by C.H. Weaver M.D. 2/2020
Genomic or Biomarker Testing - Precision Cancer Medicine
The purpose of precision cancer medicine is to define the genomic alterations in an esophageal cancers DNA that are driving the growth of that specific cancer. Precision cancer medicine utilizes molecular diagnostic & genomic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed.
By testing a cancer for specific unique biomarkers doctors can offer the most personalized treatment approach utilizing precision medicines. There are increasing numbers of precision cancer medicines that can target cancer driving mutations and more being developed in clinical trials. Patients with esophageal cancer should ensure their doctors perform genomic biomarker testing on their cancer and discuss the role of precision medicines in their treatment planning. Genomic testing can also be performed on a blood sample.
Currently there are several genomic mutations that can be targeted with precision cancer medicines.
HER2: The HER2 pathway is a biological pathway involved in cellular replication and growth. Precision cancer medicines that target HER2 have made important contributions to improving outcomes among women with HER2-positive breast cancer. Some gastric and esophageal cancers also over express the HER2 protein and are referred to as HER2-positive. Precision cancer medications that block the HER2-protein can be used for the treatment of both early and more advanced stage HER2-positive esophageal cancers.
- Herceptin: The U.S. Food and Drug Administration (FDA) expanded the approval of the anti HER2 therapy Herceptin® (trastuzumab) to include the initial treatment of HER2-positive metastatic cancer of the gastroesophageal junction in combination with chemotherapy based on the results of a Phase III clinical trial. Treatment with Herceptin® improved survival among patients with HER2-positive, advanced and inoperable stomach cancer. Research also suggests that adjuvant therapy with Herceptin may increase overall survival in advanced gastroesophageal cancer compared with chemotherapy alone. (1,2) Several more effective precision cancer medicines targeting HER2 are in development.
- Enhertu(trastuzumab deruxtecan): ADCs are a type of targeted cancer medicine that deliver cytotoxic chemotherapy (“payload”) to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. Enhertu is a smart chemotherapy comprised of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor (DXd) payload by a tetrapeptide linker. It is designed to deliver enhanced cell destruction upon release inside the cell and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered. Treatment with Enhertu results in clinically meaningful improvement in overall survival in patients with HER2-positive advanced gastric or gastroesophageal junction cancer. (5)
NTRK: NTRK fusion proteins are uncommon but if present can be targeted with Larotrectinib and other precision cancer medicines. (3)
Checkpoint Inhibitors: Checkpoint inhibitors are a novel precision cancer immunotherapy medication that helps to restore the body’s immune system in fighting cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD-L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade detection and attack by certain immune cells in the body. A checkpoint inhibitor can block the PD-1 and PD-L1 pathway and enhance the ability of the immune system to fight cancer. By blocking the binding of the PD-L1 ligand these drugs restore an immune cells’ ability to recognize and fight the esophageal cancer cells. A diagnostic test to measure the level of PD-L1 is available. (4)
The “checkpoint inhibitor” Keytruda (pembrolizumab) has significant anti-cancer activity in advanced esophageal cancer patients. Keytruda was initially reported to produce an overall response rate of 30% in patients with PD-L1–positive, advanced esophageal cancer and the Keynote 181 clinical trial confirmed that Keytruda reduces the risk of death by 31% compared to treatment with chemotherapy in patients with esophageal or esophagogastric junction cancer or adenocarcinoma of the esophagus who progressed after initial standard chemotherapy. The FDA approved Keytruda for the treatment of certain patients with advanced esophageal cancer in July 2019.
Epidermal growth factor receptor: A mutation in EGFR occurs in up to 1 in 6 individuals with esophageal cancer. EGFR is involved in cellular growth and replication. Some esophageal cancers produce too much EGFR and this leads to more rapid growth of the cancer. Some medicines specifically target EGFR and the spread of cancer can be reduced or delayed. () Researchers have reported that the anti-EGFR medication Iressa® improved survival in individuals with advanced disease by up to six months, and sometimes beyond. There are several EGFR drugs currently available and all patients with esophageal cancer should make sure they are tested for EGFR, and if positive should discuss how anti-EGFR precision cancer medicines can improve their treatment options.
- Genentech News Release. FDA Approves Herceptin for HER2-positive metastatic stomach cancer. October 20, 2010.
- Bartley A, Washington M, Colasacco C, et al. HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology. DOI: 10.1200/JCO.2016.69.4836 Journal of Clinical Oncology– published online before print November 14, 2016.
- US Food and Drug Administration. FDA approves pembrolizumab for advanced esophageal squamous cell cancer. Updated July 31, 2019. . Accessed July 31, 2019.
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