Precision Medicine Is More Than Genomic Sequencing | Health & Medical News | HealAlerts.com
Precision Medicine Is More Than Genomic Sequencing
CORNELL UNIVERSITY| MON OCT 24 16:06:36 EDT 2016
Basing decisions about cancer treatment on mutations and other somatic genomic abnormalities has become a standard of care for patients with some tumors types, but the use of targeted therapies rarely leads to cure, and responses can be incomplete. If clinical decisions are to improve, both mutation data and cell context—the cellular and genomic milieu in which the mutations are found—must be considered.
"Cell context and mutation are the 'evil twins' of cancer," said David G. Huntsman, MD, professor in the Departments of Pathology, Laboratory Medicine, and Obstetrics and Gynecology, University of British Columbia, in a presentation at the recent European Society for Medical Oncology (ESMO) annual meeting in Copenhagen. "Mutation and cell context are the two dominant factors that collude in the development of cancer and shape what a cancer is and how it potentially can be treated."
"We've been focused a little too much on the mutation side of things the past few years because of the excitement around next-generation sequencing, but now we have to rebalance the discussion and consider the cell context as well," Dr Huntsman said, in his lecture titled "One Mutation, Many Cancers."
Understanding how cell context and mutation interplay from the point of tumor origin through development and progression will help predict why some cancers respond to treatment, whereas others have primary resistance to specific therapies, he said. "Once we know that, we'll be able to improve the performance of a lot things we're doing in the clinic."
A good example is the ubiquitous BRAF gene and the prototypical BRAF V600E mutation found in some cancers, Huntsman said, in an interview after the meeting.
"You can't treat all tumors with the common BRAF mutation as being equivalent—targeting that mutation is highly effective in some tumor types and totally useless in others," he said. "Melanomas with the BRAF V600E mutation respond well to treatment with vemurafenib, whereas colorectal carcinomas with the identical mutation do not."
Another aspect of precision medicine that falls outside genomic analysis is signaling pathways that do not necessarily occur by mutations, said Carlos Becerra, MD, the medical director of the Innovative Clinical Trials Center at Baylor University Medical Center in Dallas.
"A cell has the possibility of increasing the pathway to a specific signal in the cell without a mutation, be it by amplification or even by an increase in the traffic of the signaling without amplification or mutation," Dr Becerra said.
"For example, HER2-positive breast cancer patients are given Herceptin® (trastuzumab) to control the tumor, but some HER2-negative patients can respond to treatment with Herceptin even though there's no mutation in the tumor, because it's an increase in the whole pathway," Dr Becerra said. "If our drug goes after only one signaling pathway or only after a mutation that occurs downstream, that's not going to work."
Activating mutations are of principal importance in such tumors as gastrointestinal stromal tumors and chronic myelogenous leukemia with Philadelphia chromosome, but Dr Becerra said these tumors are the exception and not the rule.
"In the majority of tumors, the number of mutations is much higher, and it's not clear what we can target," he said. "In pancreatic cancer, the average tumor has about 60 mutations, but it is estimated that six to eight different drugs are needed to control all of the signaling pathways to control the cancer," he said. "When you give the patient just two or three of those drugs, there can already be too much toxicity."
Dr Becerra said he thinks right now, genetic testing has reached its limit.
"We have to wait for more information to come through in order to be able to better treat our patients."
Mark A. Rubin, MD, a professor of Pathology and Laboratory Medicine and founding director of the Institute for Precision Medicine at Weill Cornell Medical College, agrees that there has been an overemphasis on the genomic component of precision medicine.
"Precision medicine is not just sequencing; it's looking at a patient in the context of their environment, the type of clinical care they're getting, their interaction with their environment, and then the genomic analyses," Rubin said. "The emphasis has to be on a more holistic view of the individual in the context of precision medicine, looking at the tumor genomics, the patient's clinical information, and their environment."
Tumor cells are in a microenvironment of the patient, Dr Rubin said, and that will be reflected in how the patient responds. Immunotherapy is the best example of this, he said, in that tumor cells can affect the surrounding cells so that they don't recognize the tumor cells.
"That's something typical genomics is not capturing, and it's something new tests need to focus on," Dr Rubin said. "When performing genomic sequencing of the tumor, you should look in parallel at surrounding cells and evaluate the cells in the same types of assays, and only then ask which patients' microenvironments are most likely to respond to a checkpoint inhibitor immunotherapy."
Researchers in the phase 2 SHIVA study assessed the efficacy of several targeted agents marketed in France, chosen on the basis of tumor molecular profiling but used outside their indications, in heavily pretreated patients with cancer.
The authors concluded that the use of molecularly targeted agents outside their indications did not improve progression-free survival compared with treatment of physician's choice, and recommended that off-label use of molecularly targeted agents should be discouraged.
A US oncologist disagreed strongly with that assessment.
"Some say the SHIVA trial shows that precision medicine doesn't work—that's just ludicrous," said Maurie Markman, MD, president of Medicine and Science at Cancer Treatment Centers of America in Philadelphia, in an interview. "Anyone who criticizes the concept of precision medicine simply does not understand it."
Markman said that unfortunately, precision medicine is seen by some as being an event: "In other words, at some point in time, one would declare that we have shown that precision medicine works. That is not what it is about; it is a process, and we are increasingly learning about the relevant targets in individual tumors and tumor types."
"That's going to be the future of the cancer care continuum, there is no question about it," he said. "We may not understand the targets—and even if we do understand the targets, we may not have the right drugs—but this is a process, and we will continually move forward. The point of precision medicine is that we are looking at the tumors themselves to try to understand them, and it may be a long time before we have an impact."
Massimo Cristofanilli, MD, an associate director for Precision Medicine and Translational Research at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, said that some people might believe that precision medicine cannot be a solution for a complex disease such as cancer, but he said precision medicine cannot be oversimplified.
"The more we get into the details of understanding the biology of the disease with the various molecular tests, it is clear that it is much more difficult to apply this information to change patient outcome than we believed it was going to be," Dr Cristofanilli said.
"We need to rethink how to design trials to look at the efficacy of these interventions," he said. He pointed to the NCI-MATCH (Molecular Analysis for Therapy Choice) phase 2 precision medicine trial as a good start. NCI-MATCH seeks to determine whether matching certain drugs or drug combinations in patients whose tumors have specific gene abnormalities will effectively treat their cancer, regardless of their cancer type.
Dr Cristofanilli said this is in contrast to some commercially available genomic assays that have been oversold.
"According to the first page of the [commercial assay] report, the test will be 'a solution with one easy approach to precision medicine,' but in fact it is a much more complex situation," he said. "A better approach will be academic institutions with molecular tumor boards with a multidisciplinary approach, and even better will be multiple institutions working together."
"Molecular tests, yes, but in the context of the disease and the therapy for that particular disease," Dr Cristofanilli said.
"We can't abandon pathology for the understanding of where the tumor came from; in the end, precision medicine will surely be a synthesis of the old and the new," Dr Huntsman said in his ESMO lecture. "It is important to know what the mutations and genetic alterations are, but it's also important to know what the cell of origin is and the biological context for those mutations, because you can imagine them having different effects in different tissues."
"Researchers must understand what portion of the tumor cell has the mutation they want to target—that is, whether the mutation is truncal and found in the development of the cancer, or present in some minor subclone," he said. "If the latter is true, it is unlikely this will be a useful target in that cancer, and you'll probably have to target several mutations at the same time to be successful."
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