Immune infiltrates in liver metastases of colorectal cancer and response to chemotherapy

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15069-e15069 ◽  
Author(s):  
N. Halama ◽  
S. Michel ◽  
M. Kloor ◽  
I. Zoernig ◽  
T. Pommerencke ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastases ◽  
Immune Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Predictive Marker ◽  
Response To Therapy ◽  
Time To Progression ◽  
Antibody Treatment ◽  
Primary Tumors ◽  
Response To Chemotherapy

e15069 Background: Colorectal cancer (CRC) is a major cause of death from cancer. Patients with irresectable or metastasized CRC usually receive chemotherapy in combination with a monoclonal antibody, median overall survival time is around 20- 21 months with response rates of around 50%. Almost half of the patients experience treatment related side effects without benefit. K-ras mutation is the only (negative) predictive marker for response to therapy (for EGFR-targeting antibody treatment), no biomarkers are available that help to select patients most likely responding to chemotherapy. In primary colon cancer immune infiltrates in the tumor represent an important prognostic factor. High densities of tumor infiltrating lymphocytes (TIL) were shown to be correlated with an improved survival in patients with primary CRC. TILs therefore represent a valuable prognostic tool, a high density of immune cells being associated with good outcome independently of other established prognostic markers. Little is known about an association between these immune cells and the response to chemotherapy. Methods: Here the relation between infiltrates of immune cells in liver metastases of CRC and the response to chemotherapy (using immunohistochemical staining against CD8, GranB, FOXP3, CD45RO, etc.) was investigated. Samples from 33 patients with metastasized colorectal cancer (samples from 22 patients were used as training set and samples from 11 patients as validation set) were analyzed. Results: The evaluation of positively stained TIL in the invasive margin of the liver metastasis allowed to predict response to chemotherapy. This was also observed in the analysis of the time to progression, where higher numbers of positively stained cells were associated with longer intervals. The difference between the groups with either response or no response to chemotherapy in time to progression was statistically significant in the analyzed sets (Mann-Whitney- U, p<0.001, two-tailed, z=-3,961, n=33). In primary tumors no association between TIL densities and response to chemotherapy was observed. Conclusions: Our results suggest that the immune system has an important impact on the efficacy of chemotherapy and the presented data will have implications for the assessment of therapy options. No significant financial relationships to disclose.

Tumor and microenvironment evolution during chemotherapy combine with bevacizumab in colorectal cancer liver metastasis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3568-3568
Author(s):  
Wangjun Liao ◽  
Min Shi ◽  
Dongqiang Zeng ◽  
Na Huang ◽  
Yuqi Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Liver Metastases ◽  
Peripheral Blood ◽  
Comparative Genomic ◽  
Multiple Time ◽  
Colorectal Cancer Liver Metastases ◽  
Primary Tumors ◽  
Response To Chemotherapy ◽  
Study Results

3568 Background: Identifying patterns of pathological tumor resistant to treatment regimens and improving tumor’s chemotherapy sensitivity from longitudinal and multi-omics data integration are of paramount importance in order to provide the best chances of cure, especially, for colorectal cancer liver metastases. Methods: We elucidated genomic (ctDNA and whole exome sequencing), immunomic (DNA-based T cell receptor sequencing) and transcriptomic changes from liver metastases, peripheral blood and match primary tumors that accompany the evolution of colorectal cancer liver metastases. In total, 197 histopathologically distinct areas of liver metastases and 72 peripheral blood samples at multiple time points from 15 patients with colorectal cancer were analysis in this study. Results: In responding patients, mutation load from plasma were reduced from baseline ( P < 0.001), but changed slightly in tumor tissues ( P = 0.351). Transcriptomic analysis and immunohistochemistry revealed that increased infiltration of neutrophils and monocytes were associated with worse outcomes and insensitive response to chemotherapy (Neutrophils: P = 0.003; Monocytes: P = 0.032). Activation of fatty acid metabolism, JAK-STAT, PPAR, insulin and TGF-β signaling pathway were observed in progressive tumor. TCR diversity in response metastatic regions was significantly increased compared with non-responder ( P = 0.008). Combination of bevacizumab with chemotherapy facilitated T cell infiltrating to the tumor microenvironment which might consequently benefit from checkpoint immunotherapy ( P = 0.006). Conclusions: Our integrative and comparative genomic analysis provides a new paradigm for understanding the evolution and treatment resistance of colorectal cancer liver metastases, with implications for identifying ways to advance treatment regimen and monitoring treatment response of colorectal cancer liver metastases.

scholarly journals Discordance of KRAS Mutational Status between Primary Tumors and Liver Metastases in Colorectal Cancer: Impact on Long-Term Survival Following Radical Resection

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2148
Author(s):  
Francesco Ardito ◽  
Francesco Razionale ◽  
Lisa Salvatore ◽  
Tonia Cenci ◽  
Maria Vellone ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastases ◽  
Primary Tumor ◽  
Kras Mutation ◽  
Colorectal Tumor ◽  
Term Survival ◽  
Primary Tumors ◽  
Mutation Status ◽  
Primary Colorectal Tumor ◽  
Kras Mutation Status

If KRAS mutation status of primary colorectal tumor is representative of corresponding colorectal liver metastases (CRLM) mutational pattern, is controversial. Several studies have reported different rates of KRAS discordance, ranging from 4 to 32%. Aim of this study is to assess the incidence of discordance and its impact on overall survival (OS) in a homogenous group of patients. KRAS mutation status was evaluated in 107 patients resected for both primary colorectal tumor and corresponding CRLM at the same institution, between 2007 and 2018. Discordance rate was 15.9%. Its incidence varied according to the time interval between the two mutation analyses (p = 0.025; Pearson correlation = 0.2) and it was significantly higher during the first 6 months from the time of primary tumor evaluation. On multivariable analysis, type of discordance (wild-type in primary tumor, mutation in CRLM) was the strongest predictor of poor OS (p < 0.001). At multivariable logistic regression analysis, the number of CRLM >3 was an independent risk factor for the risk of KRAS discordance associated with the worst prognosis (OR = 4.600; p = 0.047). Results of our study suggested that, in the era of precision medicine, possibility of KRAS discordance should be taken into account within multidisciplinary management of patients with metastatic colorectal cancer.

Evaluation of Histopathological Heterogeneity After Preoperative Chemotherapy in Patients With Liver Metastases from Colorectal Cancer

2021 ◽  
Author(s):  
Nobuhisa matsuhashi ◽  
Hiroyuki Tomita ◽  
Takazumi Kato ◽  
Yoshinori Iwata ◽  
Satoshi Matsui ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Liver Metastases ◽  
Surgical Oncology ◽  
Resected Specimen ◽  
Histopathological Changes ◽  
School Of Medicine ◽  
Response To Chemotherapy ◽  
Grade 3 ◽  
The Right

Abstract Background: Patients with liver metastases from colorectal cancer (CRLMs) frequently receive chemotherapy prior to liver resection. Histopathological assessment of the resected specimen can evaluate the response to chemotherapy. This study analyzed the correlation between histopathological changes in the primary site and liver metastases. Patients and Methods: This study comprised 45 patients with resectable CRLMs at the Surgical Oncology Department of Gifu University School of Medicine from January 2006 to August 2015. Results: The study included 24 men and 21 women. The primary colonic tumor was located in the right side in 13 (28.9%) patients and the left side in 32 (71.9%) patients. We evaluated patients with metastatic colorectal cancer (31/45) after excluding those in whom histopathological heterogeneity between the primary and liver metastasis changed to grade 3 after chemotherapy. We compared the group which underwent hepatectomy after chemotherapy (n=25) with that underwent hepatectomy alone (n=6). In 16 (53.3%) out of 25 patients, histopathological heterogeneity of the liver metastasis was lost (p=0.04). Conclusion: Chemotherapy appears to change histopathological heterogeneity.Our study suggests that the change of intratumoral heterogeneity reflect by the response of chemotherapy.

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.

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.

Prognostic impact of PD-L1 and PD-1 expression by primary tumor location in colorectal cancer.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 628-628 ◽  
Author(s):  
Jonna Berntsson ◽  
Anna Larsson ◽  
Bjorn Nodin ◽  
Jakob Eberhard ◽  
Karin Jirstrom
Keyword(s):  
Colorectal Cancer ◽  
Immune Cells ◽  
Primary Tumor ◽  
Tumor Location ◽  
Left Colon ◽  
Prognostic Impact ◽  
Full Cohort ◽  
Primary Tumors ◽  
Primary Tumor Location ◽  
Entire Cohort

628 Background: A plethora of studies report abundant expression of programmed death-ligand 1 (PD-L1) on tumors to be associated with poor outcome in several cancer forms, whereas immune cell-specific expression of PD-L1 has been associated with improved prognosis in colorectal cancer. However, none of these studies have investigated the association with prognosis according to primary tumor location. This study aimed to investigate the clinicopathological correlates and prognostic impact of PD-L1 and its receptor PD-1 in colorectal cancer, with particular reference to the anatomical subsite of the primary tumor. Methods: Immunohistochemical expression of PD-L1 and PD-1 was analysed in tissue microarrays with tumors from 557 incident cases of CRC from a prospective population-based cohort. Kaplan-Meier and Cox regression analyses were applied to determine the impact of biomarker expression on 5-year overall survival (OS), in the entire cohort and in subgroup analysis of right colon, left colon, and rectum. Results: High PD-L1 expression on tumor-infiltrating immune cells correlated significantly with an improved 5-year OS in univariable and multivariable analysis, adjusted for age, sex, TNM stage, differentiation grade, and vascular invasion, in the full cohort (HR = 0.49; 95 % CI 0.35-0.68), and in primary tumors of the right (HR = 0.43; 95 % CI 0.25-0.74) and the left colon (HR = 0.28; 95 % CI 0.13-0.61), but not in rectal cancer. High tumor-specific PD-L1-expression was not significantly associated with prognosis in neither the full cohort nor according to primary tumor location. High expression of PD-1 on tumor-infiltrating immune cells was significantly associated with an improved 5-year overall survival in the entire cohort (HR = 0.42; 95 % CI 0.21-0.87), but not in subsite analysis according to primary tumor location. Conclusions: This study is, to the best of our knowledge, the first to investigate the prognostic impact of PD-L1 and PD-1 expression according to primary tumor site in colorectal cancer. Dense infiltration of PD-L1+ immune cells was found to be an independent favorable prognostic factor in primary tumors of the right and left colon, but not in the rectum.

The EGF 61A/G polymorphism – a predictive marker for recurrence of liver metastases from colorectal cancer

2009 ◽  
Vol 121 (19-20) ◽  
pp. 638-643 ◽  
Author(s):  
Florian M. Kovar ◽  
Christiane Thallinger ◽  
Claudia L. Marsik ◽  
Thomas Perkmann ◽  
Harald Puhalla ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastases ◽  
Predictive Marker
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