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

Scartozzi, Mario; Mandolesi, Alessandra; Giampieri, Riccardo; Pierantoni, Chiara; Loupakis, Fotios; Zaniboni, Alberto; Galizia, Eva; Giustini, Lucio; Silva, Rosa Rita; Bisonni, Renato; Berardi, Rossana; Biagetti, Simona; Menzo, Stefano; Falcone, Alfredo; Bearzi, Italo; Cascinu, Stefano

doi:10.1002/ijc.25193

Cited by 71 publications

(58 citation statements)

References 30 publications

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“…This notion was further supported by the finding that the level of serum HGF relates to the efficacy of this treatment modality in patients with KRAS wild-type disease (23). In addition to HGF, overexpression of insulin-like growth factor I produced by cancer cells itself has been suggested to mediate resistance to cetuximab (24). Intriguingly, besides stimulation of parallel RTK pathways by ligands, also amplifications and upregulation of alternative RTKs convey resistance to anti-EGFR therapy as the case of HER2 shows (25).…”

Section: Colorectal Cancer Heterogeneity and Predictors Of Responsementioning

confidence: 89%

Colorectal Cancer Heterogeneity and Targeted Therapy: A Case for Molecular Disease Subtypes

et al. 2015

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Personalized cancer medicine is becoming increasingly important in colorectal cancer treatment. Especially for targeted therapies, large variations between individual treatment responses exist. Predicting therapy response is of utmost significance, as it prevents overtreatment and adverse effects in patients. For EGFRtargeted therapy, many mechanisms of resistance have been uncovered, for example, mutations in KRAS and BRAF, and upregulation of alternative receptors. Currently, routine testing for all known modifiers of response is unpractical, and as a result, decision-making for anti-EGFR therapy is still largely based on assessing the mutation status of an individual gene (KRAS). Recently, comprehensive classifications of colorectal cancer have been presented that integrate many of the (epi-)genetic and microenvironmental factors that contribute to colorectal cancer heterogeneity. These classification systems are not only of prognostic value but also predict therapy efficacy, including the response to anti-EGFR agents. Therefore, molecular subtypebased stratification to guide therapeutic decisions is a promising new strategy that might overcome the shortcomings of single gene testing in colorectal cancer as well as in other malignancies. Furthermore, the development of new agents in a disease subtype-specific fashion has the potential to transform drug-discovery studies and generate novel, more effective therapies. Cancer Res; 75(2); 245-9. Ó2014 AACR.

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Section: Colorectal Cancer Heterogeneity and Predictors Of Responsementioning

confidence: 89%

Colorectal Cancer Heterogeneity and Targeted Therapy: A Case for Molecular Disease Subtypes

et al. 2015

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“…Interestingly, and consistently with the hypothesis of ADCC as an important mechanism of action of cetuximab against micrometastases, we found that carriers of 131R and/or 158F alleles had a significantly lower risk of distant failure than patients homozygous for 131H and/or 158V when cetuximab was added to the study sequential treatment. It is worth noting that additional signaling pathways beyond EGFR (i.e., IGF-1R pathway) which have been shown to cross-talk with EGFR downstream effectors and mediate the ADCC-independent therapeutic effects of cetuximab are more frequently activated and potentially more clinically relevant in rectal cancer than in colon cancer (36)(37)(38). Therefore, our findings could be potentially influenced by the specific location of the primary tumor and may not apply to a population of patients with colon cancer.…”

Section: Discussionmentioning

confidence: 99%

FcγRIIaandFcγRIIIaPolymorphisms and Cetuximab Benefit in the Microscopic Disease

Sclafani

Castro

Cunningham

et al. 2014

Clinical Cancer Research

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Purpose: FcgR polymorphisms have been reported to enhance the immune-mediated effects of cetuximab in metastatic colorectal cancer. There are no data on the relationship between these polymorphisms and cetuximab in the early-stage setting. We performed a pharmacogenomic analysis of EXPERT-C, a randomized phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery, and adjuvant CAPOX AE cetuximab in high-risk, locally advanced rectal cancer.Experimental Design: FcgRIIa-H131R and FcgRIIIa-V158F polymorphisms were analyzed on DNA from peripheral blood samples. Kaplan-Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms.Results: Genotyping was successfully performed in 105 of 164 (64%) patients (CAPOX ¼ 54, CAPOX-C ¼ 51). No deviation from the Hardy-Weinberg equilibrium or association of these polymorphisms with tumor RAS status was observed. FcgRIIa-131R (HR, 0.38; P ¼ 0.058) and FcgRIIIa-158F alleles (HR, 0.21; P ¼ 0.007) predicted improved progression-free survival (PFS) in patients treated with cetuximab. In the CAPOX-C arm, carriers of both 131R and 158F alleles had a statistically significant improvement in PFS (5 years: 78.4%; HR, 0.22; P ¼ 0.002) and overall survival (OS; 5 years: 86.4%; HR, 0.24; P ¼ 0.018) when compared with patients homozygous for 131H and/or 158V (5-year PFS: 35.7%; 5-year OS: 57.1%). An interaction between cetuximab benefit and 131R and 158F alleles was found for PFS (P ¼ 0.017) and remained significant after adjusting for prognostic variables (P ¼ 0.003).Conclusion: This is the first study investigating FcgRIIa and FcgRIIIa polymorphisms in patients with early-stage colorectal cancer treated with cetuximab. We showed an increased clinical benefit from cetuximab in the presence of 131R and 158F alleles.

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“…Shen et al reported that the combination of both K-ras and IGFR1 antisense oligodeoxynucleotide cooperatively inhibited the growth of pancreatic cancer cell lines in vitro, and induced their apoptosis in vivo (22). Furthermore, combined IGF-1 and K-ras analyses have been shown to be beneficial for the better selection of colorectal cancer patients that may respond to therapy (23). Therefore, a new strategy to co-target both IGFR-1 and K-ras may be required to control lung cancers expressing IGFR1 with the K-ras mutation.…”

Section: Discussionmentioning

confidence: 99%

Insulin-like growth factor receptor-1 expression predicts postoperative recurrence in adenocarcinoma of the lung

Nakagawa

Uramoto

Shimokawa

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. Not all patients with lung cancer require postoperative adjuvant chemotherapy after a complete resection. However, no useful markers exist for either selecting appropriate candidates or for predicting clinical recurrence. The purpose of the present study was to clarify the clinical role of insulin-like growth factor receptor-1 (IGFR1) in lung adenocarcinoma. Tumor specimens were collected from 182 patients who underwent a complete resection for adenocarcinoma of the lung. The expression of IGFR1 was evaluated by immunohistochemistry. The genetic status of the epidermal growth factor receptor (EGFR) and K-ras genes was also investigated by PCR-based analyses. Immunohistochemistry and real-time PCR assays were used to evaluate the MET gene association with tyrosine phosphorylation and hepatocyte growth factor (HGF) status, and amplification, respectively. Positive expression of IGFR1 was detected in 43 (23.6%) of the 182 cases. A positive IGFR1 expression was also identified in 12 (42.9%) and 31 (20.1%) of the patients with and without recurrence, respectively (p=0.009). Logistic regression models indicated that positive staining for IGFR1 expression was an independent factor associated with tumor recurrence. IGFR1 expression was associated with a poorer disease-free survival (DFS). Multivariate analysis demonstrated positive IGFR1 expression to be independently associated with an increased risk for poor DFS. The tumors appearing positive for IGFR1 were more frequent among those with K-ras mutations when compared with the wild-type group. IGFR1 expression was associated with reduced DFS correlating with postoperative recurrence. Therefore, the expression status of IGFR1 can be a candidate surrogate marker to select patients who may benefit from adjuvant chemotherapy. IntroductionLung cancer is the leading cause of cancer-related death in the world (1). The incidence of adenocarcinoma, one of the major histological subtypes of non-small cell lung cancer (NSCLC), is increasing (2). The prognosis is dismal as the 5-year survival is only approximately 50%, even in patients who achieve complete surgical resection (3). This suggests that occult metastases are present at the time of surgical intervention. As a consequence, adjuvant chemotherapy is required (4). However, the 5-year survival rate of patients with resected stage IB NSCLC is 74% without adjuvant chemotherapy, suggesting that not all patients require chemotherapy after a complete resection (5). Therefore, it is necessary to identify patients who may benefit the most from post-operative adjuvant chemotherapy to, not only precisely select the patients who require additional treatment, but also to prevent the occurrence of adverse events in patients who do not require treatment (4). Therefore, it is important to evaluate the biological and molecular characteristics of lung adenocarcinoma to identify the factors related to recurrence following surgery. However, there are currently no useful markers that predict clinical recurrence.Insulin-like growth fa...

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

Cited by 71 publications

References 30 publications

Colorectal Cancer Heterogeneity and Targeted Therapy: A Case for Molecular Disease Subtypes

Colorectal Cancer Heterogeneity and Targeted Therapy: A Case for Molecular Disease Subtypes

FcγRIIaandFcγRIIIaPolymorphisms and Cetuximab Benefit in the Microscopic Disease

Insulin-like growth factor receptor-1 expression predicts postoperative recurrence in adenocarcinoma of the lung

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