Genetic sequencing: UW-OncoPlex at SCCA
A new diagnostic tool called UW-OncoPlex is making a positive difference in the treatments and outcomes of many Seattle Cancer Care Alliance (SCCA) patients. Developed by researchers at UW Medicine, UW-OncoPlex tests a patient’s tumor tissue for the presence of characteristic genetic abnormalities called driver mutations. Each driver mutation causes tumors to behave differently on the molecular level and, thus, have different vulnerabilities.
The UW-OncoPlex panel tests for most of the driver mutations we’ve identified as having a highly effective treatment currently available for use. If your tumor tests positive for a particular mutation, your doctor will know which treatment will likely be most effective for you.
Getting the right treatment as soon as possible greatly increases the odds of beating cancer. It’s easier to get rid of tumors before they’ve grown, multiplied, or spread to other parts of the body.
It’s also a lot easier on you, the patient. The precision of UW-OncoPlex means that doctors can avoid prescribing treatments that are known not to work on cancers caused by specific mutations. This means saving patients from adverse side effects, as well as cycles of hope followed by disappointment.
Diseases targeted and treated
Currently, frequent requests for an UW-OncoPlex assay come from doctors specializing in the diseases listed below.
Melanoma. UW-OncoPlex identifies three primary genes that cause variants of melanoma.
Lung Cancer. Non-small cell lung cancer has four characteristic mutations in the UW-OncoPlex panel. In some cases, the associated drugs have extended patients’ lives by 14 months—a significant improvement for patients with this disease.
Leukemia. Acute myelogenous leukemia (AML) patients are benefitting from comprehensive molecular testing from the UW-OncoPlex panel for disease prognostication to guide individualized treatment.
Sarcoma. Because there are actually more than 60 distinct types of sarcoma, doctors expect significant benefits as the UW-OncoPlex panel grows. Gastrointestinal stromal tumor has seen the most success to date. There is a strong correlation between this cancer, known as GIST, and mutations in two genes in the UW-OncoPlex panel.
How UW-OncoPlex works
Rapid advancements in the power of genetic sequencers, combined with new insights into the workings of cancer on the molecular level, are the key ingredients in SCCA’s diagnostic tool, UW-OncoPlex.
In laboratories around the world, researchers have successfully identified how specific genes operate via molecular pathways. These pathways transmit signals that regulate the cell by activating or suppressing key genes. In one well-known example, the pathway controls cell division. When the governing gene is mutated, the pathway fails to stop cell division when it is complete. The cell keeps replicating itself out of control—and the result is cancer.
Using a variety of techniques, drug developers have learned to disrupt faulty pathways. Some drugs use a monoclonal antibody to block a receptor site; that way, the genes in the nucleus never get the corrupted signal. Other agents neutralize the signals that cancers use to turn off or confuse the body’s natural defenders—T-cells. The re-educated T-cells can then attack and kill the cancer.
UW-OncoPlex represents a significant milestone in the development of Precision Medicine. Until recently, all patients with a particular type of cancer—for example, lymphoma or breast cancer—would most likely be treated with a similar regimen. The initial treatment would be the one with the best odds of success for the patient population as a whole. If the first treatment didn’t work, oncologists would move on to the next best option, again based on the percentages.
UW-OncoPlex introduces a more precise way of choosing the most effective treatment for many patients. By sequencing the DNA of the patient’s tumor, UW-OncoPlex can determine whether a characteristic driver mutation is causing the disease. If so, the oncologist can administer the most effective treatment as the first therapeutic option.
UW-OncoPlex provides numerous benefits. It spares the patient from the physical and emotional wear and tear of undergoing treatment that doesn’t work or, in some cases, may actually be harmful. The time factor is important as well. Cancer left untreated tends to grow, spread, and metastasize to other kinds of tissue. By attacking it with an effective agent right away, there’s a better chance of containing the cancer and forcing it into remission.
This is particularly true in the case of patients with rare forms of cancer or tumor types. If a treatment were known to be effective in only four percent of patients, it traditionally would have been used only as a last resort. But with the availability of UW-OncoPlex, statistics for the entire patient population are irrelevant. What matters is how a patient with a particular genetic variant will respond. This gives doctors a scientific basis for prescribing a “low odds” therapy as the first line of treatment—for individual patients.
In addition, because UW-OncoPlex is a genetic test, the remedies it indicates tend to be small-molecule inhibitor therapies, which work on the biomolecular pathways controlled by a particular gene. Thus, patients whose cancer can be diagnosed with UW-OncoPlex also tend to enjoy the benefits of targeted therapies. These include fewer adverse side effects, because these drugs act on specific sites on tumor cells, leaving normal healthy tissue unaffected.
The only downside is that currently UW-OncoPlex can only identify driver mutations with available treatments for a minority of the cases our doctors see in the clinic. However, the diagnostic power of UW-OncoPlex will continually increase with the growth in both our knowledge of cancer genetics and the number of immunotherapy agents in development.
Naturally, the researchers developing these drugs hoped they would be broadly effective in treating a general type of cancer—be it prostate, breast, or colon cancer. However, doctors noticed that most drugs were quite effective for a minority of patients, and useless or harmful for the rest.
This is where genetic sequencing enters the picture. With the advent of Next Generation Sequencing (NGS) in 2007, it became possible to sequence the genome of individual patients’ tumors. That’s how researchers were able to spot correlations between a mutation in a specific gene and the patient’s likelihood of responding to a particular drug.
NGS refers to the new sequencing technology that replaced Sanger sequencing—the original technique used to sequence the human genome, which took more than a dozen years and cost nearly $3 billion. Today, using NGS, it’s possible to sequence an individual’s genome in approximately one week for a cost of $10,000.
The human genome consists of about 25,000 genes, yet for the purposes of cancer diagnosis and treatment there are only about 200 genes that are currently actionable. That’s why UW-OncoPlex trains its full power on a select panel of genes of interest. As a result, the system provides a rich, deep set of data designed specifically for cancer doctors and their patients.
The future of precision medicine
Dr. Colin Pritchard, one of the key developers of UW-OncoPlex, believes that the test’s diagnostic capability is the beginning of a “paradigm shift in cancer treatment.” He immediately adds the caveat: “We are still in early days of this model.”
The ongoing challenge will be adding more genes to the panel. Technically this is not difficult. The platform is easily scalable.
What’s needed to add more genes to the panel is the identification of more actionable mutations. John Thompson, MD, an SCCA melanoma specialist, points out that researchers have already identified more than 1,000 mutations. But most of these are irrelevant “passenger mutations and not driver mutations,” Dr. Thompson says. “As clinicians, what we want are the driver mutations, the ones that are making the cancer happen and the ones for which we have a treatment.”
Fortunately, this is precisely the type of research that scientists are tackling in laboratories all over the world. Dr. Pritchard says that many clinical trials are now using the presence or absence of a particular mutation as one of the enrollment criteria. “Even if only 10 percent of these drugs actually get FDA approval, that's still going to be a large increase in the number of options that oncologists have to treat their patients with different targeted therapies,” Dr. Pritchard says.
UW-OncoPlex and other multi-marker cancer-sequencing tests are likely to have a big impact on the design of clinical trials in years to come. Renato Martins, MD, MPH, SCCA’s head of outpatient general oncology/hematology points out that the currently known driver mutations for lung cancer are present in only a small percentage of patients—from one to 10 percent. “It will be challenging to support clinical trials for these ever-smaller populations,” Dr. Martins says. “This will likely encourage more cooperation between academic centers, because one single place is not likely to have enough patients with the characteristics needed to complete the trial in a timely fashion.”
Taking this argument a step further, Elihu Estey, MD, a widely respected authority on leukemia, wonders if the current definition of statistical significance will have to be reexamined. He observes that, currently, the standard of care is based on randomized trials with large populations of patients. “One of the interesting things with UW-OncoPlex and other types of Precision Medicine will be how close we can get to certainty,” Dr. Estey says. “Once we’re very close, we won’t need to do randomized trials. I’m not sure we’ll get there in my lifetime, but UW-OncoPlex is an important step in the right direction.”
Dr. Pritchard agrees that time will be needed to bring UW-OncoPlex to its full potential. He believes that most cancers will probably require therapies that hit multiple targets—analogous to how researchers combine multiple drugs to keep human immunodeficiency virus (HIV) under control. “I think SCCA truly is at the forefront of Precision Medicine with this test,” says Dr. Pritchard. “It has already become the standard of care for certain patient populations here. And as we identify more driver mutations with actionable targeted therapies, I believe that, within 15 years, we'll develop highly effective combination treatments that can turn some of the most lethal cancers into chronic diseases. I'm quite optimistic about that.”
UW-OncoPlex is a multi-marker cancer-sequencing test developed by Colin Pritchard, MD, PhD, and his colleagues at UW Medicine’s Department of Laboratory Medicine. The team has many years of experience using genetic sequencing to assay individual genes.
The availability of high-powered Next Generation Sequencing technology, capable of sequencing entire genomes, has enabled the UW-OncoPlex team to build a panel that analyzes hundreds of genes simultaneously for mutations.
Because UW-OncoPlex is primarily a clinical tool, the focus is on actionable driver mutations. That’s why the UW-OncoPlex panel studies only genes with characteristic mutations known to cause cancer variants for which a highly effective therapy is currently available.
As of January 2013, the UW-OncoPlex panel includes 194 genes. This number will increase on a rolling basis, as the system easily scales up to accommodate new targets.
UW-OncoPlex is built on the Illumina platform, which is capable of sequencing an entire genome quickly and affordably. Using specialized techniques, UW-OncoPlex targets its full power on just a small fraction of the genes it is capable of analyzing. The result is a data set that is accurate, deep, and focused.
UW-OncoPlex evaluates entire genes, not just specific sites on genes of interest. This means that, unlike other systems, it is capable of detecting whole gene deletions, duplications, amplifications, and rearrangements. These whole gene mutations are critical for doctors and patients. “The most clinically relevant mutations inconveniently tend to be the ones that are most difficult to detect,” Dr. Pritchard says.
The UW-OncoPlex report includes both data and a detailed interpretative section to help oncologists make and support their diagnoses.
What to expect
Doctors order UW-OncoPlex just as they would any other lab test. Because UW-OncoPlex sequences a tumor’s DNA—not that of the patient’s normal cells—a tissue sample is required. The only exception is for leukemia patients; in this case, DNA is taken from blood or bone marrow samples.
Many patients will already have had surgery and/or biopsies taken prior to the UW-OncoPlex assay. In that case, nothing further may be required. It’s standard practice for labs to preserve your tissue samples; if enough is still available, we can use it to extract your tumor’s DNA. However, if there’s no tissue on file, then you and your doctor will need to discuss the risks and benefits of having a biopsy performed specifically for UW-OncoPlex.
Currently, the turnaround time for your doctor to receive the UW-OncoPlex results is approximately two months.
There is great variability in the odds of identifying a driver mutation in every case. For example, there is one melanoma gene mutation that appears in 50 percent of patients tested. But many cancers are quite rare; some of the more common lung cancer mutations appear in only five percent or less of patients.
If your UW-OncoPlex result is positive, your doctor is likely to recommend the associated treatment that’s documented to be most effective for patients whose disease has the same genetic characteristics as yours. Once you and your SCCA oncologist have discussed the protocol, and the risks and benefits, you can generally get started right away.
The process is only slightly more complicated when investigational drugs are indicated. If a clinical trial is still open and the travel requirements are not too burdensome, then your doctor will help you to enroll. However, when that’s not an option, it’s often possible to obtain the required doses from the manufacturer on the grounds of compassionate use.
The good news is that actionable drugs indicated by UW-OncoPlex have a higher-than-average success rate. That’s because they target a receptive patient population. In addition, immunotherapy drugs that work on molecular pathways have shown a positive track record in terms of persistence. Historically, the prognosis has been good for patients who have responded to immunotherapy agents.
Open configuration options