Dose KRAS Mutation Status Affect on the Effect of VEGF Therapy in Metastatic Colon Cancer Patients?

e15121 Background: Intra-tumor heterogeneity is an independent determinant of patient survival outcomes in several tumor subtypes. Spatial variations in tumor enhancement on MRI is a macroscopic imaging marker of tumor heterogeneity. The goal of this study is to evaluate the potential role of MRI-based enhancement heterogeneity measures as predictors of survival in patients with metastatic colorectal cancer. Methods: We retrospectively analyzed T1-weighted contrast-enhanced MRI images of metastatic hepatic lesions in 41 patients (mean age 57.2 ±14.2 years) who were diagnosed with stage IV colorectal cancer between 2007 and 2013. Tumor Kras mutation status and patient survival data for up to 95 months was available for all patients. The largest metastatic hepatic lesion was identified by a radiologist and manually segmented. 14 Haralick texture features were extracted from each lesion. Cox proportional hazards regression analysis was used to assess the association between the enhancement heterogeneity measures and patient survival, with adjustment for Kras mutation status as a potential confounder. Backward stepwise feature selection was performed using p > 0.1 (Wald test) to select for statistically significant features. Results:Mean survival time was 39±3.9 months for the study population (51±4.1 months for Kras-wildtype and 37±5.1 for Kras-mutants). 68% of the patients had left-sided colon cancer; 21% had concurrent pulmonary metastases and 0.5% had concurrent brain metastasis. 61%, 27% and 12% of patients were on Flofox, Folfiri or other chemotherapeutic regimen, respectively. Texture matrix homogeneity (HR > 10; p = 0.016), inverse difference moment (HR < 0.1; p = 0.020), entropy (HR < 0.1; p = 0.033) and standard deviation (HR > 10; p = 0.006) exhibited significant independent association with patient survival. With the exception of entropy, these features maintained significant contribution to survival prediction independent of Kras mutation status. Conclusions: MRI-based quantitativeintra-metastasis heterogeneity measures are associated with patient survival and may add information beyond genetic mutation status to optimize prognosis prediction in metastatic colon cancer.

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Impact of KRAS Mutation Status on Outcomes in Metastatic Colon Cancer Patients without Anti-Epidermal Growth Factor Receptor Therapy

Cancer Research and Treatment ◽

10.4143/crt.2013.45.1.55 ◽

2013 ◽

Vol 45 (1) ◽

pp. 55-62 ◽

Cited By ~ 11

Author(s):

Seung Tae Kim ◽

Kyong Hwa Park ◽

Jun Suk Kim ◽

Sang Won Shin ◽

Yeul Hong Kim

Keyword(s):

Colon Cancer ◽

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Cancer Patients ◽

Growth Factor Receptor ◽

Metastatic Colon Cancer ◽

Mutation Status ◽

Epidermal Growth ◽

Kras Mutation Status

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Association study of the let-7 microRNA-binding site polymorphism in 3'-untranslated region (UTR) of the KRAS gene in stage III colon cancers from adjuvant trial NCCTG N0147.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.3564 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 3564-3564

Author(s):

Dan Sha ◽

Adam Lee ◽

Qian Shi ◽

Steven R. Alberts ◽

Daniel J. Sargent ◽

...

Keyword(s):

Colon Cancer ◽

Association Study ◽

Cancer Patients ◽

Kras Mutation ◽

Phase Iii ◽

Stage Iii ◽

Mutation Status ◽

Stage Iii Colon Cancer ◽

Chi Squared ◽

Kras Mutation Status

3564 Background: Lethal-7 (let-7) microRNA has been shown to inhibit colon cancer cell proliferation by inducing KRAS downregulation after binding to specific sites in the 3’- UTR. Recent studies identified a KRAS 3’-UTR polymorphism in the let-7 complimentary site (LCS6) that has been shown to weaken let-7 binding and alter KRAS expression. Carriers of the LCS6 G-allele showed worse survival in metastatic colorectal cancer from prior studies of limited sample size. In the current study, we evaluated the LCS6 variant in 2,834 Stage III colon cancer patients and its association with disease-free survival (DFS), KRAS mutation status, and other clinicopathological features. Methods: In the NCCTG phase III trial (N0147), the LCS6 variant was assayed in germline DNA extracted from whole blood using RT-PCR. Extracted tumor DNA was analyzed for KRAS exon 2 mutations. Chi-squared and two-sample t test were used to compare baseline factors and KRAS mutation status between patients defined by LCS6 variant status. Log-rank tests and multivariate Cox models assessed the unadjusted and adjusted associations between LCS6 status and DFS, respectively. Results: We identified 432 (15.2%) patients heterozygous or homozygous for the LCS6 G-allele and 2402 (84.8%) patients homozygous for the LCS6 T-allele. G-allele carriers were significantly more frequent in Caucasians than other races (Chi-Squared Test, p<0.0001). No associations were found between the LCS6 genotype and T stage, positive lymph node number, tumor differentiation, or primary tumor location (all p>0.2). Moreover, the LCS6 genotype was not associated with DFS (hazard ratio = 0.93, p=0.49) even after combining LCS6 genotype with KRAS mutation status. Conclusions: We report the largest association study investigating the LCS6 polymorphism and colon cancer outcome. There is no significant evidence that the germline LCS6 genotype was associated with DFS in stage III colon cancer patients. Additional studies are needed to determine if LCS6 genotype differs between tumor and germline DNA which may further clarify its prognostic value.

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