scholarly journals IL15RA and SMAD3 Genetic Variants Predict Overall Survival in Metastatic Colorectal Cancer Patients Treated with FOLFIRI Therapy: A New Paradigm

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1705
Author(s):  
Elena De Mattia ◽  
Jerry Polesel ◽  
Rossana Roncato ◽  
Adrien Labriet ◽  
Alessia Bignucolo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
Prognostic Score ◽  
Chemotherapeutic Agents ◽  
Rank Test ◽  
P Value ◽  
Genetic Determinants ◽  
New Paradigm

A new paradigm in cancer chemotherapy derives from the interaction between chemotherapeutics, including irinotecan and 5-fluorouracil (5-FU), and the immune system. The patient’s immune response can modulate chemotherapy effectiveness, and, on the other hand, chemotherapeutic agents can foster tumor cell immunogenicity. On these grounds, the analysis of the cancer patients’ immunogenetic characteristics and their effect on survival after chemotherapy represent a new frontier. This study aims to identify genetic determinants in the immuno-related pathways predictive of overall survival (OS) after FOLFIRI (irinotecan, 5-FU, leucovorin) therapy. Two independent cohorts comprising a total of 335 patients with metastatic colorectal cancer (mCRC) homogeneously treated with first-line FOLFIRI were included in the study. The prognostic effect of 192 tagging genetic polymorphisms in 34 immune-related genes was evaluated using the bead array technology. The IL15RA rs7910212-C allele was associated with worse OS in both discovery (HR: 1.57, p = 0.0327, Bootstrap p-value = 0.0280) and replication (HR:1.71, p = 0.0411) cohorts. Conversely, SMAD3 rs7179840-C allele was associated with better OS in both discovery (HR:0.65, p = 0.0202, Bootstrap p-value = 0.0203) and replication (HR:0.61, p = 0.0216) cohorts. A genetic prognostic score was generated integrating IL15RA-rs7910212 and SMAD3-rs7179840 markers with inflammation-related prognostic polymorphisms we previously identified in the same study population (i.e., PXR [NR1I2]-rs1054190, VDR-rs7299460). The calculated genetic score successfully discriminated patients with different survival probabilities (p < 0.0001 log-rank test). These findings provide new insight on the prognostic value of genetic determinants, such as IL15RA and SMAD3 markers, and could offer a new decision tool to improve the clinical management of patients with mCRC receiving FOLFIRI.

scholarly journals Combination of germline variations associated with survival of folinic acid, fluorouracil and irinotecan-treated metastatic colorectal cancer patients

2019 ◽  
Vol 20 (17) ◽  
pp. 1179-1187
Author(s):  
Adrien Labriet ◽  
Éric Lévesque ◽  
Elena De Mattia ◽  
Erika Cecchin ◽  
Derek Jonker ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
Genetic Determinants ◽  
Tumor Expression ◽  
Public Datasets ◽  
Colorectal Cancer Patients

Aim: Germline variants could modify survival of metastatic colorectal cancer patients (mCRC). Patients & methods: The association of 285 haplotype-tagging SNPs in 11 candidate genes and overall survival (OS) was tested in two cohorts totalizing 417 FOLFIRI-treated mCRC. Gene expression was investigated in vitro and in public datasets. Results: In the combined cohort, CES1 rs9921399T>C was associated with prolonged OS (hazard ratio [HR] = 0.40) whereas ABCC1 rs17501011G>A (HR = 2.08) and UGT1 rs1113193G>A (HR = 2.12) were associated with shorter OS (p ≤ 0.005). A combined effect of these polymorphisms was observed with HR of 1.98–2.97 (p < 0.05). The ABCC1 rs17501011A variant reduced reporter-gene activity (p < 0.05) whereas ABCC1 tumor expression was associated with shorter survival (p ≤ 0.013). Conclusion: We identified a combination of genetic determinants that could predict mCRC survival.

Survival outcomes of patients with peripheral T-cell lymphomas (PTCL) treated with chemotherapy and/or novel agents: The Columbia University experience.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e19049-e19049
Author(s):  
Helen Ma ◽  
Bin Cheng ◽  
Owen A. O'Connor
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Natural History ◽  
Histone Deacetylase Inhibitors ◽  
Prognostic Score ◽  
Novel Agents ◽  
Rank Test ◽  
P Value ◽  
Columbia University ◽  
History Of

e19049 Background: CHOP-based regimens have been considered the standard of care for PTCL despite disappointing results. Several lines of evidence, including the regulatory approval of novel drugs since 2009, raise the question as to whether these drugs are changing the natural history of relapsed PTCL. Recent molecular insights into the pathogenesis of PTCL, especially in angioimmunoblastic T-cell lymphoma (AITL), have revealed a number of genetic lesions that might portend a unique vulnerability to select agents, such as histone deacetylase inhibitors (HDACi). Methods: This is a retrospective study of patients with PTCL who were seen and treated between 1994 and 2018. Kaplan-Meier curves for overall survival were generated and compared based on the log-rank test. Cox proportional hazard models were used to investigate the association by adjusting for age, gender, subtype, prognostic score and type of treatment. The analysis was done in SAS version 9.4. A p-value < 0.05 was considered statistically significant. Results: At Columbia University Medical Center, a total of 186 patients with PTCL were identified. Excluding patients with incomplete data, 168 patients were analyzed. The median overall survival was 7.5 months (95% CI 5.6-8.9) for the whole study group. Cox modeling adjusted for the aforementioned variables found little impact from the novel agents on the natural history of the disease. In particular, among patients with AITL, no survival benefit was associated with any HDACi. In addition, these data demonstrated that patients with adult T-cell leukemia lymphoma (ATLL) had a better overall survival compared to other subgroups, p = 0.0097. Conclusions: These data are concordant with other large experiences noting the poor prognosis of patients with PTCL, and in particular, those with relapsed disease. The lack of impact of HDACi on the natural history of AITL raises issues about the role of these drugs in this disease. We will present a variety of subanalyses to identify prognostic factors in PTCL. [Table: see text]

Gene polymorphisms of CCL3, CCL4, CCL5, and CCR5 network in metastatic colorectal cancer patients treated with regorafenib.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 199-199
Author(s):  
Mitsukuni Suenaga ◽  
Wu Zhang ◽  
Tetsuo Mashima ◽  
Marta Schirripa ◽  
Shu Cao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
Gene Polymorphisms ◽  
Direct Sequencing ◽  
Rank Test ◽  
Alternative Mechanism ◽  
Nucleotide Polymorphisms ◽  
Positive Correlation ◽  
Colorectal Cancer Patients

199 Background: We previously reported that genetic variant in the CCL5/CCR5 pathway predict efficacy of regorafenib in metastatic colorectal cancer patients (mCRC). CCL5 rs2280789 G allele and CCL5 rs3817655 T allele were associated with longer overall survival (OS) and severe skin toxicity due to low VEGF-A production via endothelial progenitor cell (EPC). CCL4 rs1634517 G allele and CCL3 rs1130371 C allele correlated with longer Progression-free survival (PFS) and OS. We investigated the biological role of CCL4 and CCL3 gene polymorphisms. Methods: We analyzed genomic DNA extracted from 79 samples of a Japanese cohort receiving regorafenib. Single nucleotide polymorphisms (SNPs) of genes in CCL5/CCR5 pathway were analyzed by PCR-based direct sequencing. Blood samples were obtained from 57 patients at baseline (BL), day 21 and progressive disease (PD), and serum CCR5, CCR5 ligands (CCL3, CCL4, CCL5) and VEGF-A levels were measured using ELISA. PFS and OS were analyzed using Kaplan-Meier curves and log-rank test. Results: Increased CCL3 levels at PD were associated with longer OS than decreased (12.6 vs 4.8 mos, P = 0.003). Patients with decreased CCL4 levels at day 21 had a trend toward longer PFS and tumor shrinkage. Positive correlation was observed between CCL3 and CCR5 throughout the treatment independent of other ligands (change at day 21: r = 0.426, P = 0.009). There was no significant correlation of CCL3 and CCL4 levels with VEGF-A levels. Patients with the G/G variant in CCL3 rs1130371 had increased CCL3, CCR5 and CCL5 levels at day 21 than any A allele. Similarly, patients with the C/C variant had increased CCL3, CCR5 and CCL5 levels at day 21 compared with those with any A allele. In contrast, both CCL5 rs2280789 G allele and CCL5 rs3817655 T allele were associated with increased CCL3 levels and decreased CCL4 levels at day 21 (P = 0.006, P = 0.043; P = 0.006, P = 0.043). Conclusions: Positive correlation of CCL3, CCR5 and CCL5 impact similarly on CCL3 and CCL4 SNPs, while different manner between CCL3 and CCL4 was found in CCL5 SNPs. This suggests an alternative mechanism of action in the network of CCR5 and the ligands except CCL5-VEGF-A signaling via EPC in mCRC patients receiving regorafenib.

scholarly journals The impact of the Glasgow Prognostic Score on survival in second-line chemotherapy for metastatic colorectal cancer patients with BRAF V600E mutation

2019 ◽  
Vol 11 ◽  
pp. 175883591882029 ◽  
Author(s):  
Seiichiro Mitani ◽  
Hiroya Taniguchi ◽  
Keiji Sugiyama ◽  
Toshiki Masuishi ◽  
Kazunori Honda ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
Prognostic Score ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Second Line ◽  
Second Line Chemotherapy ◽  
Colorectal Cancer Patients ◽  
Line Chemotherapy

Background: BRAF (v-raf murine sarcoma viral oncogene homolog B1) V600E mutant colorectal cancer is associated with short survival. Recently, clinical trials have been conducted to improve outcomes of second or later lines of chemotherapy. However, there is a paucity of reference data pertaining to outcomes of second-line chemotherapy and prognostic factors that are relevant only to BRAF mutant patients. Patients and methods: We retrospectively reviewed metastatic colorectal cancer patients with BRAF V600E mutation who underwent second-line chemotherapy between January 2007 and March 2017. We evaluated treatment outcomes and performed prognostic analyses. Results: A total of 52 patients were included. The median progression-free survival and overall survival (OS) were 2.5 [95% confidence interval (CI) = 1.91–4.11] and 6.5 (95% CI = 4.30–9.63) months, respectively. Overall response and disease control rates were 7% and 48%, respectively. All the regimens which elicited a partial response included BRAF inhibitors in combination with anti-epidermal growth factor receptor (EGFR) antibodies. Therefore, the overall response was 0% after exclusion of patients treated with study drugs. Multivariate analysis for OS revealed that the Glasgow Prognostic Score (GPS), elevated lactate dehydrogenase, and poor performance status were independent prognostic factors. In particular, survival curves according to the GPS stratified the patients into distinct risk groups. The median OSs in patients with GPS of 0, 1, and 2 were 9.9, 5.0, and 1.9 months, respectively. Conclusions: Outcomes of second-line chemotherapy for metastatic colorectal cancer patients with BRAF V600E mutation were extremely poor. GPS may be useful in future clinical trials.

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