Precision Medicine—An Evolving Role in Oncology
Recent advances in therapeutics and diagnostics are enabling a more targeted approach to treat an increasing number of cancers.
Dr. Frederick Racke, Medical Director, Hematology/Oncology and Coagulation, Quest Diagnostics, reviews the evolution of cancer treatment and the increasing role played by precision medicine in oncology.
Personalized Medicine in Cancer Care
“In recent decades there has been a tremendous acceleration in the development of new therapeutic approaches for cancer, as well as diagnostics in support of these treatments,” says Dr. Racke. These developments have led to the growing use of a more personalized approach to medicine, and the emergence of precision medicines.
“I view personalized medicine as using an individual’s own characteristics—something related to their genetic makeup, their immunologic makeup, or their tumor’s genetic makeup—to inform the clinician on the best way to treat the patient. Precision medicine then refers to the use of a more targeted therapy: the use of therapies based upon something unique about either the patient or the patient’s tumor to target a particular pathway. The tumor may rely on this pathway for growth and proliferation, but it is not necessarily utilized to a great extent by normal tissue, thereby reducing the toxicities that one encounters with more traditional chemotherapies.”
Pharmacogenetics deals with how certain patient characteristics can influence treatment selection, allowing us to understand how individuals may differ in the ways they metabolize certain drugs. “This difference in metabolism can render the drugs ineffective or in some cases can make them extraordinarily toxic,” notes Dr. Racke.
An example of this relates to the use of tamoxifen for breast cancer treatment. Tamoxifen is a pro-drug, which needs to be converted by cytochrome 450 system enzymes into the active metabolyte. If one does not have the appropriate isoform of this enzyme, patients will be poor metabolizers and derive no benefit from tamoxifen therapy.
There has been a lot of public interest recently in genetic makeup and how it predisposes someone to cancer development—so-called hereditary cancer risk. “We have identified an increasing number of genes that have variations in them that can be deleterious and can lead to different cancer predispositions within families,” says Dr. Racke. “BRCA1 and BRCA2 in relation to hereditary breast and ovarian cancer are obvious examples. For gastrointestinal tumors, Lynch syndrome genes would be examples of predispositions that can warrant increased surveillance with earlier colonoscopies or more frequent colonoscopies to protect patients that are at higher risk for colon cancer.”
Particular mutations in certain tumors can provide distinctive characteristics to that tumor, including a very specific sensitivity to particular drugs. “A good example of this is chronic myelogenous leukemia (CML), which is a pathognomonic molecular lesion characterized by a chromosomal translocation between chromosomes 9 and 22,” notes Dr. Racke. “This leads to a fusion of the BCR gene with the ABL1 gene to create a fusion gene called BCR/ABL1, a protein with abnormal tyrosine kinase activity, which drives the proliferation of cells. This particular lesion is treated with imatinib, which was one of the first targeted therapies, and is remarkably effective in inhibiting the growth of BCR/ABL1 positive CML.
“Different mutations in certain tumors can interact and cause a phenotype. In the chronic myeloproliferative neoplasms, for example, JAK2 is a gene that is commonly mutated in 3 different forms—polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Each of these 3 diseases has a very different clinical behavior and there is some recent evidence showing how the collaboration of a particular secondary mutation interacts with the primary mutation of JAK2 to drive the clinical behavior. This is another way in which the tumor’s genetic composition can drive the biological behavior and determine what the clinical course of the disease is likely to be.”
Immunotherapy is an element of personalized medicine that has gained much attention in recent years. “Immunotherapies are treatments that utilize a patient’s own immune system to fight cancer,” says Dr. Racke. “We all have some inherent anti-tumor immunities that our bodies develop to try to keep us free of cancer but unfortunately cancers frequently escape this immune surveillance. Immunotherapy employs some strategies to help reverse that escape mechanism. One approach uses chimeric antigen receptor (CAR) T cells, engineering a patient’s own T cells to attack a specific element of a patient’s tumor.
“Another category consists of checkpoint inhibitors, which are drugs that target an interaction between PD-1 and PD-L1—PD-1 on activated T cells and PD-L1 on tumor cells. The PD-1 PD-L1 interaction causes anergy of the T cells against the cancer cells and drugs that block that interaction can reestablish anti-tumor immunity. Some checkpoint inhibitors have received FDA approval and are in use for a variety of different tumor types: non-small-cell lung cancer, melanoma, and most recently uroepithelial carcinoma. One of the important aspects of using checkpoint inhibitors is to identify in some cases whether the patient’s tumor expresses PD-L1 to make it a target for these therapies, or whether there are tumor-infiltrating inflammatory cells that express PD-L1 that are involved in this immune escape mechanism that’s being employed by the cancers.”
Testing plays an important role in determining whether a patient is a suitable candidate for an immunotherapy. “These new immune therapies are very expensive so you really want to make sure that patients are likely to respond to them,” says Dr. Racke. “For one of the non-small-cell lung cancer drugs there’s a companion diagnostic, which means there’s a requirement to test for the presence of PD-L1 on the tumor in order to receive the drug.1,2 With the other non-small-cell cancer drug there’s a complementary test, which, although not required for using this drug, certainly informs the clinician of the degree of response a patient is likely to have.3 For example, if patients don’t express PD-L1 on their lung cancer they are only likely to respond as well to the drug as they do to conventional chemotherapy. But if their tumor expresses PD-L1 on say 10% of the cells, then they’re twice as likely to respond. So there is important clinical information that is derived from that kind of complementary test.”
Next-Generation Sequencing and Bioinformatics
Next-generation sequencing (NGS) is advanced testing technology, which allows one to interrogate large panels of genes in a tumor to get a sense of the tumor’s mutational landscape. “This provides a treating oncologist with the most in-depth knowledge of what drugs the patient is likely to respond to,” explains Dr. Racke. “For example, for a patient that has failed conventional guideline recommended therapies, an oncologist can employ one of these larger panels to look for other treatments that the patient may respond to.
“Our own NGS test for solid tumors looks across a broad number of so-called actionable genes. This means that these genes have mutations with which specific therapies are associated. On the one hand, we’re able to identify these potentially targetable or actionable mutations, and on the other hand, by working in partnership with Memorial Sloan Kettering Cancer Center, we can provide a very straightforward clinical annotation for oncologists showing what drugs might work, together with the level of evidence for these drugs. We also provide information on clinical trials that the patient may be eligible for based upon the mutations identified. It is very important to combine bioinformatics capabilities with these advanced testing technologies. We’re looking at millions of pieces of data with any test, so it’s critical we can analyze them and make something understandable out of them to determine their clinical utility—that’s the role of the annotation.
A Positive Outlook
“We’re living in a remarkable time—a sort of renaissance for cancer therapy,” concludes Dr. Racke. “There are a number of very exciting drugs that mandate testing to allow the oncologist to have the right information to know what the best drug is to use in their particular patient. This is a fundamental change in the way that we have handled cancer therapy. In the past, when we would do clinical trials we would try to get tumors of the same type and assess their response to a new therapy in comparison to a current regimen. Now, rather than looking at histologic sub-types, we’re looking at mutations and activation of specific pathways. That’s a fundamental change in the way that we treat cancer.”
1. FDA approves Keytruda for advanced non-small-cell lung cancer. Press Release FDA website. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm465444.htmUpdated 5 October, 2015. Accessed 13June, 2016.
2. List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools). FDA website. http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm Updated 9 June, 2016.
3. Garber K.Predictive biomarkers for checkpoints, first tests approved. Nature.2015. 33; 1217–1218doi:10.1038/nbt1215-1217.Accessed July 13, 2016.
Frederick K. Racke, MD, PhD
Medical Director, Hematology/Oncology and Coagulation,
San Juan Capistrano, CA