MicroRNA profiling predicts survival in anti-EGFR treated chemorefractory metastatic colorectal cancer patients with wild-type KRAS and BRAF

doi:10.1016/j.cancergen.2012.08.003

Cancer Genetics

Volume 205, Issue 11, November 2012, Pages 545-551

https://doi.org/10.1016/j.cancergen.2012.08.003 Get rights and content

Anti-EGFR monoclonal antibodies (anti-EGFRmAb) serve in the treatment of metastatic colorectal cancer (mCRC), but patients with a mutation in KRAS/BRAF and nearly one-half of those without the mutation fail to respond. We performed microRNA (miRNA) analysis to find miRNAs predicting anti-EGFRmAb efficacy. Of the 99 mCRC patients, we studied differential miRNA expression by microarrays from primary tumors of 33 patients who had wild-type KRAS/BRAF and third- to sixth-line anti-EGFRmAb treatment, with/without irinotecan. We tested the association of each miRNA with overall survival (OS) by the Cox proportional hazards regression model. Significant miR-31* up-regulation and miR-592 down-regulation appeared in progressive disease versus disease control. miR-31* expression and down-regulation of its target genes SLC26A3 and ATN1 were verified by quantitative reverse transcriptase polymerase chain reaction. Clustering of patients based on miRNA expression revealed a significant difference in OS between patient clusters. Members of the let-7 family showed significant up-regulation in the patient cluster with poor OS. Additionally, miR-140-5p up-regulation and miR-1224-5p down-regulation were significantly associated with poor OS in both cluster analysis and the Cox proportional hazards regression model. In mCRC patients with wild-type KRAS/BRAF, miRNA profiling can efficiently predict the benefits of anti-EGFRmAb treatment. Larger series of patients are necessary for application of these miRNAs as predictive/prognostic markers.

Section snippets

Patient selection

We selected 99 patients with mCRC treated at Helsinki University Central Hospital and at Turku University Central Hospital. We included, however, only those 33 patients for the final analysis 1) for whom tissue was available from the primary tumor at diagnosis before the start of any treatment; 2) who had wild-type KRAS and BRAF status; and 3) who had had third- to sixth-line treatment with cetuximab or panitumab with or without irinotecan, and were chemorefractory or intolerant to irinotecan,

Response to anti-EGFRmAb in wild-type KRAS and BRAF patients

Among CRC tumors with wild-type KRAS and BRAF, 33 of them had criteria meriting further analysis. Objective best responses for 33 patients were as follows: partial response in 8 patients, long (≥3 months) stable disease in 11, and progressive disease in 14. The PD group included 11 men and 3 women, with a median age of 59.5 years (range 37–69). The site of the primary tumor in the PD group was the colon in 11 patients and the rectum in 3. Ten men and 9 women of median age 66 years (range 37–76)

miRNAs as predictive biomarkers

In our miRNA expression study on primary untreated tumors of mCRC patients with wild-type KRAS and BRAF, we identified a signature associated with the efficacy of anti-EGFRmAb therapy. Up-regulation of miR-31* and down-regulation of miR-592 were associated with poor response to treatment. Moreover, expression of potential mRNA targets of miR-31*, ATN1, and SLC26A3 were lower in the PD group than in the DC group. Although very little is known regarding the function of miR-31*, lower expression

Acknowledgments

This study was sponsored by the Academy of Finland, project no: 132645; Amgen Ab; Merck Oy; the Sigrid Jusélius Foundation; the Finnish Cancer Organizations; the special governmental subsidy research funds appropriated to the Helsinki and Uusimaa Hospital District (HUS EVO), and a product-development project grant awarded by HUSLAB. We are grateful to Carol Norris for assistance with editing the manuscript.

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Low miR-31-3p expression was identified as predictive of anti-EGFR efficacy in RAS-wt mCRC. Primary tumor side was also proposed as a predictive factor of anti-EGFR benefit. This retrospective multicentric study evaluated the predictive role of miR-31-3p in right-sided RAS-wt mCRC patients treated with first-line CT+anti-EGFR or CT+bevacizumab (Beva).
Seventy-two right-sided RAS-wt mCRC patients treated in first-line with CT+anti-EGFR (n = 43) or Beva (n = 29) were included. Overall survival (OS), progression-free survival (PFS) and response rate (RR) were analyzed and stratified according to tumor miR-31-3p expression level and targeted therapy (TT).
BRAF V600E mutation was more frequent in high vs low miR-31-3p expressers (60.6% vs 15.4%, P < 0.001). PFS was significantly longer with CT+Beva than with CT+anti-EGFR (13 vs 7 months; P = 0.024). Among low miR-31-3p expressers, PFS, OS and RR were not significantly different between the two groups, while in high miR-31-3p expressers, only PFS was longer in the CT+Beva group (11 vs 6 months; P = 0.03). In patients treated with CT+anti-EGFR, low miR-31-3p expressers had a significantly longer OS (20 vs 13 months; P = 0.02) than high miR-31-3p expressers. ORR was not significantly different between the two groups of treatment, in both low and high miR-31-3p expressers. MiR-31-3p expression status was statistically correlated between primary tumors and corresponding metastases.
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Colorectal carcinogenesis is a multistep process involving the accumulation of genetic alterations over time that ultimately leads to disease progression and metastasis. Binding of transcription factors to gene promoter regions alone cannot explain the complex regulation pattern of gene expression during this process. It is the chromatin structure that allows for a high grade of regulatory flexibility for gene expression. Posttranslational modifications on histone proteins such as acetylation, methylation, or phosphorylation determine the accessibility of transcription factors to DNA. DNA methylation, a chemical modification of DNA that modulates chromatin structure and gene transcription acts in concert with these chromatin conformation alterations. Another epigenetic mechanism regulating gene expression is represented by small non-coding RNAs. Only very recently epigenetic alterations have been included in molecular subtype classification of colorectal cancer (CRC). In this chapter, we will provide examples of the different epigenetic players, focus on their role for epithelial-mesenchymal transition and metastatic processes and discuss their prognostic value in CRC.
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Original articleMicroRNA profiling predicts survival in anti-EGFR treated chemorefractory metastatic colorectal cancer patients with wild-type KRAS and BRAF

Section snippets

Patient selection

Response to anti-EGFRmAb in wild-type KRAS and BRAF patients

miRNAs as predictive biomarkers

Acknowledgments

Cancer Treat Rev

Cancer Treat Rev

Lancet

Trends Mol Med

J Mol Diagn

Mod Pathol

Int J Radiat Oncol Biol Phys

J Biol Chem

Blood

Ann Thorac Surg

Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer

N Engl J Med

Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer

J Clin Oncol

Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer

J Clin Oncol

Randomized phase III study of 5-fluorouracil/folinate/oxaliplatin given continuously or intermittently with or without cetuximab, as first-line treatment of metastatic colorectal cancer: the NORDIC VII study (NCT00145314), by the Nordic Colorectal Cancer Biomodulation Group [abstract]

J Clin Oncol

Optimized high-throughput microRNA expression profiling provides novel biomarker assessment of clinical prostate and breast cancer biopsies

Mol Cancer

Diagnostic assay based on hsa-miR-205 expression distinguishes squamous from nonsquamous non-small-cell lung carcinoma

J Clin Oncol

A microRNA expression signature of human solid tumors defines cancer gene targets

Proc Natl Acad Sci U S A

Original article
MicroRNA profiling predicts survival in anti-EGFR treated chemorefractory metastatic colorectal cancer patients with wild-type KRAS and BRAF