Correlation of activated AKT and MAPK expression in liver metastases with clinical outcome in colorectal cancer patients receiving irinotecan/cetuximab treatment.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 449-449
Author(s):  
Mario Scartozzi ◽  
Riccardo Giampieri ◽  
Alessandra Mandolesi ◽  
Elena Maccaroni ◽  
Michela Del Prete ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Outcome ◽  
Cancer Patients ◽  
Primary Tumour ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Wild Type ◽  
Altered Expression ◽  
Phosphorylated Akt ◽  
Colorectal Cancer Patients

449 Background: An aberrant activation of the EGFR downstream signaling pathway via MAP-kinase and Akt could be responsible for resistance to anti-EGFR treatment. We tested the interaction between phosphorylated Akt and MAPK in primary colorectal tumours and corresponding metastases and clinical outcome in terms of response rate (RR), progression free survival (PFS) and overall survival (OS) to identify a group of patients more likely to benefit from EGFR-targeted treatment among those harbouring a K-RAS wild type status. Methods: Seventy-two advanced K-RAS wild type colorectal cancer patients treated with irinotecan-cetuximab were analysed. Primary tumour were available in all cases, whereas paired tumour samples from metastatic sites were available in 37 patients. Phosphorylated Akt and MAPK were analyzed by immunohistochemistry. Results: Akt resulted overexpressed in 31 primary tumours (43%) and 23 metastases (62%), whereas MAPK was over-expressed in 32 primary tumours (44%) and 20 metastases (54%). Akt altered expression in primary tumours correlated with a statistically significant worse median PFS (2.4 months vs. 6.5 months, p= 0.0006) and OS (7.8 months vs. 26.7 months, p < 0.0001), without any significant correlation with RR. No significant correlation could be found between MAPK expression in primary tumours and RR, PFS or OS. In metastases Akt expression correlated with RR (9% vs, 58%, p= 0.004), PFS (2.3 months vs.9.2 months p < 0.0001) and OS (6.1 months vs.26.7 months p < 0.0001). Analogously MAPK expression in metastases correlated with RR (10% vs, 47%, p = 0.002), PFS (2.3 months vs.8.6 months p < 0.0001) and OS (7.8 months vs.26 months p = 0.0004). At multivariate analysis Akt and MAPK status in metastases was able to independently predict PFS. Akt status in metastases independently correlated with RR as well. Conclusions: We suggest that Akt and MAPK expression in metastases may have a relevant role in determining the activity of anti-EGFR treatment strategies. Our observations seem also to indicate that for some molecular determinants of resistance the biological profile in metastases is prominent.

LDH serum levels as a predictive factor for global outcome in pretreated colorectal cancer patients receiving regorafenib: Implications for clinical management.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 497-497 ◽  
Author(s):  
Michela Del Prete ◽  
Mario Scartozzi ◽  
Tiziana Prochilo ◽  
Luca Faloppi ◽  
Riccardo Giampieri ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Outcome ◽  
Cancer Patients ◽  
Progression Free Survival ◽  
Serum Levels ◽  
Roc Curve Analysis ◽  
Group A ◽  
Group B ◽  
Colorectal Cancer Patients

497 Background: Although a demonstrated clinical efficacy, a non negligible proportion of colorectal cancer patients does not seem to benefit from regorafenib and are consequently exposed to unnecessary toxicity. LDH serum levels represent an indirect marker of tumour hypoxia, neo-angiogenesis and worse prognosis in many tumour types. In colorectal cancer LDH showed a correlation with treatment outcome for patients receiving antiangiogenetic treatment, thus suggesting a possible interaction with the activity profile of these drugs. We analyzed the role of LDH serum levels in predicting clinical outcome for pre-treated metastatic colorectal cancer patients receiving regorafenib. The final aim was to individuate a potentially reliable and easy to use marker for patients stratification. Methods: 118 colorectal cancer patients treated with regorafenib were available for our analysis. For all patients, LDH values were collected within one month before the procedure and after treatment end. LDH cutoff value was determined by ROC curve analysis, patients were then divided into two groups (A and B, below and above cut-off level respectively). Patients were also classified according to the variation in LDH serum levels pre- and post-treatment (increased patients vs. decreased patients). Results: Patients in group A and B proved homogeneous for all clinical characteristics analyzed. In group A patients median progression free survival (PFS) was 3.18 months, whereas it was 1.87 months in group B patients (p = 0.0018). Median overall survival (OS) was 6.23 months and 3.28 months in group A and B respectively (p = 0.048). Significant differences were not noted among the 2 groups for response rate. All the other clinical variables analyzed failed to show any correlation with patients outcome. Conclusions: Our observations seem to suggest a role of LDH as a marker of clinical outcome in colorectal cancer patients receiving regorafenib. We can then speculate that high LDH patients may not be optimal candidates for regorafenib. After further confirmation in larger trial, these findings may be relevant for a better patients stratification and selection.

The Association of FCGR2A and FCGR3A polymorphisms with outcomes in cetuximab treated metastatic colorectal cancer patients: CCTG and AGITG CO.20 trial analysis.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 633-633
Author(s):  
Daniel Shepshelovich ◽  
Amanda Rose Townsend ◽  
Osvaldo Espin-Garcia ◽  
Lidija Latifovic ◽  
Christopher J. O'Callaghan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
Progression Free Survival ◽  
Wild Type ◽  
Genotype Combination ◽  
Trial Analysis ◽  
Germline Polymorphism ◽  
Intermediate Outcomes ◽  
Colorectal Cancer Patients

633 Background: We previously reported that the Fc-gamma receptor (FCGR) germline polymorphism in the FCGR2A gene (rs1801274; His (H) to Arg (R) substitution) but not FCGR3A (rs396991; Phe (F) to Val (V)) was associated with cetuximab benefit on overall survival (OS) in metastatic colorectal cancer patients (CCTG CO.17 trial). We performed a validation of these results in CO.20, a randomized trial of cetuximab+placebo vs. cetuximab+brivanib for metastatic, chemotherapy refractory, wild type K-RAS colorectal cancer. Methods: After genotyping DNA extracted from whole blood, the polymorphism relationships with OS and progression-free survival (PFS) were assessed using log-rank tests and hazard ratios (HR) from Cox proportional hazard models, adjusting for known prognostic factors. Results: Of 592/725 (82%) K-RAS wild type patients with available DNA and genotyping, those carrying the higher affinity FCGR2A H/H genotype (N = 165; 28%) had improved OS (HR 0.53; 95%CI:0.41-0.68) and PFS (HR 0.65; 95%CI:0.51-0.83) compared to those carrying the lower affinity R/R genotype (N = 128; 22%), corresponding to median absolute benefits of 3.7 (OS) and 3.3 months (PFS). The H/R genotype (N = 299; 50%) had intermediate outcomes. No significant associations were found between FCGR3A genotype and OS or PFS. No interaction between FCGR polymorphisms and treatment arm was observed. Patients carrying the double wild type combination of FCGR2A H/H and FCGR3A F/F genotypes (N = 45; 7.6%) had significantly better outcomes than other patients, particularly those carrying the rare (N = 11; 2%) R/R+ V/V genotype combination, corresponding to median absolute benefits of 12.5 (OS; HR 0.33 95%CI:0.16-0.68) and 4.5 (PFS; HR 0.45 95%CI:0.22-0.92) months. There were no significant associations between FCGR polymorphisms and either any grade of 3/4 toxicity or skin rash. Conclusions: In KRAS-wild type, cetuximab-treated patients, FCGR2A polymorphism was independently replicated to be associated with clinical outcome without affecting toxicity profiles. Additionally, in this large dataset, FCGR3A appears to modulate the relationship between FCGR2A polymorphism and outcome.

scholarly journals Angiogenesis genotyping and clinical outcome during regorafenib treatment in metastatic colorectal cancer patients.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 595-595 ◽  
Author(s):  
Riccardo Giampieri ◽  
Lisa Salvatore ◽  
Michela Del Prete ◽  
Tiziana Prochilo ◽  
Marco D'Anzeo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Outcome ◽  
Cancer Patients ◽  
Progression Free Survival ◽  
Therapeutic Index ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Colorectal Cancer Patients ◽  
Ecog Ps

595 Background: The introduction of regorafenib for the treatment of colorectal cancer represented a sure medical achievement though at a cost of relevant toxicity. As a consequence the lack of predictive factors made the use of regorafenib in the clinical practice challenging. Previous observations suggested that polymorphisms of VEGF and its receptor (VEGFR) genes may regulate angiogenesis and lymphangiogenesis and potentially influence outcome during anti-angiogenesis treatment. Aim of our study was to evaluate the role of VEGF and VEGFR genotyping in determining clinical outcome for colorectal cancer patients receiving regorafenib. Methods: From a multicentre experience 138 samples (tumour or blood samples) of colorectal cancer patients receiving regorafenib were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients’ progression-free survival (PFS) and overall survival (OS) were analysed. Results: Results from angiogenesis genotyping showed that only VEGF-A rs2010963 maintained an independent correlation with PFS and OS (respectively HR: 0.49, 95% CI: 0.33-0.81, p=0.003 and HR: 0.52, 95% CI: 0.34-0.99, p=0.04). A correlation with disease control rate (DCR) was also observed (DCR 55% vs. 26%, p=0.02). Among clinical factors only ECOG PS was independently correlated with OS (HR: 0.52, 95% CI: 0.21-0.81, p=0.009), whereas no correlation with PFS was evident. Grouping together observations from angiogenesis genotyping and ECOG PS allowed further patients stratification into 3 prognostic groups: favourable, intermediate and unfavourable. Median OS resulted progressively decreased across these groups (OS not reached, 7.8 and 3.9 months respectively in the favourable, intermediate and unfavourable group, p<0.0001). Conclusions: VEGF-A rs2010963 genotyping may represent an important tool for a more accurate selection of candidates for regorafenib. This selection opportunity will ultimately improve the therapeutic index of such a treatment approach by limiting treatment to potentially responding patients and sparing unnecessary toxicity to those unlikely to benefit.

scholarly journals Genomic Profiling of KRAS/NRAS/BRAF/PIK3CA Wild-Type Metastatic Colorectal Cancer Patients Reveals Novel Mutations in Genes Potentially Associated with Resistance to Anti-EGFR Agents

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 859 ◽  
Author(s):  
Anna Maria Rachiglio ◽  
Matilde Lambiase ◽  
Francesca Fenizia ◽  
Cristin Roma ◽  
Claudia Cardone ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
De Novo ◽  
Progression Free Survival ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Wild Type ◽  
Single Nucleotide Variants ◽  
Colorectal Cancer Patients ◽  
De Novo Resistance

Previous findings suggest that metastatic colorectal carcinoma (mCRC) patients with KRAS/NRAS/BRAF/PIK3CA wild-type (quadruple-wt) tumors are highly sensitive to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs). However, additional molecular alterations might be involved in the de novo resistance to these drugs. We performed a comprehensive molecular profiling of 21 quadruple-wt tumors from mCRC patients enrolled in the “Cetuximab After Progression in KRAS wild-type colorectal cancer patients” (CAPRI-GOIM) trial of first line FOLFIRI plus cetuximab. Tumor samples were analyzed with a targeted sequencing panel covering single nucleotide variants (SNVs), insertions/deletions (Indels), copy number variations (CNVs), and gene fusions in 143 cancer-related genes. The analysis revealed in all 21 patients the presence of at least one SNV/Indel and in 10/21 cases (48%) the presence of at least one CNV. Furthermore, 17/21 (81%) patients had co-existing SNVs/Indels in different genes. Quadruple-wt mCRC from patients with the shorter progression free survival (PFS) were enriched with peculiar genetic alterations in KRAS, FBXW7, MAP2K1, and NF1 genes as compared with patients with longer PFS. These data suggest that a wide genetic profiling of quadruple-wt mCRC patients might help to identify novel markers of de novo resistance to anti-EGFR MoAbs.

scholarly journals Insulin-like growth factor 1 expression correlates with clinical outcome in K-RAS wild type colorectal cancer patients treated with cetuximab and irinotecan

2010 ◽  
Vol 127 (8) ◽  
pp. 1941-1947 ◽  
Author(s):  
Mario Scartozzi ◽  
Alessandra Mandolesi ◽  
Riccardo Giampieri ◽  
Chiara Pierantoni ◽  
Fotios Loupakis ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Clinical Outcome ◽  
Cancer Patients ◽  
Insulin Like Growth Factor ◽  
Wild Type ◽  
Colorectal Cancer Patients

Clinical usefulness of mtTFA expression as a predictive marker in colorectal cancer patients treated with FOLFOX

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4059-4059
Author(s):  
Y. Yoshida ◽  
J. Hasegawa ◽  
R. Nezu ◽  
Y. Kim ◽  
M. Hirota ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Outcome ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
Progression Free Survival ◽  
Physical Interaction ◽  
Primary Tumors ◽  
P53 Expression ◽  
Response To Chemotherapy ◽  
Colorectal Cancer Patients

4059 Background: We previously reported that mitochondrial transcription factor A (mtTFA; also designated Tfam) preferentially recognizes cisplatin-damaged DNA via physical interaction with p53 and is upregulated by the treatment with cisplatin and 5-FU (Yoshida et al, Cancer Res. 2003). The aim of this study was to evaluate whether expression of mtTFA predicts clinical outcome in patients with metastatic colorectal cancer treated with modified FOLFOX6 (mFOLFOX6). Methods: From January 2006 to April 2008, 59 patients who had metastatic lesions from colorectal cancer treated with mFOLFOX6 at the Osaka Rosai Hospital were included in this study. They consisted of 25 women (42.4%) and 34 men (57.6%), with a median age of 62 years (29–84). Patients were treated with oxaliplatin 85mg/m2 plus leucovorin 200mg/m2 as a 2-h infusion at day 1, followed by 5-FU bolus 400mg/m2 and 46-h continuous infusion of 2400 mg/m2. Treatment was repeated in 2-week intervals for at least 4 cycles. The expressions of mtTFA and p53 of resected primary tumors were examined by immunohistochemistry. Results: Among 59 patients, one complete response and 32 partial responses were observed (response rate, 55.9%) . The positive rates was 44.1% (26/59; CR 1, PR 7, SD/PD 18) for mtTFA and 59.3% (35/59; CR 1, PR 19, SD/PD 15) for p53, respectively. Strong expression of mtTFA was detected in 8 of 33 CR/PR (24.2%) and in 18 of 26 SD/PD (69.2%), indicating that the expression of mtTFA correlated significantly with response to chemotherapy (P<0.01). On the other hand, there was no significant correlation between response to chemotherapy and p53 expression (P=0.82). mtTFA expression was significantly associated with overall survival (P=0.036) and progression free survival (P=0.037). Multivariate analysis revealed that mtTFA expression significantly impacted on OS (Hazard ratio 2.10, P=0.036). Conclusions: Immunohistochemical study of mtTFA may be useful in prediction of the clinical outcome of metastatic colorectal cancer patients treated with FOLFOX. No significant financial relationships to disclose.

Sign in / Sign up

Export Citation Format

Share Document