From our collaborators at Johns Hopkins Medicine International | Genetic therapy drives precision cancer care
In this article and video exclusive to Medcan, Dr. Lauring explains the potential of targeted therapies for revolutionizing cancer treatment
There has been a lot of excitement recently about the concept of “personalized” or “precision” medicine, and oncology is one of the fields leading the way in application of these approaches. In its simplest sense, personalized oncology means treating a patient according to the characteristics of his or her unique tumor, rather than as a representative of a type, such as breast cancer. Such an approach has been made possible by a revolution in our understanding of cancer as a genetic disease.
Genomics is transforming outcomes in cancer management
Successive scientific breakthroughs beginning over 50 years ago led to our current recognition that cancer is characterized by the acquisition of mutations in key genes that regulate cell growth and genome integrity. The discovery of commonly mutated “driver” genes, such as HER2 in breast cancer and BCR-ABL in chronic myelogenous leukemia, led directly to highly effective drugs targeting these genes, such as trastuzumab and imatinib. These drugs have transformed outcomes for these diseases, leading to the hope that identifying all of the major cancer driver genes will lead to matched targeted therapies for all patients, perhaps replacing conventional chemotherapy. The first draft sequence of the human genome was only released in 2001, after years of work and several billion dollars. With the advent of newer technologies capable of sequencing an entire human genome in a matter of days for a few thousand dollars, there has been an explosion in our understanding of the detailed landscapes of mutated genes in most cancer types.
Discovery of driver mutations has led to new clinical trial design
One of the exciting things we have discovered is that some of these “actionable” driver mutations are shared across tumor types from different organs. For example, although HER2 alterations were originally described in breast cancer, they are found at a lower frequency in a number of other tumor types, including stomach, colon and lung cancer. Recent reports have shown that patients with HER2-altered non-breast cancers can respond to HER2-targeted drugs approved for breast cancer, like trastuzumab. This key finding that targetable cancer drivers can be shared across tumor types has led to the design of so-called umbrella, or basket, clinical trials, where patients are enrolled not by tumor organ of origin but by a specific molecular alteration. Such trials will be the best way to demonstrate the clinical utility of tumor sequencing and matched targeted therapies as an individualized precision oncology strategy.
DNA sequencing identifies genes suitable for targeted therapy
In just the past few years, academic and commercial laboratories have begun to offer DNA sequencing for individual patients’ tumors. Typically, they will sequence anywhere from 50 to 400 cancer-related genes to identify mutations or other genetic abnormalities. The goal is to identify mutant driver genes that can be targeted for therapy. For some of these driver genes, we have effective FDA-approved targeted therapies, like trastuzumab, which can be an alternative to cytotoxic chemotherapy. Such testing offers the promise of personalizing treatment based on the particular genetic makeup of each individual patient’s cancer.
Precision medicine today: limitations to consider
However, our ability to perform clinical sequencing has rapidly outpaced our knowledge of how to use the information. The evidence that a particular gene can be targeted is often weak or indirect. Assigning therapies based on such evidence is often more appropriate for a clinical trial than for off-label use of medicines, which are typically extremely expensive and often have significant side effects. At Johns Hopkins, we have a molecular tumor board to help oncologists understand the results of tumor sequencing reports and to weigh the evidence for possible matched targeted therapies.
Unfortunately, many of the most commonly mutated genes across all cancers are still untreatable by drugs, and many patients therefore lack a truly actionable mutation. Sometimes these tests raise a red flag that the patient might be a carrier for a heritable mutation in a cancer-predisposing gene, such as BRCA1 or BRCA2. Patients and their physicians need to be aware of the possibility of such surprises and have a plan for what to do with the information.
It is worthwhile to speak to your physician to learn what precision medicine can do for you and what risks and benefits to note. Although there is great promise, you want to be sure that your treating physician is educated and aware of what these tests can and cannot do for you.
In this video, Dr. Josh Lauring provides an overview of the promise and limitations of clinical sequencing and precision cancer care.
Josh Lauring, MD, PhD is the assistant professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. The content was reproduced with permission of the office of Marketing and Communications for Johns Hopkins Medicine International. Additional reuse and reprinting is not allowed. The information aims to educate readers and is not a substitute for consultation with a physician.
