Genetically Informed
Genetically Informed | Personalized Medicine, Genetically Informed, Oncogenes, Oncology, Cancer, Vanderbilt-Ingram Cancer Center, VICC, Vanderbilt University Medical Center, The Sarah Cannon Cancer Center, Sarah Cannon Research Institute, SCRI, Saint Thomas Research Institute, Baptist Hospital, William Pao, John Hainsworth, Karl Rogers, Insight Genetics, Dave Hout, Chris Callaghan, Dan Roden, ALK, PI3K, eMERGE

 Personalizing Oncology Care Plans

Physicians have long recognized that one size does not fit all when it comes to cancer treatments. Decades before the human genome was mapped, physicians had first-hand experience with one group of patients responding beautifully to the standard of care while others didn’t fare nearly as well. Increasingly, physician-scientists are learning why this is true. (See related articles below)

At the most basic level, all tumors are not created equally, and multiple variations are beginning to be recognized within a diagnosis. As the body of knowledge grows about the instigators that turn normal cells rogue, researchers are learning to specifically target those triggers and find ways to shut them off … or at least slow them down. This new approach results in genetically informed cancer treatment plans that are personalized to the specific molecular alterations found within individual tumors.

In Nashville, the major oncology programs all use some form of personalized medicine. Whether adopting the new treatments with targeted agents as they become available or engaging in clinical trial research seeking to inform future treatment options, the city’s healthcare community is taking a lead role in changing the approach to cancer care.

Vanderbilt Expands Personalized Medicine Program to Include New Breast Cancer Test

Recently, Vanderbilt-Ingram Cancer Center (VICC) launched their latest line of mutation testing for breast cancer. Research spearheaded by Carlos Arteaga, MD, professor of Medicine and Cancer Biology and director of the Vanderbilt Breast Cancer Program led to the latest initiative.

“We are screening for a PI3 kinase mutation panel, which includes multiple mutations within a number of genes in the PI3 kinase cancer survival pathway,” he explained. When these mutations are present in the tumor, they super-activate the PI3K pathway, which makes it easier for the cancer to withstand standard therapies and then grow and spread. The mutations occur in more than 30 percent of breast cancers and are more common in tumors that are positive for estrogen receptors or HER2. VICC is currently enrolling patients in several clinical trials for drugs that block the PI3K pathway.


Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center (VICC) are at the national forefront of efforts to move genomic science from bench to bedside. William Pao, MD, PhD, director, Personalized Cancer Medicine at VICC and the Ingram Associate Professor of Cancer Research, was recruited to Nashville to launch the academic institution’s personalized oncology program. When the initiative went live last summer, VICC became the first cancer center in the Southeast and one of the first in the country to routinely offer tumor genotyping to help guide therapy.

“As of July 1, 2010, we’ve been offering multiplex mutational profiling of lung cancers and melanomas in Vanderbilt’s CAP- and CLIA-certified molecular diagnostic laboratories,” he said, adding that breast cancer mutational testing has recently been added to the mix (see box). “Clinicians can use that information to help prioritize treatment.”

For example, he continued, “In lung cancer, if your tumor has a certain EGFR (epidermal growth factor receptor) mutation, you can get Tarceva® (erlotinib) as a first-line treatment instead of chemotherapy.” He added that for these 10 percent of non-small cell lung cancer (NSCLC) patients whose tumors harbor somatic EGFR mutations (most typically with identifiable damage to the tyrosine kinase portion of the receptor), multiple prospective clinical studies have shown a significant statistical difference in progression-free survival, response rate, and quality of life with drugs like Tarceva. “It makes a big difference in terms of lifestyle,” he noted for the subset of patients affected.

Pao added that in large-scale prospective trials for metastatic NSCLC, the overall survival with chemotherapy is 10-12 months. For patients with the EGFR mutation who receive drugs like Tarceva, the average overall survival is 27-30 months. “So we’ve already more than doubled survival in a specific subset of patients, which gives us hope that we can do even better in this subset, as well as other subsets of lung cancer.”

Another exciting development is the very recent FDA approval of Zelboraf™ (vemurafenib) for the treatment of BRAF V600E mutation-positive, metastatic or inoperable melanoma found in about half of all cases of melanoma. On Aug. 17, the FDA gave fast-track approval to the drug by Roche Holdings Ltd. and simultaneously approved Roche’s diagnostic test, cobas 4800 BRAF V600 Mutation Test, to identify patients who might benefit from the therapy.

Pao said Vanderbilt, which began using the drug while it was still in the investigational stage, had recently completed a detailed analysis of 150 patients with melanoma of which 82 had metastatic disease. In that group, more than half (54) had a mutation and 21 of the 54, or just under 40 percent, went into a genotype-driven clinical trial. “In the past, we would have treated all those patients the same way with chemotherapy or immunotherapy,” Pao noted of life before genetic profiling. With the increasing ability to test for such mutations, he continued, “We think it’s helping us make a much more rational decision about how to prioritize treatment.”

In the absence of a genetically-informed approach, oncologists have to use much broader strokes in discussing treatments with patients. “When I’m about to give a patient chemotherapy, I have to say, ‘I don’t know if this will work in you. In about one-third of the patients, it will shrink tumors. In about one-third, there will be no change; and in about one-third, the tumor will actually grow despite the treatment,’” said Pao. “If on the other hand, I can say, ‘In patients with your type of mutation, out of 100 patients 70 will have a tumor shrink within a month of treatment,’ I think they feel more confident with this approach.”

Like Vanderbilt, Sarah Cannon Research Institute (SCRI) has taken an active role in the sea change in how oncologists view personalized cancer care. John Hainsworth, MD, chief scientific officer for SCRI, the clinical research engine of The Sarah Cannon Cancer Center, said clinical trials of various targeted drugs have transitioned tumor profiling from interesting science into actionable information.

He noted that despite being able to recognize certain gene mutations for quite some time, it’s only in the last several years that the knowledge made much real difference to a patient. “What changed is that there started to be drugs that targeted specific mutations. It wasn’t until those drugs were around that it made sense to do routine measurement of all those different molecular abnormalities in tumors.”

While there are still only a handful of FDA-approved drugs, Hainsworth said the field is undoubtedly escalating. Helping move the process along is the SCRI Phase One Unit, which conducts targeted drug development research on potentially useful agents.

“We have between 30 and 40 trials at any given time,” said Hainsworth, adding that typically meant 20-25 new targets being explored, since some of the drugs hit the same target.  “Still, that’s a lot bigger spectrum than you have in practice where there are only a few FDA approved (options).” Like Vanderbilt, SCRI was also involved in trials using the newly-approved vemurafenib for melanoma while it was still in the investigational stage.

He added, “When patients that are candidates for these new drugs, we’re screening them for critical changes or mutations in the tumor itself and using those results to recommend the most appropriate trial.”

Currently, samples are sent to an outside lab, but Hainsworth said SCRI is developing a partnership with a large pathology group to be able to test large panels on site. “Our goal is to have all that up and running certainly within this year.”

Hainsworth continued, “There are probably 50 mutations that are known to be involved in the conversion of normal cells to cancer cells. What we’ll be doing is testing routinely somewhere between 35 and 50 mutations.” He added that this is becoming much more commonplace among large oncology centers and that the impetus to do routine genomic testing will only increase as more targeted drugs become available on the market.

Kathy Taylor, managing director of the Saint Thomas Research Institute, the research arm of Saint Thomas Health, said their oncologists are also changing the approach to cancer treatment through tumor research. “We are working with DiaTech,” said Taylor. “The company has an assay that is very effective in personalizing the treatment for oncology patients. The MiCK assay has the ability to determine which chemotherapy or combination of chemotherapies is going to be most effective for that patient.”

Karl Rogers, MD, a medical oncologist with Nashville Oncology Associates, PC and Baptist Hospital, said, “I think the MiCK assay has primarily two roles. First is to pick the best therapy for patients. With this assay, we can find out if the tumor is even sensitive to selected chemotherapy agents prior to any administration of drugs to the patient. The positive is that the MiCK assay helps guide the oncologist to choose a personalized treatment plan that is most effective in killing tumor cells for each individual patient.”

He continued, “Some tumors are inherently resistant to the types of chemotherapy we would normally use. Patients may have had two to three regimens of chemotherapy with no effect on the tumor. It’s a remarkable find when the tumor is sensitive to something that hasn’t been tried before and then we can select that particular drug and maximize the effects of chemotherapy.”

The second role, Rogers noted, is to minimize the toxicities to patients. “When you have a tumor that is equally sensitive to two or three drugs, we can now select the drug with the least toxicity to minimize the side effects on the patient. One classic example is that of a gentleman with pancreatic cancer whose tumor sensitivity testing indicated insensitivity to the commonly used pancreatic drugs but sensitivity to an alternative regimen. The patient was treated using the results of the MiCK assay and did remarkably well with minimal toxicity and is alive today.”

Taylor said the assay could typically be run off the tissue obtained for a biopsy. “It does appear to be a new wave in the standard of care,” she said of personalized medicine efforts. Taylor added tumor research in conjunction with DiaTech is currently being done on breast, colon and lung tissue. She also said Saint Thomas Research Institute is in the process of setting up a research model at their three metro hospitals — Saint Thomas, Baptist and Middle Tennessee Medical Center — designating a pathologist at each facility as the principal investigator to facilitate the collection of tumor samples and to streamline the process in order to launch it on a broader scale.

As therapeutic agents become more targeted and specialized, the concept of a “blockbuster drug” will likely change. For example, Hainsworth said mutations in anaplastic lymphoma kinase (ALK) that cause it to bind with other genes forming an oncogenic ALK fusion gene have been implicated in about 5 percent of NSCLC patients. Pfizer is currently testing an ALK inhibitor that has demonstrated measurable efficacy in early trials.

Hainsworth doesn’t think other manufacturers will shy away from useful drugs focused on a smaller base population, either. “The thing is if they work well, they’ll be successful because they’ll be broadly used in the target group and used for a long time,’ he said. He added Gleevec® (imatinib), which is used in chronic myelogenous leukemia (CML), is another perfect example of big success in a relatively small pool. Hainsworth said that because it is a rare disease — less than 5,000 people a year are typically diagnosed with CML — the assumption would be that Gleevec wouldn’t have a major impact on manufacturer Novartis’ bottom line. “Turns out it’s a huge drug. It’s given to every CML patient, and every CML patient takes it for years.”

Hainsworth said it is his hope that this is a story that will be repeated over and over as drug development companies and academic centers look to create drugs that specifically target mutations and have a true significance when it comes to median survival rates.

In the end, Pao noted, not everyone will have ‘actionable mutations,’ but knowing that also could impact a patient’s decision about whether or not to pursue treatment. Either way, having information helps put power back in patients’ hands when it comes to working with their medical team to decide what is best for them … and that’s the ultimate meaning of personalized medicine.



Related Article 1

Testing, Testing

Insight Genetics Develops Test for ALK

A spinout of Genetic Assays, a clinical diagnostics services firm, Insight Genetics was established in late 2007 to pursue molecular testing, particularly for cancer.

Initially housed in the CET Life Sciences Center, one of the company’s early advisors has been Stephan W. Morris, MD, an oncologist in the Department of Pathology at St. Jude Children’s Research Hospital, who is internationally recognized as the discoverer and a leading researcher on anaplastic lymphoma kinase (ALK).

“ALK is normally in utero, shortly after birth and  expressed in some neuronal tissues throughout life but is otherwise silent in other tissues of the body,” explained Dave Hout, PhD, director of research and development for Insight Genetics. “If ALK is expressed in an adult in any of its forms in any tissues other than the nervous system — either as full-length ALK or a truncated and fused form — it usually indicates some type of cancer.”

Xalkori® (crizotinib), an ALK inhibitor drug by Pfizer that has shown very robust efficacy in patients with ALK-driven, non-small cell lung cancer and other cancers caused by ALK mutations, has received a fast-track designation for FDA approval and is likely to be approved for use before the end of this year. “Not only is there a need for drugs to target ALK, there is also a need for better diagnostic testing. That’s where we come in,” noted Chris Callaghan, DPA, president and COO of Insight Genetics. It is critical for healthcare providers to determine if their patient’s cancer is caused by a mutation in ALK as opposed to a different gene since ALK inhibitor therapy has little or no effectiveness against tumors caused by mutated genes other than ALK.

“When we first started to work on ALK, there were a couple of tests out there, but they were laborious, costly and unreliable … missing some patients whose tumors were caused by ALK mutations,” said Hout. “We developed a very cost effective, easy-to-use, easy-to-interpret and highly reliable assay to diagnose cancers caused by ALK.”

He added that their test, which detects ALK in a tumor and is able to characterize it, has been internally validated both by Insight Genetics and several CLIA laboratory partners. The company plans to obtain FDA approval for its assay.

Recently, the FDA came out with guidelines calling for companion molecular diagnostics to specifically identify patients whose tumors are most likely to respond to a given therapeutic agent. “Getting to the essence of what’s driving the tumor is important to physicians’ decisions on therapy,” said Callaghan.

“Many tumors are addicted to a particular known oncogene. In lung cancer, approximately 5 percent of cases are caused by ALK mutations and respond to ALK inhibitor therapy,” added Hout.

“And therein lies the opportunity for pharma,” continued Callaghan. “Instead of blockbuster drugs designed to treat all patients with a particular form of cancer, the companies are beginning to focus more on niche buster drugs because such targeted therapies are usually both more effective and safer for patients.”

With a narrower population base, Hout and Callaghan said it would be more important than ever to accurately pre-screen patients through molecular diagnostic testing to ensure that the proper candidates are enrolled in experimental clinical trials to maximize the potential to show efficacy and shorten the time to FDA approval.

In addition to creating tests to diagnose ALK-driven cancers, Insight Genetics also is developing tests that will determine the mechanisms underlying treatment resistance in those patients whose tumors stop responding to ALK inhibitor therapy over time. 

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NIH-Supported eMERGE Network Moves Closer to Tailored Treatments

Vanderbilt Receives Grant Funding

Researchers in the Electronic Medical Records and Genomics (eMERGE) network will receive $25 million over the next four years to demonstrate that patients’ genomic information linked to disease characteristics and symptoms in their electronic medical records can be used to improve their care. The grants are from the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH), which supports research by the network’s seven institutions and coordinating center.

“Our goal is to connect genomic information to high quality data in electronic medical records during the clinical care of patients. This will help us identify the genetic contributions to disease,” said NHGRI Director Eric D. Green, MD, PhD. “We can then equip healthcare workers everywhere with the information and tools that they need to apply genomic knowledge to patient care.”

The first phase of eMERGE, which wrapped up in July, demonstrated that data about disease characteristics in electronic medical records and patient’s genetic information could be used in large genetic studies. Genome-wide association studies represent a powerful approach researchers can use to study hundreds of thousands of genetic variants in people with and without certain health conditions to identify genes that cause or contribute to diseases.

Vanderbilt University Medical Center was among the prestigious list of network members receiving funds. For fiscal year 2011, Dan M. Roden, MD, at Vanderbilt will receive approximately $772,000. In addition, Vanderbilt University will also receive $846,000 in fiscal year 2011 to establish the eMERGE coordinating center for supporting and facilitating the work by network investigators. Jonathan L. Haines, PhD, has been tapped to lead this effort.

For more information about the eMERGE network, please go to