Human Epidermal Growth Factor Receptor 2–Targeting Approaches for Colorectal Cancer: Clinical Implications of Novel Treatments and Future Therapeutic Avenues

Abstract

The treatment paradigm for colorectal cancer (CRC) has changed significantly over the past decade with targeted therapeutics. Human epidermal growth factor receptor 2 ( HER2) amplification is seen among 3%-4% of patients with metastatic CRC (mCRC). The biological discovery of HER2 amplification in cancer cells has led to practice-changing drug development for several solid tumors, including breast, gastric, and esophageal cancers. HER2 amplification is now highly actionable in CRC with distinct therapeutic combinations, including the combination of monoclonal antibodies and HER2 receptor–specific tyrosine kinase inhibitors, as well as antibody-drug conjugates, that delivers targeted cytotoxic agents. However, it is essential to define the therapeutic role and sequence of these different combinations, some of which are already part of standard clinical practice. In this review article, we discuss recent clinical studies demonstrating the clinical benefits of each distinct therapeutic approach and their impacts on the current management of HER2-amplified mCRC. We also review ongoing clinical trials targeting the HER2 pathway in mCRC and elaborate on novel therapeutic opportunities in this space that may further define the changing paradigm of HER2-targeted therapy for CRC.

The Impact of Molecular Biology in the Seeding, Treatment Choices and Follow-Up of Colorectal Cancer Liver Metastases—A Narrative Review

“…This is seen in approximately 3–4% of patients with CRCLM, especially in RAS-RAF wild-type tumours. It is associated with shorter survival [ 40 , 41 ]. In these types of patients, dual HER2-targeting is recommended, with a combination of trastuzumab with pertuzumab, tucatinib or lapatinib [ 40 ].…”

“…It is associated with shorter survival [ 40 , 41 ]. In these types of patients, dual HER2-targeting is recommended, with a combination of trastuzumab with pertuzumab, tucatinib or lapatinib [ 40 ].…”

Precision Medicine in Metastatic Colorectal Cancer: Targeting ERBB2 (HER-2) Oncogene

“…Several ongoing clinical trials are exploring anti-ERBB2 therapies that evaluate the efficacy of small molecule inhibitors, ADCs, and their combination with established therapies [ 84 ].…”

Challenges in the Management of Patients With HER2-Amplified Colorectal Cancer

“…In the companion to this editorial, Karan et al 1 present a clinical review of the progress made in targeting HER2 amplification in advanced colorectal cancer (CRC). Although multiple phase III randomized controlled trials have shown the benefit of targeting HER2 amplifications in patients with breast and esophagogastric cancer, the optimal treatment regimen and sequencing of HER2 -directed treatment for patients with HER2 -amplified CRC is less clear.…”