title: 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.
authors.affiliation: From University of California San Francisco, Hellen Diller Family Comprehensive Cancer Center, San Francisco, California.
authors.forename: Aparna
authors.initials: A
authors.lastname: Parikh
authors.affiliation: From University of California San Francisco, Hellen Diller Family Comprehensive Cancer Center, San Francisco, California.
authors.forename: Chloe
authors.initials: C
authors.lastname: Atreya
authors.affiliation: From University of California San Francisco, Hellen Diller Family Comprehensive Cancer Center, San Francisco, California.
authors.forename: W Michael
authors.initials: WM
authors.lastname: Korn
authors.affiliation: From University of California San Francisco, Hellen Diller Family Comprehensive Cancer Center, San Francisco, California.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Venook
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use; D001706:Biopsy; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D059186:Chemoradiotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D004252:DNA Mutational Analysis / Q000379:methods; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000008:administration & dosage / Q000627:therapeutic use; D005784:Gene Amplification; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D010535:Laparoscopy; D002955:Leucovorin / Q000008:administration & dosage / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000556:secondary / Q000628:therapy*; D008297:Male; D008453:Maytansine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods*; D056687:Off-Label Use; D010166:Palliative Care / Q000379:methods; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D014057:Tomography, X-Ray Computed; D000068878:Trastuzumab; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014463:Ultrasonography
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D002166:Camptothecin; D005472:Fluorouracil; D002955:Leucovorin; D008453:Maytansine; D016271:Proto-Oncogene Proteins c-myc; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D016159:Tumor Suppressor Protein p53; C489427:MYC protein, human; C495901:TP53 protein, human