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.

526 MICROSATELLITE INSTABILITY IN GASTRO-ESOPHAGEAL ADENOCARCINOMAS

2020 ◽  
Vol 33 (Supplement_1) ◽  
Author(s):  
A Katz ◽  
G Evaristo ◽  
M Issac ◽  
J Ramirez-GraciaLuna ◽  
M Park ◽  
...  
Keyword(s):  
Overall Survival ◽  
Microsatellite Instability ◽  
Cox Regression ◽  
Significant Proportion ◽  
Genomic Analysis ◽  
Poor Response ◽  
Tissue Microarrays ◽  
Braf V600e ◽  
Chi Square ◽  
Response To Chemotherapy

Abstract   Microsatellite instability (MSI) in gastro-esophageal adenocarcinomas (GEAs) is associated with poor response to chemotherapy; however, this association is poorly understood. The aim of this study is to better understand the clinical relevance and mutational landscape of MSI in GEA. Methods In order to assess the status of mismatch repair (MMR) proteins, we performed immunohistochemistry for MLH1, MSH2, MSH6, PMS2 and BRAF V600E on tissue microarrays constructed from 161 patients with esophageal adenocarcinoma and 65 patients with gastric adenocarcinoma, operated between 2011 to 2019. MMR- deficient (MMR-D) status was confirmed using full sections of tumors. Demographics, tumor, and treatment details, operative variable and overall survival were evaluated. Genomic characterization of 3 MSI-H and 10 MSS patients was performed using deep targeted sequencing of 234 potential oncogenic genes. Statistical analysis was performed using Cox regression, logistic regression, ANOVA or Chi-square tests. Results Among the 28 (12%) MMR-D immunophenotype patients identified: 25 showed a combined MLH1/PMS2 loss, one case with MSH2/MSH6 loss and two cases with isolated MSH6 or MSH2 loss. Patients in the MMR-D were older (74 ± 14 vs 67 ± 11 years, p = 0.01) and with more Siewert-III and sub-cardia tumors [64%(18) vs 40%(79), p = 0.002] compared to MMR-Stable patients. All other variables including sex, stage and grade were not significantly different. MMR-D immunophenotype was associated with better overall survival (Median survival of 5.7vs2.3 years, p < 0.04) (Figure 1A). Genomic analysis linked patients with D-MMR with a higher mutational burden with some potentially targetable mutations (Figure 1B). Conclusion The significant proportion of MMR-D immunophenotype identified in this gastroesophageal cohort and the different pattern of overall survival and genetic mutations associated with this phenotype, highlight the importance of further characterization and understanding the mechanisms and role of MMR status in GEAs.

Predicting biomarkers of hepatic metastasis in Chinese colorectal cancer patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15545-e15545
Author(s):  
Honghua Peng ◽  
Tianhao Mu ◽  
Yaping Sheng ◽  
Yingmei Li ◽  
Peiguo Cao
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Cancer Patients ◽  
Hepatic Metastasis ◽  
Primary Tumor ◽  
Potential Candidate ◽  
Poor Overall Survival ◽  
Primary Tumors ◽  
Distant Spread ◽  
Colorectal Cancer Patients

e15545 Background: Hepatic metastasis is the most common site of distant spread from colorectal cancer. About 15-25% patients with colorectal cancer harbors hepatic metastasis. The molecular mechanism and predicting biomarkers in colorectal cancer are still not fully understood. Methods: 57 Chinese colorectal cancer patients were enrolled in a cohort study. Samples of primary tumor were collected in these patients and underwent whole exome sequencing. Mutation profiles of primary tumors between the patients with metastasis and those without metastasis were analyzed and compared. Results: In the cohort, 54.4% (31/57) patients presented hepatic metastasis at the time of diagnosis, while 45.6% (26/57) did not. The patients were divided into 2 groups—with hepatic metastasis and without hepatic metastasis. The mutation landscape of primary tumor indicated that the Top 3 most frequently mutated genes of both groups were the same and presented mutated TP53, APC, and KRAS. 2. Interestingly, compared with the patients without hepatic metastasis, the patients with hepatic metastasis presented a higher frequency of mutated TCF7L2 (35.5% vs 3.85%) and TRIM77 (16.1% vs 0%). Moreover, in the patients with hepatic metastasis, the patients with TRIM77 mutation in primary tumor showed a worse overall survival (p < 0.0001). Conclusions: TCF7L2 and TRIM77 may be identified as potential candidate predicting biomarkers for hepatic metastasis in colorectal patients. In addition, mutated TRIM 77 predicted a poor overall survival in hepatic metastasis from colorectal cancer.

Overall survival based on MSI and BRAF mutation status for stage II/III colorectal cancer.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 132-132
Author(s):  
Sophiya Karki ◽  
Rashna Madan ◽  
Sarah Schmitt ◽  
Ziyan Y. Pessetto ◽  
Andrew K. Godwin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Microsatellite Instability ◽  
Median Survival ◽  
Braf Mutation ◽  
Prognostic Value ◽  
Stage Ii ◽  
Age At Diagnosis ◽  
Mutation Status ◽  
Braf Mutant

132 Background: Colorectal cancer (CRC) is the second leading cause of cancer-associated deaths in the United States. Some of the poor prognostic factors for metastatic CRC (mCRC) include BRAF V600E mutation and microsatellite instability (MSI) that result from mutation or loss of mismatch-repair genes. While the prognostic value of MSI-high CRC for early-stage patients treated with resection and adjuvant chemotherapy is favorable, the prognostic value of BRAF mutation is still unclear. Furthermore, the impact of BRAF mutation with concurrent microsatellite instability on overall survival has not been well investigated. Methods: Here, we collected BRAF mutation status and MSI status of stage II/III CRC patients (n=106) treated at the University of Kansas Cancer Center between September 2009 and July 2020 and compared overall survival between 4 subtypes:MSI-H/BRAF mutant (n=16), MSS/BRAF mutant (n=4), MSI-H/BRAF WT (n=17) and MSS/BRAF WT (n=69), further stratifying patients by age at diagnosis and tumor location. Molecular data were obtained from molecular oncology laboratory as PCR or IHC-based or acquired from outside records. Subgroup analyses were done for stage II and stage III cancers. Results: Table shows the patient characteristics. From our preliminary analysis, MSI-H CRC was found to be primarily a right-sided tumor (MSI-H/BRAF mutant: 94% and MSI-H/BRAF WT 76%). On the contrary, MSS CRC had a more heterogenous localization, spanning left colon, right colon and rectum. In our patient cohort, median survival was not reached for stage II patients whereas for stage III patients, BRAF mutation was associated with poor median survival irrespective of MSI status (MSS/BRAF mutant: 27 months and MSI-H/BRAF mutant 29 months). Median overall survival was found to be 87 months, not reached, 27 months and 29 months for MSS/BRAF WT, MSI-H/BRAF WT, MSS/BRAF mutant and MSI-H/BRAF mutant, respectively. Although associated with poor survival, MSI-H/BRAF mutant displayed later age at diagnosis (mean age 73) compared to MSS/BRAF mutant (mean age 60, p-value<0.029). Conclusions: Our finding suggests that BRAF mutation has poor prognosis even at earlier stages of the disease and that MSS/BRAF mutation, in particular, has the worst prognostic features. These findings highlight the need for BRAF-targeted therapy for CRC at any stage. Due to small sample size, however, our results warrant validation in a larger cohort. [Table: see text]

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.

Impact of M1a and M1b staging in patients (pts) with metastatic colorectal cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3590-3590 ◽  
Author(s):  
Hagen F. Kennecke ◽  
Jason Yu ◽  
Sharlene Gill ◽  
Winson Y. Cheung ◽  
Charles Davic Blanke ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Primary Tumor ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Cox Proportional Hazards ◽  
Prognostic Impact ◽  
Primary Tumors ◽  
7Th Edition ◽  
The Impact

3590 Background: In 2009, pts with M1 colorectal cancer were divided into two subsets for the American Joint Committee on Cancer (AJCC) 7th edition. Pts with metastases (mets) confined to one organ or site at initial diagnosis became stage M1a while multiple sites or peritoneal mets became M1b. The objectives of the study are to evaluate the impact of site of mets and M1a/b staging among pts with M1 colorectal cancer. Methods: All pts referred to the BC Cancer Agency from 1999-2007 with newly diagnosed M1 colon or rectal cancer were included. Demographic, treatment, and outcome data were prospectively collected. The prognostic impact of individual sites of mets was assessed by hazard ratio estimates from univariate Cox models. Multivariable Cox proportional-hazards models were used to determine variables associated with overall survival in the entire cohort and in those undergoing resection of their primary tumor. Results: 2,049 pts with M1 disease were included. Median age was 66 years; 71% had colonic origin; 70% had their primary tumor resected; and 69% received chemotherapy. In univariate analysis, solitary mets were associated with improved survival. In multivariable analysis, M1a/b status still had significant prognostic effect. The effect remained significant in the subgroup analysis of pts with resected primary tumors when histology, T and N stage were included. Conclusions: Pts with solitary mets, including peritoneum, have superior overall survival as compared to those with multiple sites of mets. AJCC 7th edition staging that includes M1a/b provides significant prognostic information and should be considered in clinical practice and trials of pts with M1 disease who otherwise have few prognostic factors. [Table: see text]

Nivolumab versus nivolumab with ipilimumab versus trifluridine/tipiracil for metastatic microsatellite instability-high colorectal cancer: A modeling decision analysis.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 829-829
Author(s):  
Jacqueline N. Chu ◽  
Jin G. Choi ◽  
Sassan Ostvar ◽  
James A. Torchia ◽  
Kerry Lynn Reynolds ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Cost Effectiveness ◽  
Microsatellite Instability ◽  
Cost Effective ◽  
Checkpoint Blockade ◽  
Base Case ◽  
Life Years ◽  
Third Line ◽  
Line Chemotherapy

829 Background: Microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) patients who have failed chemotherapy have shown response to checkpoint blockade. We investigate optimal third-line treatment in MSI-H mCRC with regard to overall survival, quality of life years gained (QALYs), and cost-effectiveness. Methods: A Markov Model was created for a base case of a 57 year old man with MSI-H mCRC refractory to two lines of chemotherapy. Treatments compared were nivolumab, nivolumab with ipilimumab, and trifluridine/tipiracil. Patients could remain stable, progress to fourth-line chemotherapy or palliative care, experience drug toxicity, die from age/sex mortality, or die from cancer over their simulated lifetimes. Transitions between health states were based on the CheckMate 142 and RECOURSE trials. Outcomes were survival or unadjusted life years, QALYs, and incremental cost-effectiveness ratios (ICERs). The willingness to pay threshold was $100,000/QALY. Results: Nivolumab with ipilimumab was the most effective strategy as it yielded more unadjusted life-years (4.24) and QALYs (2.53) compared to nivolumab (3.95 LY, 2.33 QALYs) and trifluridine/tipiracil (0.74 LY, 0.07 QALYs). However, nivolumab with ipilimumab was not cost-effective compared to nivolumab and neither treatment strategy was cost-effective compared to trifluridine/tipiracil. Sensitivity analysis found nivolumab monotherapy could be cost-effective with decrease in drug cost to $2000/dose. Conclusions: Our modeling analysis finds that both single and dual checkpoint blockade yield significantly increased overall survival and QALYs for MSI-H mCRC compared to third-line chemotherapy, but were not cost-effective because of nivolumab cost. Decreases in drug pricing and/or duration of maintenance nivolumab could make nivolumab monotherapy cost-effective. [Table: see text]

In Situ Cytotoxic and Memory T Cells Predict Outcome in Patients With Early-Stage Colorectal Cancer

2009 ◽  
Vol 27 (35) ◽  
pp. 5944-5951 ◽  
Author(s):  
Franck Pagès ◽  
Amos Kirilovsky ◽  
Bernhard Mlecnik ◽  
Martin Asslaber ◽  
Marie Tosolini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Tumor Recurrence ◽  
Large Scale ◽  
Immune Reaction ◽  
Early Stage ◽  
Tissue Microarrays ◽  
T Helper 1 ◽  
Specific Tumor ◽  
Independent Effects

Purpose Many patients who present with early-stage colorectal cancer (International Union Against Cancer TNM stages I and II) are nevertheless at high risk of relapse. We hypothesized that intratumoral immune reaction could influence their prognosis. Patients and Methods The intratumoral immune reaction was investigated in 29 tumors by large-scale real-time polymerase chain reaction. Cytotoxic (CD8) and memory (CD45RO) T cells were quantified by immunohistochemical analyses of tissue microarrays from the center (CT) and the invasive margin (IM) of the 602 tumors from two independent cohorts. The results were correlated with tumor recurrence and patient survival. Results Patients with a strong infiltration of CD45RO+ cells in the tumor exhibited an increased expression of T-helper 1 and cytotoxicity-related genes. Densities of CD45RO+ and CD8+ cells in tumor regions (CT/IM) classified the patients into four distinct prognostic groups based on the presence of high density of each marker in each tumor region. The four groups were associated with dramatic differences in disease-free, disease-specific, and overall survival (all P < .0001). Five years after diagnosis, only 4.8% (95% CI, 0.6% to 8.8%) of patients with high densities of CD8+ plus CD45RO+ cells had tumor recurrence, and 86.2% (CI, 79.4% to 93.6%) survived. In contrast, the tumor recurred in 75% (95% CI, 17% to 92.5%) of patients with low densities of these cells, and only 27.5% (95% CI, 10.5% to 72%) survived (all P < .0001). Multivariate analyses showed that the immune criteria had independent effects on the rates of complete remission and survival. Conclusion The combined analysis of CD8+ plus CD45RO+ cells in specific tumor regions could provide a useful criterion for the prediction of tumor recurrence and survival in patients with early-stage colorectal cancer.

scholarly journals Quasimonomorphic Mononucleotide Repeats for High-Level Microsatellite Instability Analysis

2004 ◽  
Vol 20 (4-5) ◽  
pp. 251-257 ◽  
Author(s):  
Olivier Buhard ◽  
Nirosha Suraweera ◽  
Aude Lectard ◽  
Alex Duval ◽  
Richard Hamelin
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Screening Test ◽  
Consensus Meeting ◽  
Dinucleotide Repeats ◽  
Primary Tumors ◽  
Low Level ◽  
High Level ◽  
Msi Analysis ◽  
Microsatellite Instability Analysis

Microsatellite instability (MSI) analysis is becoming more and more important to detect sporadic primary tumors of the MSI phenotype as well as in helping to determine Hereditary Non-Polyposis Colorectal Cancer (HNPCC) cases. After some years of conflicting data due to the absence of consensus markers for the MSI phenotype, a meeting held in Bethesda to clarify the situation proposed a set of 5 microsatellites (2 mononucleotide repeats and 3 dinucleotide repeats) to determine MSI tumors. A second Bethesda consensus meeting was held at the end of 2002. It was discussed here that the 1998 microsatellite panel could underestimate high-level MSI tumors and overestimate low-level MSI tumors. Amongst the suggested changes was the exclusive use of mononucleotide repeats in place of dinucleotide repeats. We have already proposed a pentaplex MSI screening test comprising 5 quasimonomorphic mononucleotide repeats. This article compares the advantages of mono or dinucleotide repeats in determining microsatellite instability.

scholarly journals Colorectal cancer molecular classification using BRAF, KRAS, microsatellite instability, and CIMP status: Prognostic implications and response to chemotherapy.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 668-668
Author(s):  
Oscar Murcia ◽  
Miriam Juárez ◽  
Eva Hernández-Illán ◽  
Maria Rodriguez-Soler ◽  
Mar Giner-Calabuig ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Braf Mutation ◽  
Kras Mutation ◽  
Cpg Island ◽  
Disease Free Survival ◽  
Molecular Classification ◽  
Hazard Ratio ◽  
Tnm Stage ◽  
Response To Chemotherapy

668 Background: The aim of this study was to validate a molecular classification of colorectal cancer (CRC) based on microsatellite instability (MSI), CpG island methylator phenotype (CIMP) status, BRAF, and KRAS and investigate each subtype’s response to chemotherapy. Methods: This retrospective observational study included a population-based cohort of 878 CRC patients. We classified tumours into five different subtypes based on BRAF and KRAS mutation, CIMP status, and MSI. Patients with advanced stage II (T4N0M0) and stage III tumours received 5-fluoruracil (5-FU)-based chemotherapy or no adjuvant treatment based on clinical criteria. The main outcome was disease-free survival (DFS). Results: Patients with the combination of microsatellite stable (MSS) tumours, BRAF mutation and CIMP positive exhibited the worst prognosis in univariate (log rank P < 0.0001) and multivariate analyses (hazard ratio 1.75, 95% CI 1.05-2.93, P = 0.03) after adjusting for age, sex, chemotherapy, and TNM stage. Treatment with 5-FU-based regimens improved prognosis in patients with the combination of MSS tumours, KRAS mutation and CIMP negative (log rank P = 0.003) as well as in patients with MSS tumours plus BRAF and KRAS wild-type and CIMP negative (log-rank P < 0.001). After adjusting for age, sex, and TNM stage in the multivariate analysis, only patients with the latter molecular combination had independently improved prognosis after adjuvant chemotherapy (hazard ratio 2.06, 95% CI 1.24-3.44, P = 0.005). Conclusions: We confirmed the prognostic value of stratifying CRC according to molecular subtypes using MSI, CIMP status, and somatic KRAS and BRAF mutation. Patients with traditional chromosomally unstable tumours obtained the best benefit from adjuvant 5-FU-based chemotherapy.

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