Research ArticleExperimental Studies

Amphiregulin/epiregulin mRNA Expression and Primary Tumor Location in Colorectal Cancer

HIDEKAZU KURAMOCHI, GO NAKAJIMA, KAZUHIKO HAYASHI, TATSUO ARAIDA and MASAKAZU YAMAMOTO
Anticancer Research September 2019, 39 (9) 4729-4736; DOI: https://doi.org/10.21873/anticanres.13655

Abstract

Background/Aim: Amphiregulin (AREG) and epiregulin (EREG) mRNA expression levels are predictors of response to anti-EGFR antibody therapy. Left-sided colon cancer is more sensitive to anti-EGFR antibodies than right-sided, although the mechanism is unclear. The aim of this study was to determine the relationship between AREG, EREG mRNA expression levels and tumor location as well as the efficacy of anti-EGFR antibody agents. Materials and Methods: Real-time PCR was used to assess AREG and EREG mRNA expression in metastatic colorectal cancer (CRC) samples from 153 patients. Results: Among KRASwt samples, high AREG expression (AREGHigh) was significantly more common in left-sided tumors than in right-sided. Among patients who received anti-EGFR antibody, response rates were significantly higher in AREGHigh than in AREGLow. In the left-sided tumor group, overall survival was significantly longer in patients with high EREG levels than with low levels, whereas the right-sided tumor group showed no survival difference between them. Conclusion: AREG and EREG mRNA expression levels in left-sided CRC were higher than in right-sided tumors. This may help explain why left-sided CRC is more responsive to anti-EGFR antibodies.

Amphiregulin (AREG) and epiregulin (EREG) belong to the epidermal growth factor (EGF) family, and act as mitogenic stimulators through binding to EGFRs (1). Recently, patients with high AREG and EREG expression in tumor cells were reported to respond better to anti-EGFR antibody agents (cetuximab [CTX]/panitumumab [Pmab]; C/P) and survive longer than those with low expression among patients with unresectable/metastatic RAS-wild-type colorectal cancer (CRC) (2-13). Thus, AREG and EREG are potential alternative biomarkers for anti-EGFR antibodies.

Tumor location is also associated with prognosis in CRC. Patients with left-sided tumors show a better survival than those with right-sided tumors, regardless of therapy (14). Tumor location is also associated with response to C/P. In the CALGB 80405 study, among patients with RAS/BRAF-wild-type tumors, in the subset with left-sided CRC, those treated with CTX had 2 months' gain in overall survival (OS) compared to those treated with bevacizumab, whereas in the right-sided subset, patients treated with CTX showed 16 months' loss of OS compared to those treated with bevacizumab (15). Although many studies support the consensus that anti-EGFR antibody agents are more effective on left-sided tumors than right-sided ones, (16-19) the reason for this difference of efficacy is unclear. Lee et al. reported that EREG and AREG expression was inversely correlated with both methylation and right-sidedness in primary tumors, which suggests that these differences are related to the association between tumor location and C/P efficacy (20).

In this study, we compared mRNA expression levels of AREG and EREG in left-sided and right-sided tumors in 153 CRC patients, and evaluated the association between AREG and EREG expression and tumor location with efficacy of C/P in 49 patients.

Materials and Methods

Patients and samples. We analyzed data and specimens from 153 patients with metastatic or relapsed CRC who had undergone resection of primary colorectal adenocarcinomas between 2003 and 2013 in the Department of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan (n=136), or Tokyo Women's Medical University, Yachiyo Medical Center, Chiba, Japan (n=17).

The patients' relevant characteristics are shown in Table I. Of the 153 samples, 100 were KRAS exon 2 (codon 12, 13) wild-type (KRASwt) and 53 were mutant type (KRASMut). Of these 153 patients, 49 patients (KRASwt: n=37; KRASMut: n=10; unknown: n=2) had received anti-EGFR antibodies (C/P).

Primary specimens were classified as having right-sided CRC if they were located in the cecum, ascending colon, hepatic flexure, or transverse colon, and left-sided CRC if the tumor site was within the splenic flexure, descending colon, sigmoid colon, or rectum.

This study was approved by the Ethics Committee of Tokyo Women's Medical University and performed in accordance with the Declaration of Helsinki. All patients were Japanese, and all had given their written informed consent according to the institutional regulations.

Microdissection. Formalin-fixed, paraffin-embedded tumor specimens were cut into 10-μm-thick serial sections. For pathological diagnosis, one slide for each specimen was stained with hematoxylin and eosin and evaluated by a pathologist. Manual microdissection using a scalpel was performed if histology was homogeneous and contained >90% cancer cells. For all other samples, laser-capture microdissection (P.A.L.M. Microlaser Technologies AG, Munich, Germany) was performed to ensure that only tumor cells were dissected.

RNA isolation and cDNA synthesis. Isolation of RNA from formalin-fixed paraffin-embedded (FFPE) specimens was performed using a RNeasy FFPE Kit (Qiagen, Tokyo, Japan) according to the manufacturer's instructions. We converted cDNA from the total RNA yielded, using a High Capacity cDNA Reverse Transcription Kit (Applied Biosystems, Tokyo, Japan).

Reverse transcription-PCR. cDNA was pre-amplified using a TaqMan PreAmp Master Mix Kit (Applied Biosystems) according to the manufacturer's instructions. mRNA expression of AREG, EREG, and a single internal reference gene (beta-2-macrogloblin) was measured by a fluorescence-based real-time polymerase chain reaction (PCR) detection method. Primers and probes were provided from TaqMan Gene Expression Assays (Applied Biosystems). The PCR Primer ID were AREG: Hs00950669_m1, EREG: Hs00914312_m1, and beta 2-microglobulin: Hs99999907_m1. The PCR methodology has been described previously (21). The 2−ΔΔCT number was used for relative mRNA quantification. The samples from Tokyo Women's Medical University Hospital were measured using StepOne real-time PCR system (Applied Biosystems), and the samples from Yachiyo Medical Center were measured using Illumina ECO Real-time PCR system (Illumina, San Diego, CA, USA). Because PCR machines differed between the two institutes, median values of AREG and EREG expression in each institute were used as cut-off values, to divide high and low expression.

Screening for KRAS mutation. DNA was extracted from the FFPE specimens using a Qiamp DNA FFPE Tissue Kit (Qiagen) according to the manufacturer's instructions. KRAS exon-2 mutations were detected by direct-sequencing, as previously described (22).

Statistical analysis. Frequencies of high and low gene expression were compared between left- and right-sided tumors using Fisher's exact test. Response rates and carcinoembryonic antigen (CEA) changing rates were compared between high- and low-gene expression groups using the Wilcoxon signed-rank test. The Kaplan–Meier method was used to construct survival curves and the log-rank test for statistical analysis. The Cox proportional hazard regression model was used in multivariate analysis.

View this table:
Table I.

Demographic and clinical parameters of 153 patients with metastatic colorectal cancer.

View this table:
Table II.

Demographic and clinical parameters of 37 patients with KRAS wild-type metastatic colorectal cancer treated with anti-EGFR therapy.

Figure 1.
Figure 1.

Percentages of AREGHigh patients by tumor side among KRAS wild-type and KRAS-mutant samples. Among KRAS wild-type patients, the percentage of AREGHigh patients was significantly higher in the left-sided subset than in the right-sided subset.

OS was defined as the time from the first administration of anti-EGFR antibodies to death from any cause. CEA changing rate was defined as minimum serum CEA levels minus baseline CEA levels, divided by baseline CEA levels. Statistical analyses were performed using JMP 11 (SAS Institute, Cary, NC, USA). p-Value <0.05 was considered significant. All values are two-sided.

Results

AREG/EREG mRNA expression and tumor location. In the cohort as a whole, AREG/EREG mRNA expression levels did not significantly differ between left and right CRC. However, among KRASwt samples (n=100), AREGHigh expression was significantly more common in left-sided CRC (high: n=41, low: n=28) than in right-sided CRC (high: n=9, low: n=22; p=0.0089; Figure 1). Similar results were observed with EREG expression, although not significantly so (left–high: n=39, low: n=30; right–high: n=11, low: n=20; p=0.08). However, among KRASMut patients (n=53), no association was observed in AREG or EREG mRNA expression levels between left- and right-sided tumors (AREG: left–high: n=13, low: n=18; right–high: n=11, low: n=11; p=0.58. EREG: left–high: n=12, low: n=19; right–high: n=8, low: n=14; p=1.00).

AREG/EREG mRNA levels and response to anti-EGFR antibodies. Of the 153 patients, 49 received anti-EGFR antibodies (CTX/Pmab). As KRAS testing was only approved in Japan in 2010, 10 patients who were treated before approval had KRASMut tumors and two patients had unknown KRAS status; the other 37 patients had KRASwt tumors (Table II). Twenty-three patients received CTX-containing regimens, and 14 were administered Pmab regimens, mostly as 2nd- or 3rd-line treatments.

Response rates (RRs) for KRASwt tumors were: 32.4% (12/37), KRASMut tumors: 0% (0/10). In the KRASwt group (n=37), RRs significantly differed between the AREGHigh group (47.6%, 10/21), and the AREGLow group (12.5%, 2/16; p=0.035), where the median value from each testing institution was used as the cut-off. RRs by EREG expression showed a similar trend (EREGHigh: 40.9%, EREGLow group: 20%), but was not significant (p=0.28).

Figure 2.
Figure 2.

Overall survival (OS) in patients by AREG expression and EREG expression in patients who received anti-EGFR therapy. EREG expression levels clearly separated the patients with good and poor prognosis.

CEA changing rate was defined as ([minimum serum CEA] – [baseline CEA])/(baseline CEA). Median CEA changing rate in the AREGHigh group (−0.63) was significantly lower than in the AREGLow group (−0.13; p=0.027); and significantly lower in the EREGHigh group (−0.22) than in the EREGLow group (0.035; p=0.0038). AREG and EREG mRNA levels and OS in C/P-treated patients. For all 49 C/P-treated patients, median survival time (MST) was significantly longer in the EREGHigh group (735 days) than in the EREGLow group (193 days, p=0.0008; hazard ratio [HR]=0.30; 95% confidence interval [CI]=0.13–0.62; Figure 2). This difference was even more pronounced in the KRASwt group (n=37; MST: not reached vs. 169 days, p=0.0035, HR=0.29; 95%CI=0.12–0.70).

AREG showed a similar trend for MST, but was not significant (all patients: AREGHigh: 552 days, AREGLow: 197 days, p=0.09, HR=0.60, 95%CI=0.24-1.62; Figure 2; KRASwt: AREGHigh: 735, AREGLow: 193 days, p=0.17, HR=0.56, 95%CI=0.23–1.32).

Figure 3 shows a Kaplan–Meier curve for OS that combines KRAS and EREG status. The KRASwt/EREGHigh group had the most favorable outcome (MST: not reached). Interestingly, MST in the subgroup of EREGLow/KRASwt patients who were treated with C/P (169 days) was fairly similar to that of the KRASMut group (226 days; Figure 3), which implies that the EREGLow patients derived no benefit from C/P.

C/P response by tumor location and AREG/EREG mRNA levels. We considered tumor location in KRASwt tumors treated with anti-EGFR antibodies (n=37). The proportion of AREGHigh tumors was significantly higher in left-sided CRC (73%) than right-sided CRC (18%, p=0.003). EREG showed a similar trend, but was not significant (left: 69%, right: 36%, p=0.06).

Among patients with left-sided CRC, RRs to C/P in the AREGHigh group (n=19) were 47.4%, and in the AREGLow group (n=7) 28.6%. Among those with right-sided tumors, the AREGHigh group (n=2) included one responding patient (50%), whereas no patients in the AREGLow group (n=9) showed any response at all (0%).

Tumor location and OS in patients treated with C/P. In the KRASwt group, among patients treated with C/P (n=37), MST was longer in the left-sided group (735 days) than in the right-sided group (169 days), but was not significant (p=0.13). In the left-sided CRC (n=26), MST was significantly longer in the EREGHigh group (MST: not reached) than in the EREGLow group (199 days; p=0.018; Figure 4). The EREGHigh/left-sided group had the most favorable outcome, whereas OS in EREGLow group, even with left-sided CRC, was similar to those with right-sided CRC. In multivariate analysis, only EREG expression was an independent prognostic indicator (p=0.0088), whereas AREG expression (p=0.41), tumor sidedness (p=0.52), age (cut-off: 65 years; p=0.98), sex (p=0.18), and use of C/P (p=0.93) were not significantly relevant.

Figure 3.
Figure 3.

Overall survival (OS) by KRAS status and EREG expression in patients who received anti-EGFR therapy. The KRAS-wild-type/EREGHigh group had the most favorable outcome, whereas OS in the KRAS wild-type/EREGLow group was similar to the KRAS-mutant group.

Discussion

Many recent studies support the association of tumor sidedness with response to C/P by metastatic CRC (16-19). Arnold et al. reported that OS and RR of patients who received anti-EGFR antibodies were significantly higher than those who did not receive anti-EGFR antibodies among patients with left-sided primary tumors, whereas no benefit from C/P was observed in patients with right-sided tumors by meta-analysis of six clinical trials (16). However, the mechanism of this phenomenon is unclear.

In the present study, our data showed that high AREG mRNA expression is significantly more common in left-sided tumors than right-sided tumors. Lee et al. reported that AREG/EREG expression was highly inversely correlated with the methylation of loci within the AREG/EREG promoters, and was inversely correlated with right-sided tumors and CpG island methylator phenotype (CIMP) status (20). They also reported that high CIMP status is associated with inferior progression-free survival (PFS) after C/P treatment (20), although they did not directly evaluate AREG/EREG expression and PFS. Our data are compatible with their report, and directly show the association between tumor location, AREG/EREG expression, and prognosis of patients who received C/P, which implies that these factors are connected to the underlying mechanism of why C/P is more effective in left-sided primary tumors than in right-sided tumors. Although our study cohort was relatively small, one patient in the AREGHigh/right-sided tumor group responded to C/P, although there were no responders in the AREGLow/right-sided tumor group. Even among patients with left-sided tumors, OS of the EREGLow subgroup was similar to that in the right-sided tumor group. As variations in response to C/P reflect differences in molecular profiles such as AREG/EREG expression, tumor location may be just a surrogate marker of these differences.

Figure 4.
Figure 4.

Overall survival (OS) by EREG expression and tumor sidedness among patients who received anti-EGFR therapy. The EREGHigh/left-sided group had the most favorable outcome, whereas among the right-sided group, EREGLow and EREGHigh patients had similar outcomes.

High AREG/EREG expression is associated with better outcome in C/P-treated patients with CRC. Khambata-Ford et al. used microarrays to compare the expression of various genes between a disease control group and a non-responders group in a cohort of 80 CRC patients who received CTX monotherapy; AREG and EREG showed significant differential expression, with the lowest p-values (2). They showed that CTX-treated patients with high EREG- or AREG-expressing tumors have significantly longer PFS than patients with low expression. Jacobs et al. found that EREG and AREG expression was significantly associated with RR, disease control, PFS, and OS in 121 patients with irinotecan-refractory, KRASwt metastatic CRC who received a combination of CTX and irinotecan (3). Several other reports showed similar results; high AREG and/or EREG expression were related to better response for patients who received C/P (4-13). Similarly, our study also showed the patients with high AREG/EREG had better RR and longer OS than those with low levels among CP-treated patients with KRASwt CRC. These results were reproducible in every reported study, which indicates that AREG and EREG could be reliable biomarkers when combined with RAS/BRAF mutation status.

In contrast to these investigations, two studies on first-line treatments failed to show the benefit of AREG and EREG as predictive biomarkers in CRC in patients treated with CTX combined with multiple cytotoxic agents (9, 23). Cytotoxic chemotherapy shows promising effect along with biological agents in first-line settings, demonstrating remarkable additional survival benefit with biological agents may be difficult. The CRYSTAL trial, which compared FOLFIRI + CTX vs. FOLFIRI alone in the first-line setting, showed only a 0.9-month median gain in PFS (24), whereas late-line use of biological agents showed longer survival gains with remarkable hazard ratio improvement (25, 26). Where our study also showed remarkable OS separation by EREG expression, most of our cohort patients in our study received anti-EGFR agents as second- or third-line treatments. Thus, these reports (9, 23) do not show AREG and EREG to be equivocal predictive markers for C/P response in the first-line setting. Sunakawa et al. showed the effectiveness of AREG as a predictive biomarker for response to CTX in a first-line setting (11).

Our study showed that EREG was more likely to affect survival time, whereas AREG was more likely to affect response rate. AREG and EREG are both located in 4q13.3 chromosome, and their expression levels were strongly correlated. We previously reported strong correlations between AREG mRNA expression and EREG mRNA expression (Rs=0.82, p<0.0001, Spearman correlation test) (21). Thus, AREGHigh tumors are also likely to be EREGHigh. Oliveras-Ferraros et al. reported that stable silencing of either AREG or EREG was found to reduce the expression of the other ligand in a squamous cell carcinoma cell line (27). As their expression is strongly correlated, the significance of AREG and EREG as biomarkers might not intrinsically differ.

This study has several limitations. First, this was a retrospective observational study with somewhat diverse patient backgrounds, relatively few patients received C/P, tissue collection timing varied, and minor RAS and BRAF mutations were not examined. Although many previous studies report AREG and EREG to be promising biomarkers for predicting response to C/P, several problems must be overcome to make them practicable. Most previous studies measured AREG/EREG mRNA expression as biomarkers, either using microarray or real-time RT-PCR. When quantitative PCR is used, relative quantitative values may change under various conditions, such as probe/primer design, length of amplicon, internal reference genes, types of PCR machines and protocols. Standardizing these conditions among various laboratories may be difficult. Optimal cut-off values are also undetermined. For quality control, standardization of methods for RNA extraction, reverse transcription, and PCR conditions are critical for obtaining consistent and reliable gene expression measurement for clinical use.

In conclusion, AREG and EREG expression was a reliable predictor of response to C/P, and was higher in left-sided CRC than in right-sided CRC. Although these data may help explain why C/P is more effective in left-sided tumors than in right-sided tumors, further studies are warranted to elucidate the mechanism of this phenomenon.

Acknowledgements

The Authors thank Mr. Kanta Osuga, Ms. Saki Okamoto, Ms. Mieko Hirokawa, and Ms. Sachie Ishibashi for technical assistance of the experiment. The Authors also thank Mr. Tomotaka Yokochi for statistical advices, and Marla Brunker, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

Footnotes

  • Author's Contributions

    H.K. and G.N. designed and performed experiments, analyzed the data. H.K. wrote the manuscript. K.H., T.A., and M.Y. organized the study, and reviewed and edited the manuscript.

  • Conflicts of Interest

    The Authors declare that there are no conflicts of interest regarding this study.

  • Received July 31, 2019.
  • Revision received August 15, 2019.
  • Accepted August 16, 2019.

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Amphiregulin/epiregulin mRNA Expression and Primary Tumor Location in Colorectal Cancer
HIDEKAZU KURAMOCHI, GO NAKAJIMA, KAZUHIKO HAYASHI, TATSUO ARAIDA, MASAKAZU YAMAMOTO
Anticancer Research Sep 2019, 39 (9) 4729-4736; DOI: 10.21873/anticanres.13655
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