Response to Trastuzumab and Lapatinib in a Metastatic Colorectal Cancer Harboring HER2 Amplification and HER2 S310F Mutation.

Dual HER2-targeted therapy has been associated with clinical responses and prolonged progression-free survival and overall survival in RAS-wild type HER2-amplified colorectal cancer (CRC). However, no clinical benefits have been reported in patients with CRC with HER2 mutations. Activated HER2 mutations have been largely deemed resistant to trastuzumab and to dual HER2 targeting. This report describes a patient with metastatic CRC with concurrent HER2 amplification and a HER2 S310F mutation, which is an active mutation located in the extracellular dimerization domain of HER2. Treatment with trastuzumab + lapatinib resulted in an excellent response that lasted for 10 months. Upon disease progression, treatment with the antibody-drug conjugate trastuzumab-deruxtecan resulted in a short-lived response. This is the first case report of successful HER2 targeting in metastatic CRC with concurrent HER2 amplification and a HER2 S310F mutation.