Prolonged Response to HER2-Directed Therapy in a Patient With HER2-Amplified, Rapidly Progressive Metastatic Colorectal Cancer

Abstract

HER2 gene amplifications and activating mutations in the HER2 receptor tyrosine kinase are present in 4% of metastatic colorectal cancers (mCRCs). HER2-targeted therapy is not standard of care, although preclinical and clinical data suggest that patients with HER2 amplifications and/or HER2-activating mutations may benefit from HER2-directed therapy. HER2 amplifications and activating mutations have also been implicated in resistance to anti–epidermal growth factor receptor–based therapy. This report describes a patient with KRAS, NRAS, and BRAF wild-type mCRC who experienced disease progression on first-line treatment with FOLFIRI and cetuximab after only 5 months, and subsequently experienced progression on second-line treatment with capecitabine and oxaliplatin plus bevacizumab after 2 months with significant functional decline. Next-generation sequencing of the primary tumor identified HER2 amplification, and we were able to obtain trastuzumab-DM1 for off-label use. The patient had symptomatic clinical benefit from trastuzumab-DM1 and had radiographic disease control for 7 months. On progression, therapy was changed to trastuzumab and pertuzumab, but the patient’s disease progressed 3 months later. Treatment with the trastuzumab-DM1 resulted in a sustained response that was longer than his prior responses in the first and second lines of treatment, with a dramatic improvement in the patient’s functional status. This case represents the first report, to our knowledge, of successful single-agent treatment of HER2-amplifed CRC with trastuzumab-DM1. Clinical trials targeting patients with HER2-mutated and -amplified metastatic colon cancer are currently underway. Molecular insights from investigating HER2 activation and the impact of HER2-directed therapies in a wide variety of solid tumors will create the needed evidence base to more broadly inform patient care.

Targeting HER2 in colorectal cancer: The landscape of amplification and short variant mutations in ERBB2 and ERBB3

“…B). Recent studies have further emphasized the potential of targeting ERBB2 sequence mutations in the absence of ERBB2 amplification in mCRC using combinations of kinase inhibitors and antibody therapeutics . The preliminary success described in these reports have generated further interest in expanding clinical trials to include ERBB2 SV mutations when there are no copy number changes in ERBB2 .…”

Pharmacogenomics of Targeted Agents for Personalization of Colorectal Cancer Treatment

“…Consistent with this suggestion, a recent case report assessed the off-label use of trastuzumab emtansine (TDM-1) in a mCRC patient that underwent rapid progression to cetuximab, likely because of the presence of HER-2 amplification. TDM-1 administration resulted in a significant improvement in the patient’s functional status and response to targeted agent, suggesting that this mAb can be used in the management of CRC [ 47 ]. Moreover, a phase II trial (HERACLES) evaluated the effectiveness of trastuzumab combined with either the reversible HER-2 inhibitor lapatinib or anti-HER-2 mAb pertuzumab in 27 mCRC patients with tumoral wild-type KRAS exon 2; this study reported that an objective response was achieved in 30% and complete response in 4% of the trastuzumab/lapatinib cohort, suggesting that this combination has synergic positive effectiveness in mCRC patients refractory to commonly used anti-EGFR mAbs [ 48 ].…”

MiR-29b inhibits the growth of glioma via MYCN dependent way

“…The past decade has witnessed the evolving progress of biological molecular therapies for diverse tumors and multiple biomarkers and biological targets have been found, several of which have been successfully applied in clinical tumor treatment, such as trastuzumab which is an antibody of human epidermal growth factor receptor type 2 (HER2) and nivolumab which is an antibody of the programmed cell death-1 (PD-1) [ 12 – 16 ]. Studies have also validated nonconding RNAs, which were formerly classified as RNA junk, as vital biomarkers and therapeutic biological targets for diverse human diseases, such as inflammatory diseases, metabolic diseases and cancers.…”