instability-high (MSI-high) tumors. Methods: In this study, we determined the CIMP status using eight methylation markers in 92 MSI-high CRC patients after excluding five germline mismatch repair (MMR) gene mutations analyzed by next-generation sequencing (NGS) and confirmed by Sanger sequencing. The mutation spectra of 22 common CRC-associated genes were analyzed by NGS. Results: Of the 92 sporadic MSI-high tumors, 23 (25%) were considered CIMP-high (expressed more than 5 of 8 markers). CIMP-high tumors showed proximal colon preponderance and female predominance. The mutation profiles of CIMP-high tumors were significantly different from those of CIMP-low or CIMP-0 tumors (i.e., higher frequencies of BRAF, POLD1, MSH3, and SMAD4 mutations but lower frequencies of APC, TP53, and KRAS mutations). Multivariate analysis demonstrated that tumor, node, metastasis (TNM) stage was the independent prognostic factor affecting overall survival (OS). Among the MSI-high cases, the CIMP status did not impact the outcome of patients with MSI-high tumors. Conclusions: Only TNM stage was a statistically significant predictor of outcomes independent of CIMP profiles in MSI-high CRC patients. Sporadic MSI-high CRCs with different mechanisms of carcinogenesis have specific mutation profiles and clinicopathological features.

Use of microsatellite instability in non-hereditary advanced colorectal cancer to predict response to chemotherapy and overall survival: A study of the Dutch Colorectal Cancer Group (DCCG)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4118-4118
Author(s):  
M. Koopman ◽  
G. A. Kortman ◽  
L. Mekenkamp ◽  
M. J. Ligtenberg ◽  
N. Hoogerbrugge ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Microsatellite Instability ◽  
Early Stage ◽  
Tissue Microarrays ◽  
Primary Tumors ◽  
Mlh1 Promoter ◽  
Cancer Group ◽  
Response To Chemotherapy ◽  
Embedded Blocks

4118 Background: Microsatellite instability (MSI) is present in 10–20% of patients (pts) with non-hereditary colorectal cancer (CRC) and is generally associated with improved overall survival. The effect of chemotherapy in such pts is uncertain, and most data are derived from early stage CRC. Therefore the outcome of treatment in relation to presence or absence of MSI was studied in pts with non- hereditary advanced CRC. Methods: Data were collected from previously untreated advanced CRC pts randomized between 1st line capecitabine (Cap), 2nd line irinotecan (Iri), and 3rd line Cap + oxaliplatin (CapOx) vs 1st line CapIri and 2nd line CapOx. Formalin-fixed, paraffin embedded blocks of primary tumors and normal tissue were collected and tissue microarrays were made. Expression of the mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 was examined by immunohistochemistry. Additionally MSI analysis and hypermethylation of the MLH1-promoter were performed. Pts with a tumor showing MSI caused by hypermethylation of the MLH1-promoter were included to study the correlation between MSI status and response to 1st line treatment and overall survival. Results: MSI caused by hypermethylation of the MLH1-promoter was found in 14 (3%) of 512 eligible pts. In 461 evaluable pts, disease control (CR+PR+SD=4 months) in 12 pts with MSI was 58% [95% CI 28%- 85%] and in 449 without MSI 83% [95% CI 79%-86%, p= 0.03].The median OS in pts with MSI was 7 months [95% CI 4–17] and in pts without MSI 18 months [95% CI 16–19, log rank p=0.08]. Conclusions: MSI in advanced non-hereditary CRC is very rare, and predicts a significantly worse outcome in terms of response to chemotherapy with a trend towards a decreased OS. No significant financial relationships to disclose.

Does panitumumab have a clinical benefit in cetuximab-refractory KRAS wild-type metastatic colorectal cancer?

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 654-654
Author(s):  
Toshiyasu Watanabe ◽  
Eiji Shinozaki ◽  
Sho Kijima ◽  
Yoshihito Ohhara ◽  
Yasutoshi Kuboki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Tumor Marker ◽  
Clinical Benefit ◽  
Chemotherapy Response ◽  
Chimeric Mouse ◽  
Serum Tumor Marker ◽  
Wild Type ◽  
Tumor Marker Level ◽  
Marker Level

654 Background: Panitumumab and cetuximab can be used in metastatic colorectal cancer (mCRC) and these drugs are IgG2 fully human and IgG1 chimeric (mouse/human) monoclonal antibody against the epidermal growth hactor receptor (EGFR) respectively. The efficacy of panitumumab as a salvage chemotherapy after cetuximab-based chemotherapy failure is not clarified. Methods: This study aimed to evaluate the panitumumab efficacy to KRAS wild-type mCRC patients who failed cetuximab-based chemotherapy. Response, progression-free survival (PFS) and serum tumor marker level (CEA and CA19-9), were assesed. We studied response by days from last cetuximab-based chemotherapy to panitumumab induction (C-P days). Results: 22 patients (11 men, 11 women, median age 54 years m4 0-78 n) were enrolled. All of thease patients were cetuximab-based chemotherapy refractory KRAS wild-type mCRC. After progression, they received panitumumab monotherapy (6 mg/kg every 2 weeks).The best response was SD 10/22 (45.5%), PD 11/22 (50%) and NE 1/22 (4.5%). Overall median PFS was 90 days (13 to 182). The patients C-P days less than 30 days were 15 patients(5:SD, 10:PD). The patients more than 79 days were 7 patient(5:SD, 1:PD, 1:NE). Serum tumor marker level was decreased more than 50% patients. Conclusions: This study suggested that it might be limited as possibility of clinical benefit with panitumumab administration after cetuximab failure.

scholarly journals Decitabine Augments Chemotherapy-Induced PD-L1 Upregulation for PD-L1 Blockade in Colorectal Cancer

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 462 ◽  
Author(s):  
Kevin Chih-Yang Huang ◽  
Shu-Fen Chiang ◽  
William Tzu-Liang Chen ◽  
Tsung-Wei Chen ◽  
Ching-Han Hu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Therapeutic Efficacy ◽  
Dna Methyltransferase ◽  
Chemotherapeutic Agents ◽  
Dna Hypomethylation ◽  
Chemotherapeutic Regimen ◽  
Response To Chemotherapy ◽  
Clinical Benefits

Programmed cell death-1 (PD-1) has demonstrated impressive clinical outcomes in several malignancies, but its therapeutic efficacy in the majority of colorectal cancers is still low. Therefore, methods to improve its therapeutic efficacy in colorectal cancer (CRC) patients need further investigation. Here, we demonstrate that immunogenic chemotherapeutic agents trigger the induction of tumor PD-L1 expression in vitro and in vivo, a fact which was validated in metastatic CRC patients who received preoperatively neoadjuvant chemotherapy (neoCT) treatment, suggesting that tumor PD-L1 upregulation by chemotherapeutic regimen is more feasible via PD-1/PD-L1 immunotherapy. However, we found that the epigenetic control of tumor PD-L1 via DNA methyltransferase 1 (DNMT1) significantly influenced the response to chemotherapy. We demonstrate that decitabine (DAC) induces DNA hypomethylation, which not only directly enhances tumor PD-L1 expression but also increases the expression of immune-related genes and intratumoral T cell infiltration in vitro and in vivo. DAC was found to profoundly enhance the therapeutic efficacy of PD-L1 immunotherapy to inhibit tumor growth and prolong survival in vivo. Therefore, it can be seen that DAC remodels the tumor microenvironment to improve the effect of PD-L1 immunotherapy by directly triggering tumor PD-L1 expression and eliciting stronger anti-cancer immune responses, providing potential clinical benefits to CRC patients in the future.

Metastases resection in colorectal cancer patients with mutation in oncogene BRAF or tumors located on the right side: Experience at the HGUGM.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4041-4041
Author(s):  
Laura Ortega ◽  
Marianela Bringas Beranek ◽  
Natalia Gutiérrez Alonso ◽  
Javier Soto Alsar ◽  
Manuel Alva Bianchi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Disease ◽  
Positive Impact ◽  
Wild Type ◽  
Primary Tumors ◽  
Metastatic Lesions ◽  
Common Location ◽  
The Right ◽  
The Impact

4041 Background: Approximately 25% of patients with colorectal cancer (CRC) debut with metastatic disease. In addition, 25-35% of patients with localized disease at diagnosis develop metastatic lesions during the evolution of their disease. Consequently, approximately 50-60% of patients with CRC will present metastatic lesions at some point in their lives. Metastasis resection has improved the prognosis of these patients, achieving overall survival (OS) that exceed 40 months. However, there are doubts about the benefit of this approach in patients with mutations in oncogene BRAF or tumors located on the right-side, due their poor prognosis. The aim of the study is to analyze the impact of metastases resection on OS of these populations. Methods: We conducted a retrospective analysis of patients with mCRC attended in the Medical Oncology Department of the Hospital General Universitario Gregorio Marañón (Spain) between January 2010 and 2018. Results: 487 patients were identified and included in the analysis. Median age was 71 years (62-81). Most patients were males (62.4%). 55.2% had metastatic lesions at diagnosis. Most patients had ECOG 0-1 at diagnosis of metastatic disease (91.0%). 8.9% of patients had BRAF mutations (n = 21) and 31.8% of patients had primary tumors located on the right-side (n = 152). 474 patients received first-line chemotherapy (97.3%). OS of the entire cohort was 29.67 months; 30.69 months in BRAF mutated patients vs 35.89 in wild-type patients (p = 0.161); 25.29 months in right-side tumors vs 31.02 in left-side tumors (p = 0.044). 306 patients (62.8%) underwent metastases resection. Most common location was liver (51.4%). 147 patients (30.2%) underwent a second metastases resection. Mean number of metastases surgeries was 1.35 (+/-1.40). OS since metastases resection was 24.83 months in BRAF mutated patients vs 41.55 months in wild-type patients (p = 0.020). According to location, it was 35.49 months in right-side tumors vs 43.78 months in left-side tumors (p = 0.106). In BRAF mutated patients, OS was 38.19 months in patients underwent metastases resection vs 18.52 months in non-surgical patients (p = 0.043); 41.51 months vs 16.18 months respectively in patients with tumors located on the right-side (p < 0.001). Conclusions: Metastases resection has a positive impact on overall survival of patients with mutations in oncogene BRAF or right-side tumors, even though their prognosis is still poor compared to patients without these alterations.

BRCA mutations in metastatic colorectal cancer (mCRC) and response to chemotherapy.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 235-235
Author(s):  
Sophie Feng ◽  
Laith Al-Showbaki ◽  
Monika K. Krzyzanowska ◽  
Rebecca M. Prince ◽  
Tracy Stockley ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Case Series ◽  
Molecular Characteristics ◽  
Small Subset ◽  
Chemotherapy Response ◽  
First Line ◽  
Brca Mutations ◽  
Response To Chemotherapy ◽  
Brca 1 ◽  
The Impact

235 Background: Mutations in BRCA 1/2 are typically associated with breast, ovarian, pancreatic and prostate cancers. BRCA mutations have been reported in colorectal cancer in sporadic case series. Unlike other cancers, the significance of BRCA mutations in mCRC is not known. We report the prevalence and molecular characteristics associated with BRCA 1/2 mutations in mCRC, and investigate the impact of these mutations on chemotherapy response since both oxaliplatin (OX) and irinotecan (IRI) interfere with DNA repair pathways. Methods: The Ontario-wide Cancer Targeted Nucleic Acid Evaluation (OCTANE) database was queried to identify mCRC patients (pts) harbouring BRCA 1/2 mutations. BRCA 1/2 mutations were detected using panel-based next generation sequencing (NGS) on archival tumour tissue. Clinical and molecular variables were collected, together with treatment outcomes. Results: Of 279 mCRC pts within the OCTANE database as of March 2019, 9 pts with BRCA 1/2 mutations were identified (3.2%): 4 BRCA 1 and 5 BRCA 2 mutations. Each patient had a unique variant with 8/9 missense mutations and 1/9 splicing error. Allele frequency ranged from 0.11 to 0.57. RAS or BRAF mutations were present in 67%. Common co-mutations included TP53 (56%), APC (56%), TSC1 (44%), ROS1 (33%) and ATM(33%). 2 pts were mismatch repair deficient. Median age was 48.5 years (range: 31-69 years), 56% males. 5 pts presented with de novo metastatic disease. First line OX-containing chemotherapy was administered to 4 pts, and IRI to 3 pts. 2 pts did not receive chemotherapy (1 had surgery only post-adjuvant OX, and 1 immunotherapy). Overall response rate (ORR) was 71%, with all pts achieving a partial response or stable disease. The median progression-free survival was 7.5 months (range: 1.8- 31.7 months) and median overall survival 68.5 months (range: 10.5- 68.5 months) respectively. Conclusions: BRCA 1/2 mutations are present in a small subset of mCRC pts. Pts with these mutations tend to be younger at diagnosis. BRCA 1/2 mutations are associated with favourable response to first line chemotherapy. Targeting BRCA 1/2 mutations may broaden treatment options for these patients.

Tumor-Specific Nascent Nine-Peptide-Epitopes Prediction and Bioinformatics Characterization in Human Colorectal Cancer

2020 ◽  
Vol 10 (6) ◽  
pp. 1338-1345
Author(s):  
Ying Zhu ◽  
Bo Hu ◽  
Long Xu ◽  
Lili Yang ◽  
Congjie Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Cd8 T Cells ◽  
Translesion Synthesis ◽  
Gene Mutations ◽  
Wild Type ◽  
Peptide Epitopes ◽  
Binding Force ◽  
Tumor Tissues ◽  
Mutant Genes

Background/Aims: Neoantigens are peptides produced by translation of mutant exons and existed in tumor tissues instead of normal tissues, thus, we desired to investigate the antigenic peptide epitopes of cancerspecific neoantigen, to detect the affinity of the nonapeptide with the corresponding Human Leukocyte Antigen I (HLA I) allele molecule, in order to understand the relationship of mutant exon genes of Colorectal Cancer (CRC) patients and the drive genes that are currently known for tumorigenesis of CRC. Methods: The next generation sequencing (NGS) method was used to detect the whole genome sequence and HLA I allele types of tumor tissues and adjacent tissues of 5 CRC patients. pVAC-Seq was applied to identify the nascent nonapeptides generated from exon mutations. The affinity of polypeptides with respective HLA I molecules in CRC was calculated by using NETMHC 4.0 Server. The molecular localization, molecular function, and signal pathways of mutant genes in 5 CRC patients were performed by FunRich 3.1.3 software. The TIMER website was applied to predict the analysis of intratumoral immune cell infiltration associated with the gene mutations in 5 CRC patients. Results: Fifty-six tumor-specific neo-nonapeptides were predicted from 54 different exon gene mutations. The 56 tumor new nonapeptide sequences were different from the shared motif of the HLA I allele. We explored that the tumor-specific nascent nonapeptide mainly bound to HLA-A.02*03, HLA-B.58*01 and HLA-B.11*01, and the affinity analysis results suggested that 14 of the nonapeptides had strong binding force, 20 nonapeptides had weak binding force, and 22 nonapeptides had no binding force. 54 mutant exons of 5 CRC patients were chiefly located in Leading edge membrane, Fanconi anaemia nuclear complex, and Azurophil granule. The molecular functions of these genes were involved in DNA-directed DNA polymerase activity, Vitamin or cofactor transporter activity, and Receptor signaling protein tyrosine kinase activity. 54 gene mutations had key roles in Translesion synthesis by Pol zeta, Translesion synthesis by DNA polymerases bypassing lesion on DNA template, and DNA Damage Bypass. We found that the mutant FMN2 had more infiltration of CD8+ T cells in the tumor than the wild type, and the mutant ZNF717 had more infiltration of CD8+ T cells and neutrophils in the tumor than the wild type, the difference was statistically significant. Conclusion: This study provides a preliminary result to illustrate that the prediction and bioinformatics feature of tumor-specific new nine-peptide-epitopes in CRC. It is hoped that the cancer-specific neoantigen will be used for adjuvant immunotherapy after radical surgery of colorectal cancer, and the mutant genes of CRC can also be used as landmarks for postoperative recurrence and metastasis of colorectal cancer.

scholarly journals The Prognostic and Predictive Value of SOX2+ Cell Densities in Patients Treated for Colorectal Cancer

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1110
Author(s):  
Tim J. Miller ◽  
Melanie J. McCoy ◽  
Tracey F. Lee-Pullen ◽  
Chidozie C. Anyaegbu ◽  
Christine Hemmings ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Cox Regression ◽  
Predictive Marker ◽  
Chemotherapy Response ◽  
Poor Overall Survival ◽  
Historical Cohort ◽  
Kaplan Meier ◽  
Response To Chemotherapy ◽  
Cell Densities

SOX2 (sex-determining region-Y homeobox-2) is a transcription factor essential for the maintenance of pluripotency and is also associated with stem-cell-like properties in preclinical cancer models. Our previous study on a cohort of stage III colon cancer patients demonstrated high SOX2+ cell densities were associated with poor prognosis. However, most patients were treated with adjuvant chemotherapy so the prognostic value of SOX2 could not be assessed independently from its value as a predictive marker for non-response to chemotherapy. This study aimed to assess whether SOX2 was a true prognostic marker or a marker for chemotherapy response in a historical cohort of patients, a high proportion of whom were chemotherapy-naïve. SOX2 immunostaining was performed on tissue micro-arrays containing tumor cores from 797 patients with stage II and III colorectal cancer. SOX2+ cell densities were then quantified with StrataQuest digital image analysis software. Overall survival was assessed using Kaplan–Meier estimates and Cox regression. It was found that high SOX2+ cell densities were not associated with poor overall survival. Furthermore, all patients had a significant improvement in survival after 5-fluorouracil (5-FU) treatment, irrespective of their SOX2+ cell density. Therefore, SOX2+ cell densities were not associated with prognosis or chemotherapy benefit in this study. This is in contrast to our previous study, in which most patients received oxaliplatin as part of their treatment, in addition to 5-FU. This suggests SOX2 may predict response to oxaliplatin treatment, but not 5-FU.

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