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Aparna Parikh, Chloe Atreya, W. Michael Korn and Alan P. Venook

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.

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Al B. Benson III, Alan P. Venook, Mahmoud M. Al-Hawary, Mustafa A. Arain, Yi-Jen Chen, Kristen K. Ciombor, Stacey A. Cohen, Harry S. Cooper, Dustin A. Deming, Ignacio Garrido-Laguna, Jean L. Grem, Sarah E. Hoffe, Joleen Hubbard, Steven Hunt, Ahmed Kamel, Natalie Kirilcuk, Smitha Krishnamurthi, Wells A. Messersmith, Jeffrey Meyerhardt, Eric D. Miller, Mary F. Mulcahy, Steven Nurkin, Michael J. Overman, Aparna Parikh, Hitendra Patel, Katrina S. Pedersen, Leonard B. Saltz, Charles Schneider, David Shibata, John M. Skibber, Constantinos T. Sofocleous, Elena M. Stoffel, Eden Stotsky-Himelfarb, Christopher G. Willett, Alyse Johnson-Chilla, Kristina M. Gregory and Lisa A. Gurski

Small bowel adenocarcinoma (SBA) is a rare malignancy of the gastrointestinal tract that has increased in incidence across recent years. Often diagnosed at an advanced stage, outcomes for SBA are worse on average than for other related malignancies, including colorectal cancer. Due to the rarity of this disease, few studies have been done to direct optimal treatment, although recent data have shown that SBA responds to treatment differently than colorectal cancer, necessitating a separate approach to treatment. The NCCN Guidelines for Small Bowel Adenocarcinoma were created to establish an evidence-based standard of care for patients with SBA. These guidelines provide recommendations on the workup of suspected SBA, primary treatment options, adjuvant treatment, surveillance, and systemic therapy for metastatic disease. Additionally, principles of imaging and endoscopy, pathologic review, surgery, radiation therapy, and survivorship are described.