by Dr. C. H. Weaver M.D. 11/2019
Precision cancer medicines that target the HER2 receptor in breast, colon and other cancers represent an effective treatment option for individuals with HER2-positive (HER2+) disease. Researchers are evaluating various drug combinations that target the HER2 receptor in colorectal cancers because HER2 directed therapy is effective and can avoid the complications of chemotherapy. (1-5)
About HER2-positive (HER2+) Colo-rectal Cancer
In the U.S. an estimated 140,250 patients will be diagnosed with cancer of the colon or rectum in 2020, and approximately 50,000 are estimated to die of their disease. (1) The HER2 receptor is a protein that is normally found on the surface of several different types of cells in the body but over expressed in multiple cancer types including ~4-5% of patients with colorectal cancer. (2)
The HER2 receptors span into the cell and are part a biologic pathway that is involved in cellular replication. Sometimes a gene that is responsible for the HER2 receptor becomes mutated, and too many receptors are produced. This, in turn, results in cells that divide and spread without their normal biologic controls. Cancer cells that have too many HER2 receptors are referred to as HER2-positive. Several precision cancer medicines have been developed that bind to different sites within the HER2 pathway resulting in decreased cell division and spread. (2,3)
Herceptin (trastuzumab) and Tykerb (lapatinib) are two precision cancer medicines that bind along the HER pathway at different points, both producing anti-cancer effects in HER2+ breast cancer. When evaluated in advanced HER2+ wild type KRAS patients with advanced colon cancer the combination is also active and well tolerated in treatment-refractory patients with HER2+ disease. (3,4)
More recently the MOUNTAINEER and TRIUMPH clinical trials evaluated other anti-HER2 combinations. Tucatinib is a very attractive precision medicine because this tyrosine kinase inhibitor drug is highly selective for HER2 without significant inhibition of EGFR. Inhibition of EGFR is associated with significant side effects including skin rash and diarrhea.
About the MOUNTAINEER Clinical Trail
The single arm phase 2 clinical trial known as MOUNTAINEER evaluated the effectiveness of combination HER2 therapy for the treatment of HER2+ advanced colorectal cancer. The trial evaluated the highly potent anti-HER2 medication Tucatinib in combination with Herceptin in 26 patients with HER2+ RAS wild-type metastatic colorectal cancer after treatment with first- and second-line standard-of-care therapies. The combined Herceptin-Tucatinib regimen demonstrated encouraging activity and was well tolerated. Overall, 52% of patients responded to treatment with a median duration of response of 10.4 months and an average overall survival of 18.7 months.
Herceptin-Perjeta (pertuzumab) Combination
The combination of Herceptin-Perjeta also has demonstrated promising activity in patients with metastatic CRC with RAS wild-type and HER2 amplification in the TRIUMPH clinical trial. Overall ~35% of 19 patients with RAS wild-type and HER2-amplified metastatic CRC that were refractory to standard chemotherapy responded to treatment. With the combination some treatment-related cardiac and infusion related side effects were reported.
- Higher HER2 expression as measured by immunohistochemistry score (3+ versus 2+) appears to be associated with greater response rates and delayed cancer progression.
- The identification of clonal oncogenic ctDNA driver mutations, such as KRAS, BRAF, PIK3CA, or HER2 appeared to predict for resistance to treatment.
Patients with advanced colorectal cancer should undergo genomic testing and evaluation for HER2 over expression or amplification. Genomic testing can determine if patients have HER2+ cancers or other targetable mutations. Those with HER2+ disease should be offered precision cancer medicines that target the HER2 receptor. Several precision medicines that target HER2 are available and the most potent agent to date, Tucatinib is currently under review by the US Food and Drug Administration.
- American Cancer Society, Cancer Facts and Figures 2018-2019.
- Loibl S, Gianni L (2017). HER2-positive breast cancer. The Lancet 389(10087): 2415-29.
- Slamon D, Clark G, Wong S, et al. (1987). Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235(4785): 177-82.
- Sartore-Bianchi A, Trusolino L, Martino C, et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncology. Published online April 20, 2016. DOI: [access here](http://dx.doi.org/10.1016/S1470-2045(16%2900150-9). Accessed May 10, 2016.
- Strickler JH, Zemla T, Ou F-S, et al. Trastuzumab and tucatinib for the treatment of HER2 amplified metastatic colorectal cancer (mCRC): Initial results from the MOUNTAINEER trial.
- Nakamura Y, Okamoto W, Kato T, et al. TRIUMPH: Primary Efficacy of a Phase II Trial of Trastuzumab (T) and Pertuzumab (P) in Patients (pts) with Metastatic Colorectal Cancer (mCRC) with HER2 (ERBB2) Amplification (amp) in Tumor Tissue or Circulating Tumor DNA (ctDNA): A GOZILA Sub-study.