High EREG Expression Is Predictive of Better Outcomes in Rectal Cancer Patients Receiving Neoadjuvant Concurrent Chemoradiotherapy

Abstract

Background/Aim: A great proportion of patients with rectal cancer initially present with locally advanced disease and can potentially benefit from neoadjuvant concurrent chemoradiotherapy (CCRT) for downstaging before surgery. However, risk and clinical outcome stratification remain a great challenge. We aimed to find the potential biomarker to predict the effect of neoadjuvant CCRT on rectal cancer. Methods: We identified epiregulin (EREG) as the most significant predictive marker for neoadjuvant CCRT response from the published rectal cancer transcriptome data set GSE35452. We collected 172 biopsy specimens from rectal cancer patients who received neoadjuvant CCRT followed by radical proctectomy, performed EREG immunohistochemistry, and analyzed the H-scores. We further examined the correlations between the expression level of EREG and clinicopathological features, tumor regression grade, and survival, including disease-specific survival (DSS), locoregional recurrence-free survival (LRFS), and metastasis-free survival (MeFS). Results: High EREG expression was significantly related to early pretreatment (pre-Tx) and posttreatment (post-Tx) tumor status (T1, T2, p = 0.047 and p < 0.001), pre-Tx and post-Tx negative nodal status (N0, p < 0.001 and p = 0.004), less vascular and perineurial invasion (p = 0.015 and p = 0.023), and higher tumor regression grade (p < 0.001). In the survival analysis, high EREG expression was significantly associated with better DSS (p < 0.0001), LRFS (p = 0.0004), and MeFS (p < 0.0001). In the multivariate analysis, high EREG expression remained prognostically significant for better DSS (p = 0.003; hazard ratio: 5.599). Conclusion: These data suggest that EREG is a potential predictive marker and therapeutic target in rectal cancer patients receiving neoadjuvant CCRT.

The Role of EREG/EGFR Pathway in Tumor Progression

“…Table 1 summarizes the potential functions of EREG. EREG is usually overexpressed in various human cancers such as bladder cancer [ 51 , 52 , 53 ], brain cancer [ 54 , 55 , 56 , 57 ], breast cancer [ 38 , 39 , 58 , 59 , 60 , 61 , 62 , 63 ], ovarian and cervical cancer [ 36 , 64 ], colorectal cancer [ 47 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ], head and neck cancer [ 11 , 37 , 73 , 74 , 75 , 76 ], liver cancer [ 77 , 78 ], lung cancer [ 31 , 79 , 80 , 81 , 82 ], pancreatic cancer [ 83 ], prostate cancer [ 84 ], gastric cancer (GC) [ 85 , 86 ], and thymic cancer [ 35 ].…”

“…In addition, high expression of EREG mRNA, but not AREG, was correlated with longer OS and progression-free survival (PFS) in patients with mCRC receiving first-line irinotecan-based chemotherapy [ 68 ]. Moreover, EREG can serve as a potential predictive marker, and high EREG protein levels were associated with better survival outcomes in patients with CRC receiving neoadjuvant concurrent chemoradiotherapy [ 71 ]. Moreover, increased EREG protein expression in patients with glioblastoma was highly correlated with a higher tumor grade and poor OS [ 55 ].…”

Upregulated MUC2 Is an Unfavorable Prognostic Indicator for Rectal Cancer Patients Undergoing Preoperative CCRT

“…However, whether heavily glycosylated MUC2 can orchestrate REG4 to evade immune elimination needs further validation. In contrast, the epiregulin ( EREG ) gene was one of the top 200 genes that were co-downregulated with MUC2 (Spearman’s correlation: −0.379) ( Supplementary Figure S1B ) and one of the favorable factors among rectal cancer patients receiving CCRT in our previous research [ 27 ]. Collectively, these results indicate that the molecular characterization of rectal cancer is complicated and interactive, and integration of these favorable and unfavorable biomarkers can more precisely guide treatment.…”

Biomarkers and cell-based models to predict the outcome of neoadjuvant therapy for rectal cancer patients

“…Epiregulin is in the EGF family of proteins and is an EGFR agonist. In one study, epiregulin was examined with immunohistochemistry in 172 rectal cancer biopsies collected before neoadjuvant chemoradiotherapy [37]. The study showed that higher epiregulin expression prior to treatment was significantly associated with better disease-specific survival, locoregional recurrence-free survival, and metastasis-free outcome, thus suggesting that epiregulin could be a potential therapeutic target and predictive marker.…”