HER2 in Metastatic Colorectal Cancer: Pathology, Somatic Alterations, and Perspectives for Novel Therapeutic Schemes

Abstract

HER2 is an emerging biomarker in colorectal cancer (CRC). This oncogene plays an essential role in regulating cell proliferation, differentiation, migration, and, more in general, tumorigenesis and tumor progression. The most frequent types of HER2 alterations in CRC include gene amplification and missense mutations in 7–8% of CRC, often being mirrored by HER2 protein overexpression, representing founder events in solid tumors, including CRC. There are currently no approved HER2-targeted therapy guidelines for CRC; however, several studies have shown that HER2 can be effectively targeted in meta-static CRC settings. In this review, we discuss the current knowledge of HER2 testing in CRC and the immediate future perspectives for HER2 targeting in the metastatic setting.

A perspective on emerging therapies in metastatic colorectal cancer: Focusing on molecular medicine and drug resistance

“…In CRC, HER2 amplification rates varied, with membranous expression rates ranging from 2 to 11 percent and cytoplasmic expression rates from 47 to 68 percent. Using patient‐derived data, a proof‐of‐concept study was conducted 64 …”

“…Using patientderived data, a proof-of-concept study was conducted. 64 HER2 was a valuable therapeutic target in Cetuximab-resistant mCRC in patient-derived xenograft (PDX) models. According to clinical studies in patients with similar clinicopathological traits, Pertuzumab and Lapatinib (a dual TKI EGFR/HER2) increased the response rate and caused tumor regression.…”

Anti‐angiogenesis in colorectal cancer therapy

“…54 Gene amplification and missense mutation are the most common alterations in HER2 in 7%-8% CRC. 55 Approximately 5% of metastatic CRC tumors are facilitated by amplification or mutation of HER2, which might be a cancer-promoting factor, a prognostic and diagnostic biomarker, and a promising treatment target in CRC. 56 EGFR was found to be highly expressed in 85.2% of the 54 patients with cancer and correlated with tumor sizes and invasion depth (p = 0.043 and p = 0.05, respectively).…”

“…HER2 is a special member of the EGFR family, which is activated by heterodimerizing with other ligand‐bound receptors but not ligands 54 . Gene amplification and missense mutation are the most common alterations in HER2 in 7%–8% CRC 55 . Approximately 5% of metastatic CRC tumors are facilitated by amplification or mutation of HER2, which might be a cancer‐promoting factor, a prognostic and diagnostic biomarker, and a promising treatment target in CRC 56 .…”

Synthesis and Biological Assessment of Chalcone and Pyrazoline Derivatives as Novel Inhibitor for ELF3-MED23 Interaction

“…Numerous studies have consistently identified HER2 overexpression across diverse cancer types including breast, colorectal, ovarian, pancreatic, prostate, bladder, lung, gastric, and gastroesophageal cancers [5]. The frequency of HER2 overexpression varies: approximately 20% in breast cancers [6], 5–30% in ovarian cancers [7], 7–8% in colorectal cancers [8], 0–82% in pancreatic cancers [9], and 7.3–20.2% in gastric and gastroesophageal cancers [10]. In these cases, HER2 status serves as an important prognostic marker, correlating positively with tumor size, invasiveness, and lymph node metastasis [2, 6, 8, 10, 11].…”