K-ras Status Does Not Predict Successful Hepatic Resection of Colorectal Cancer Metastasis

Kastrinakis, William V.; Ramchurren, Nirasha; Maggard, Melinda A.; Steele, Glenn; Summerhayes, Ian C.

doi:10.1001/archsurg.1995.01430010011001

Cited by 36 publications

(23 citation statements)

References 30 publications

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“…In two studies of resected liver metastasis no prognostic effect of the KRAS mutations status could be demonstrated nor was there a proliferative advantage for KRAS mutant over WT metastases [16,17]. A strong prognostic effect of KRAS in mCRC is unlikely, as the RASCAL study could only demonstrate a significant prognostic effect of KRAS in Dukes' C but not Dukes' D patients [18].…”

Section: Interaction Between Kras Mutation Status and Early Radiologimentioning

confidence: 97%

KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab

et al. 2008

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Background: KRAS mutation status is a candidate marker for predicting survival in patients with metastatic colorectal cancer (mCRC) treated with cetuximab (CTX). Patients and methods:We studied the KRAS mutation status of 113 patients with irinotecan refractory mCRC treated with CTX in clinical trials. A predictive model for objective response (OR), progression-free survival (PFS) and overall survival (OS) was constructed using logistic and Cox regression.Results: OR was seen in 27 of 66 KRAS wild-type (WT) patients versus 0 of 42 in KRAS mutants. Median OS was significantly better in KRAS WT versus mutants (43.0 versus 27.3 weeks; P = 0.020). Decrease in tumor sizes was significantly larger at all time points in WT patients. KRAS WT patients with an initial relative decrease of tumor size >9.66% at week 6 had a significantly better median OS compared with all other patients (74.9 versus 30.6 weeks; P = 0.0000025). Within KRAS WT patients OS was significantly better in patients with an initial decrease compared with those without [median OS: 74.9 versus 30.6 weeks (P = 0.00000012)].Conclusions: KRAS WT status is associated to survival benefit in CTX treated mCRC. This benefit is even more pronounced in those patients with early radiological response. These characteristics may be exploited for response prediction.Key words: cetuximab, colorectal cancer, EGFR, KRAS, survival introduction A recent advance in oncology is the targeting of the epidermal growth factor receptor (EGFR) in the treatment of many tumor types. Cetuximab (CTX) (ErbituxÒ, Merck KGaA, Darmstadt, Germany) is a chimeric immunoglobulin G1 monoclonal antibody which binds the EGFR with high affinity and competitively inhibits ligand binding [1]. This prevents activation of downstream signalling pathways such as the PI3K/ Akt, RAS/Erk and STAT pathways, resulting in the inhibition of cellular proliferation and in the induction of apoptosis. However, for many tumor types including metastatic colorectal cancer (mCRC), it is not clear what proportion of tumors are dependent on EGFR signalling for their survival, nor how additional molecular alterations present in the tumor may influence primary or secondary resistance to EGFR inhibitors. CTX is approved for irinotecan-resistant mCRC expressing EGFR by immunohistochemistry (IHC). Response rates in this group however only amount to 23% in combination with chemotherapy and about 10% in monotherapy [2,3]. Increased response rates in the combination arm did not translate into increased survival. As yet no clinical or molecular markers are available to identify those patients with a longer overall survival (OS). Predictive markers of response and survival benefit after CTX are urgently required to allow the rational and effective use of these drugs.In a small series, Lièvre et al. [4] have shown objective response (OR) to CTX to be excluded in KRAS-mutated CRC and most importantly, showed an increase in OS for the KRAS wild-type (WT) patients. We retrospectively studied the ability of KRAS mutations and tumo...

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Section: Interaction Between Kras Mutation Status and Early Radiologimentioning

confidence: 97%

KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab

et al. 2008

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“…The reported prevalence of KRAS mutations in liver metastases varies from 15% to 44%. While several studies have reported no statistically significant association between KRAS mutation and metastatic progression, proliferative index, or survival has been reported [105][106][107][108][109] , Nash et al [110] did report a prevalence of 27% KRAS mutation in liver metastasis and noted an independent association between KRAS mutation and worse survival after liver resection (Figure 2). In a separate study, Karagkounis et al [111] reported KRAS and BRAF analysis performed on 202 patients undergoing surgery for CRLM at the Johns Hopkins Hospital.…”

Section: Kras Brafmentioning

confidence: 99%

Surgery for colorectal liver metastases: The evolution of determining prognosis

Spolverato

Ejaz

Azad

et al. 2013

WJGO

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Despite improvements in the multi-modality treatment of colorectal liver metastasis (CRLM), survival after resection remains varied. Determining prognosis after surgical resection has historically been predicated on preoperative clinicopathological factors such as primary tumor stage, carcinoembryonic antigen levels, number of liver metastases, presence of extrahepatic disease, as well as other factors. While scoring systems have been developed by combining certain preoperative factors, these have been inconsistent in accurately determining prognosis. There has been increasing interest in the use of biologic and molecular markers to predict prognosis following CRLM. The role of markers such as KRAS, BRAF, p53, human telomerase reverse transcriptase, thymidylate synthase, Ki-67, and hypoxia inducible factor-1α and their correlation with accurately predicting survival after surgical resection have been supported by several studies. Furthermore, other elements such as pathological response to chemotherapy and the presence of circulating tumor cells have shown promise in accurately determining prognosis after resection for colorectal liver metastasis. We herein review past, present, and possible future markers of prognosis among colorectal cancer patients with liver metastasis undergoing resection with curative intent.© 2013 Baishideng Publishing Group Co., Limited. All rights reserved.Key words: Colorectal; Metastasis; Prognosis; Risk score; Molecular markers; Outcomes Core tip: Historically, prognosis after resection has been largely assessed based on preoperative clinicopathologic features. Data validating the prognostic value of patient and tumor specific factors have been mixed, with many recent studies showing these scoring systems to correlate poorly with survival. Rather, there has been an emerging interest in biological or molecular markers of prognosis to more effectively assess patient prognosis after resection of colorectal liver metastasis. In this review, we discuss past, present, and possible future markers of prognosis among colorectal cancer patients with liver metastasis undergoing resection with curative intent.

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“…The reasons for exclusion of studies were as follows: insufficient data to allow for estimation of the HR for 17 studies [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] ; the use of blood samples for the detection of K-ras gene mutations for 3 studies 48-50 ; the use of secondary hepatic tumor samples of primary colorectal cancer for the detection of K-ras gene mutations for 4 studies [51][52][53][54] ; the presence of an interaction between the K-ras gene and other gene mutations for 2 studies 55,56 ; and the use of disease-specific survival or relapse-free survival as a prognostic indicator for 3 studies. [57][58][59] The process of identifying eligible articles is summarized in Figure 1, and the main characteristics are listed in Table 1.…”

Section: Study Selection and Characteristicsmentioning

confidence: 99%

Is K-ras Gene Mutation a Prognostic Factor for Colorectal Cancer

Ren

et al. 2012

Diseases of the Colon &Amp; Rectum

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K-ras Status Does Not Predict Successful Hepatic Resection of Colorectal Cancer Metastasis

Abstract: Neither the presence of a K-ras mutational event nor the precise nucleotide change are predictive of less aggressive tumor behavior, and genetic alterations at this locus alone cannot be used to select patients undergoing resection of hepatic metastases from colorectal carcinoma.

Cited by 36 publications

References 30 publications

KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab

KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab

Surgery for colorectal liver metastases: The evolution of determining prognosis

Is K-ras Gene Mutation a Prognostic Factor for Colorectal Cancer

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