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

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.

The role of HER-3 expression in the prediction of clinical outcome for advanced colorectal cancer patients receiving irinotecan/cetuximab.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 404-404 ◽  
Author(s):  
M. Scartozzi ◽  
A. Mandolesi ◽  
R. Giampieri ◽  
A. Zaniboni ◽  
E. Galizia ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Outcome ◽  
Cancer Patients ◽  
Advanced Colorectal Cancer ◽  
Biological Indicator ◽  
Wild Type ◽  
Colorectal Cancer Cells ◽  
Key Factor ◽  
Her3 Expression ◽  
Colorectal Cancer Patients

404 Background: Preclinical data suggested that in presence of HER3 altered activation colorectal cancer cells may escape anti-EGFR mediated cell death. HER3 overexpression may then represent a key factor for resistance to anti-EGFR antibodies in colorectal cancer. The aim of our analysis was to investigate a possible correlation between HER3 expression and clinical outcome in KRAS wild-type advanced colorectal cancer receiving cetuximab and irinotecan. Methods: We retrospectively analyzed immunoreactivity for HER3 in KRAS wild-type advanced colorectal cancer patients receiving irinotecan-cetuximab. Results: Eighty-four advanced KRAS wild- type colorectal cancer patients were available for HER3 analysis. Forty patients (48%) showed HER3 negative colorectal tumor, whereas the remaining 44 cases (52%) were deemed HER3 positive. In HER3 negative and HER3 positive tumors we observed a partial response in 17 (42%) and 8 (18%) patients respectively (p = 0.04). Progressive disease was obtained in 11 (35%) and 26 (53%) patients with respectively HER3 negative and positive tumor (p = 0.007). No differences were observed for stable disease. Median PFS was 6.3 months in patients showing HER3 negative tumors and 2.8 months for those who had HER3 overexpressing tumors (p < 0.0001). Median overall survival was 13.6 months in patients showing HER3 negative tumors and 10.5 months for those who had HER3-expressing tumors (p = 0.01). Conclusions: HER3 proved to be a predictive factor for clinical outcome in KRAS wild-type colorectal cancer patients treated with cetuximab. Combined HER3 and KRAS analysis may represent an effective strategy for a better selection of responding colorectal tumors. Furthermore besides identifying colorectal cancer patients refractory to EGFR directed treatment, HER3 overexpression may also represent a potential biological indicator for the development of a new class of antineoplastic agents in this setting. No significant financial relationships to disclose.

Prognostic stratification of k-RAS wild type colorectal cancer patients receiving irinotecan-cetuximab treatment: Preliminary results of a prospective study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3591-3591
Author(s):  
Mario Scartozzi ◽  
Riccardo Giampieri ◽  
Alessandra Mandolesi ◽  
Khaled Mahmoud Abouelkhair ◽  
Cristian Loretelli ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Outcome ◽  
Cancer Patients ◽  
Genetic Profile ◽  
Wild Type ◽  
Third Line ◽  
Exon 20 ◽  
Colorectal Cancer Patients ◽  
A Prospective Study ◽  
Selection Of

3591 Background: Translational research identified numerous putative markers for a “beyond-k-RAS” selection of colorectal cancer patients receiving cetuximab, but none of these entered clinical practice mainly because prospective validation is lacking. The aim of our study was to evaluate whether a panel of biomarkers, prospectively analysed may be able to predict patients’ clinical outcome more accurately than k-RAS status alone. Methods: Metastatic, K-RAS wild type colorectal cancer patients, candidate to receive second/third-line cetuximab with chemotherapy have been prospectively allocated, after informed consent, into 2 groups on the basis of their genetic profile: favourable (BRAF and PIK3CA exon 20 wild type, EGFR GCN ≥ 2.6, HER-3 Rajkumar score ≤ 8, IGF-1 immunostaining < 2) and unfavourable (any of the previous markers altered or mutated). All patients received cetuximab treatment as planned by treating physician who was unaware of biomarkers results. To detect a difference in terms of response rate (RR) among patients with an unfavourable profile (estimated around 25%) and patients with a favourable profile (estimated around 60%), assuming a probability alpha of 0.05 and beta of 0.05, required sample size will be 46 patients. Results: 31 patients have been enrolled, most patients (27, 86%) received cetuximab as third-line. Eleven patients (35%) were allocated to the favourable profile and 20 patients (75%) to the unfavourable profile. Patients with the unfavourable profile showed 1 BRAF mutation, 2 PIK3CA exon 20 mutations, 12 cases of EGFR GCN < 2.6, 13 cases of HER-3 and 11 cases of IGF-1 overexpression respectively. RR in the favourable and unfavourable group was 7/11 (64%) and 1/20 (5%) (p= 0.008) respectively. The favourable group also showed an improved median TTP (8 months vs. 2.6 months, p = 0.0007) and OS (16 months vs. 6 months, p = 0.0002). Conclusions: Our results suggest that prospective selection of candidates for cetuximab may be able to improve clinical outcome in patients with a favourable profile. This approach, if confirmed, may also allow an early switch to alternative treatment in patients with an unfavourable profile.

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