Histopathologic image of gastrointestinal stromal tumor of the stomach. Hematoxylin-eosin stain.
The strategy of using targeted therapies to attack tumors has demonstrated signifi cant results in the past decade, and biological markers that help clinicians choose which treatment options to pursue for particular patients are attracting increased research interest.
Here is a summary of 5 key areas in which biomarkers are either already in clinical use or are showing promise as future signposts.
Established Breast Cancer Marker Explored
Human epidermal growth factor receptor 2, also known as HER2/neu (ERBB2), is a receptor tyrosine kinase that helps regulate cell survival and proliferation. Extra copies of the HER2
gene are found in 20% to 25% of breast cancers, and they cause excess production of HER2, prompting tumors to grow faster and recur more frequently. Overexpression of HER2 also occurs in some ovarian, stomach, lung, and uterine cancers.
HER2 bulges outside affected cancer cells rather than hiding inside, making it a good target for drugs. Trastuzumab (Herceptin) binds with HER2, suppressing the HER2
gene, reducing HER2 production, and blocking signaling pathways. The drug, which is being studied for use in other HER2-positive cancers, also promotes immune response, stimulating the body to attack cancers directly.
Another HER2-targeting drug is lapatinib (Tykerb), a dual tyrosine kinase inhibitor that disrupts different cell signaling pathways. Unlike trastuzumab, lapatinib is a small molecule that can cross the blood-brain barrier for cancers that have spread there. It binds to mutated HER2
, where the receptor does not protrude properly from the cell.
Another monoclonal antibody, pertuzumab, which inhibits dimerization of HER2 with other HER receptors, is in advanced clinical trials. Genentech, a member of the Roche Group, recently announced that the pivotal phase III CLEOPATRA trial demonstrated that the combination of pertuzumab and Herceptin plus docetaxel chemotherapy significantly improved progression-free survival compared with Herceptin and docetaxel alone for patients with HER2-positive metastatic breast cancer.
The targeted agents are not likely to be effective against breast cancers that do not exhibit an excess of HER2, nor are they effective in all HER2-positive cases. Patients are screened for potential eligibility through immunohistochemistry and either silver, chromogenic, or fluorescence in situ hybridization. tiny.cc/yfprf
Disease State Linked to Several Genes
Gastrointestinal stromal tumors (GISTs), which are newly diagnosed in 3000 to 6000 people in the United States annually, are associated with several different oncogenes and proteins that can help improve diagnosis and determine treatment for individual patients.
About 85% of all GIST cases can be attributed to 2 types of mutations: a mutation in the KIT gene and a mutation in platelet-derived growth factor receptor alpha (PDGRFα).
Mutations in the KIT
gene, whose protein products are KIT or CD117, are observed more frequently than the PDGRFα mutation, being found in 80% to 85% of all GIST cases. The most common of those mutations generally respond well to treatment with imatinib (Gleevec), though secondary mutations are often spotted after patients develop resistance to that drug.
Mutations in PDGFRα occur in about 5% of all GIST cases. Of the 4 common mutations, only the PDGFRα exon 18 mutation in GIST (D842V) confers lowered responsiveness to standard treatments, most often imatinib.
Mutations in BRAF—a serine/threonine protein kinase involved in cell proliferation, differentiation, and transcriptional regulation—are rare but deadly. They occur in less than 1% of cases but carry an increased risk of malignancy and resistance to existing KIT/PDGFRα tyrosine kinase inhibitors.
For the approximately 10% to 15% of patients whose GIST tumors show no abnormalities in any of these proteins, treatment with sunitinib (Sutent), which is the second-line treatment for most GISTs, has been demonstrated to be effective in 1 of 3 patients who are resistant to imatinib.
Other targeted therapies that have been tested against different types of GIST include sorafenib (Nexavar), nilotinib (Tasigna), and dasatinib (Sprycel). tiny.cc/zeou1