PTEN Expression and KRAS Mutations on Primary Tumors and Metastases in the Prediction of Benefit From Cetuximab Plus Irinotecan for Patients With Metastatic Colorectal Cancer

Loupakis, Fotios; Pollina, Luca Emanuele; Stasi, I.; Ruzzo, Annamaria; Scartozzi, Mario; Santini, Daniele; Masi, Gianluca; Graziano, Francesco; Cremolini, Chiara; Rulli, Eliana; Canestrari, Emanuele; Funel, Niccola; Schiavon, Gaia; Petrini, Iacopo; Magnani, Mauro; Tonini, Giuseppe; Campani, Daniela; Floriani, Irene; Cascinu, Stefano; Falcone, Alfredo

doi:10.1200/jco.2008.20.2796

Cited by 381 publications

(319 citation statements)

References 38 publications

Supporting

Mentioning

299

Contrasting

Unclassified

Order By: Relevance

“…Loupakis 55 metastases from patients with irinotecan refractatory mCRC treated with irinotecan and cetuximab: 12 (36%) of 33 patients with PTEN-positive metastases were responders compared with one (5%) of 22 who had PTEN-negative metastases. 50 Patients with PTENpositive metastases and KRAS wild type had longer PFS compared with other patients.…”

Section: Pten-pi3k-akt-mtor Pathway Alterationsmentioning

confidence: 97%

“…45 PTEN is a tumor suppressor that acts as a negative regulator of PI3K signaling by converting PIP3 to PIP2, and truncating mutations which result in loss of PTEN expression, reported in~20% of MSI colon cancers. [46][47][48][49][50][51] The molecular alteration of PTEN is often caused by epigenetic mechanisms, 45 supporting the detection of the intact protein by IHC as a better diagnostic tool than gene sequencing, as it potentially covers more mechanisms of alteration. PIK3CA mutation and PTEN expression status predicts response of colon cancer cells to the EGFR inhibitor cetuximab distinguishing drug sensitive and resistant cell lines.…”

Section: Pten-pi3k-akt-mtor Pathway Alterationsmentioning

confidence: 99%

See 1 more Smart Citation

Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy?

Rizzo

Bronte

Fanale

et al. 2010

Cancer Treatment Reviews

Self Cite

103

View full text Add to dashboard Cite

s u m m a r yAn important molecular target for metastatic CRC treatment is the epidermal growth factor receptor (EGFR). Many potential biomarkers predictive of response to anti-EGFR monoclonal antibodies (cetuximab and panitumumab) have been retrospectively evaluated, including EGFR activation markers and EGFR ligands activation markers. With regard to the "negative predictive factors" responsible for primary or intrinsic resistance to anti-EGFR antibodies a lot of data are now available. Among these, KRAS mutations have emerged as a major predictor of resistance to panitumumab or cetuximab in the clinical setting and several studies of patients receiving first and subsequent lines of treatment have shown that those with tumors carrying KRAS mutations do not respond to EGFR-targeted monoclonal antibodies or show any survival benefit from such treatments. The role of B-RAF mutations, mutually exclusive with KRAS mutations, in predicting resistance to anti-EGFR mAbs is not yet consolidated. It therefore appears that BRAF mutations may play a strong negative prognostic role and only a slight role in resistance to anti-EGFR Abs.

show abstract

Section: Pten-pi3k-akt-mtor Pathway Alterationsmentioning

confidence: 97%

Section: Pten-pi3k-akt-mtor Pathway Alterationsmentioning

confidence: 99%

Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy?

Rizzo

Bronte

Fanale

et al. 2010

Cancer Treatment Reviews

Self Cite

103

View full text Add to dashboard Cite

show abstract

“…The loss of PTEN protein expression (30% of colorectal tumours) may therefore be an additional factor of PI3K/AKT pathway activation, which may be responsible for resistance to anti-EGFR antibodies, as it was firstly reported in a small series of 27 patients in which PTEN protein expression was evaluated by immunohistochemistry (Frattini et al, 2007). However, subsequent studies have reported discrepant results on the predictive value of loss of PTEN expression (Razis et al, 2008;LaurentPuig et al, 2009;Sartore-Bianchi et al, 2009;Loupakis et al, 2009a), in part, due to the use of different methods for the determination of PTEN status and to the absence of standardization of immunohistochemistry. These findings show that, as for PIK3CA mutations, loss of PTEN expression cannot be currently used as a single marker for prediction of resistance to cetuximab in mCRC patients.…”

Section: Pik3ca Mutations and Loss Of Pten Expressionmentioning

confidence: 99%

Oncogenic mutations as predictive factors in colorectal cancer

2010

View full text Add to dashboard Cite

“…3). Loss-of-function mutations, deletions, or epigenetic silencing by promoter methylation of PTEN, a negative regulator of phosphoinositide 3-kinase (PI3K), have also been linked to resistance to anti-EGFR mAbs in colorectal cancers (4)(5)(6). Loss of PTEN expression, assessed by immunohistochemistry, is found in as many as 40% of colorectal cancer tumors (4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Molecular Profiling of Patients with Colorectal Cancer and Matched Targeted Therapy in Phase I Clinical Trials

Dienstmann

Serpico

Rodón

et al. 2012

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Clinical experience increasingly suggests that molecular prescreening and biomarker enrichment strategies in phase I trials with targeted therapies will improve the outcomes of patients with cancer. In keeping with the exigencies of a personalized oncology program, tumors from patients with advanced chemorefractory colorectal cancer were analyzed for specific aberrations (KRAS/BRAF/PIK3CA mutations, PTEN and pMET expression). Patients were subsequently offered phase I trials with matched targeted agents (MTA) directed at the identified anomalies. During 2010 and 2011, tumor molecular analysis was conducted in 254 patients: KRAS mutations (80 of 254, 31.5%), BRAF mutations (24 of 196, 12.2%), PIK3CA mutations (15 of 114, 13.2%), KRAS and PIK3CA mutations (9 of 114, 7.9%), low PTEN expression (97 of 183, 53.0%), and high pMET expression (38 of 64, 59.4%). In total, 68 patients received 82 different MTAs: phosphoinositide 3-kinase (PI3K) pathway inhibitor (if PIK3CA mutation, n ¼ 10; or low PTEN, n ¼ 32), PI3K pathway inhibitor plus MEK inhibitor (if KRAS mutation, n ¼ 10; or BRAF mutation, n ¼ 1), second-generation anti-EGF receptor monoclonal antibodies (if wild-type KRAS, n ¼ 11), anti-hepatocyte growth factor monoclonal antibody (if high pMET, n ¼ 10), mTOR inhibitor plus anti-insulin-like growth factor-1 receptor monoclonal antibody (if low PTEN, n ¼ 5), and BRAF inhibitor (if BRAF mutation, n ¼ 3). Median time-to-treatment failure on MTA was 7.9 versus 16.3 weeks for their prior systemic antitumor therapy (P < 0.001). Partial response was seen in 1 patient [1.2%, PI3K inhibitor with PIK3CA mutation] and stable disease >16 weeks in 10 cases (12.2%). These results suggest that matching chemorefractory patients with colorectal cancer with targeted agents in phase I trials based on the current molecular profile does not confer a significant clinical benefit. Mol Cancer Ther; 11(9); 2062-71. Ó2012 AACR.

show abstract

PTEN Expression and KRAS Mutations on Primary Tumors and Metastases in the Prediction of Benefit From Cetuximab Plus Irinotecan for Patients With Metastatic Colorectal Cancer

Abstract: PTEN loss in metastases may be predictive of resistance to cetuximab plus irinotecan. The combination of PTEN IHC and KRAS mutational analyses could help to identify a subgroup of patients with mCRC who have higher chances of benefiting from EGFR inhibition.

Cited by 381 publications

References 38 publications

Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy?

Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy?

Oncogenic mutations as predictive factors in colorectal cancer

Molecular Profiling of Patients with Colorectal Cancer and Matched Targeted Therapy in Phase I Clinical Trials

Contact Info

Product

Resources

About