Molecular Diagnostics

The Era of Personalized Medicine in Cancer

In the 40 years since the Nixon Administration declared the war on cancer, real inroads in terms of improving the burden of the disease have been frustratingly elusive despite an enormous investment in research, considerable gains in knowledge, and some notable treatment successes. Today’s rapid advances in technology coupled with a deeper understanding of cancer biology, however, are set to transform the field and make it one of the most fertile for personalized medicine. This prolific period is leading to new paradigms of cancer drug and biomarker development as new companion diagnostics enter the market, causing hospitals to carefully consider their test menus and policies around genetic and proteomic testing, and emphasizing the role of laboratorians as part of multidisciplinary cancer treatment teams, according to speakers at AACC’s 2011 Annual Meeting in July and other experts.

“More so than ever before, new technologies, both genomic and proteomic, are providing new opportunities for clinical laboratorians and pathologists to join the healthcare delivery team and play an intimate role in patient management. Many of these opportunities are through the practice of personalized medicine that require laboratorians to become clinical consultants, explaining more than traditional lab results,” said Gregory Tsongalis, PhD, director of molecular pathology and co-director of the pharmacogenomics program at Dartmouth-Hitchcock Medical Center in Lebanon, N.H. “The biggest challenges are getting folks out of the lab and back up to the floors or into clinical conferences, and staying up-to-date with the latest advances in these technologies and their applications.” Tsongalis was one of three panelists who spoke on personalized medicine in cancer management during a Full Day Short Course at AACC’s Annual Meeting.

Why Cancer, Why Now?

That cancer has become the poster child for personalized medicine has to do with the confluence of at least four factors, according to Lynda Chin, MD, professor and chair of the department of genomic medicine and scientific director of the Institute for Applied Cancer Science at the University of Texas M.D. Anderson Cancer Center in Houston. “Genomic technologies, especially next-generation or massively parallel sequencing, has really changed the way we can think about genomics, what our study designs can be and how quickly they can be done, and it’s dramatically lowered the cost and increased the throughput of analyzing tumors. We also now have an information technology structure that allows massive amounts of data to be processed and managed,” she observed. “At the same time, there’s an increasing appreciation of the complexity of cancer that is changing how we look at the disease on both technical and conceptual levels. And, very importantly, we have a few good examples of success that have solidified in the community’s mind the power of personalized medicine.”

No More Fishing Expeditions

To most observers, the era of personalized medicine in cancer dates to 1998 when the Food and Drug Administration (FDA) approved the use of trastuzumab in metastatic breast cancer patients whose tumors were human epidermal growth factor receptor (HER) 2-positive. Over the ensuing years, FDA approved both expanded indications for trastuzumab, new drugs, and at least 11 tests that either predict response to specific medications or risk of recurrence in malignancies like non-small cell lung cancer (NSCLC), colon, breast, and gastric cancer, and chronic myelogenous leukemia.The tests, which use methods ranging from immunohistochemistry and fluorescence in situ hybridization to real-time polymerase chain reaction (PCR) and microarrays, identify a host of biochemical changes in cancer, including somatic and inherited mutations, polymorphisms, gene expression, amplification or copy number variations, and protein over-expression, loss, mutations and copy number variations. The good news is these tests are merely the opening act in what promises to be a long-running production coupling ever more sophisticated analysis with specific biological insights to target therapy for individual patients.

“The concept of personalized medicine has been there for a while, but what’s really new in cancer is our ability with molecular profiling techniques to no longer spend a lot of time analyzing individual molecules. With massively parallel sequencing, microRNAs, single nucleotide polymorphism analysis and other techniques, we can compare thousands of molecules simultaneously. That’s improved very much the power of detection of new markers of personalized medicine so that we’re not on a fishing expedition anymore,” said George Yousef MD, PhD, FRCPC, staff surgical pathologist at St. Michael’s Hospital and associate professor of laboratory medicine and pathobiology at the University of Toronto. “We also can look at pathways and crosstalk between molecules and can integrate multiple molecular levels of analysis including genes, proteins, and microRNA in the same setting. The technology’s kept advancing in the last few years, and it’s unbelievable the degree of accuracy, productivity, and speed that we have now.” Yousef co-presented with Tsongalis during the Full Day Short Course on Personalized Medicine in Cancer Management at AACC’s Annual Meeting.

The march of technology has been such that methods are available now to evaluate not only the cancer cells and their byproducts, but also the tumor microenvironment, the patient’s response, and the dynamic interaction between all three (See Figure, below). Indeed, a host of biomarkers that could be useful in cancer treatment have been proposed, but most have not held up in validation studies.

Which Method Will Carry the Day?

Which of the rapid-fire diagnostic advances will hold the most sway in sorting through the complex web of mutation and dysregulation that characterizes cancer? Some experts argue that high-throughput whole genome sequencing holds the greatest potential, while others are more excited about emerging technologies like circulating tumor cell and microRNA analyses. David Sidransky, MD, is in the former camp. “I have to be on the show-me side, and with a few exceptions, signatures like microRNA, methylation, and messenger RNA have been in an acceptable range for testing in terms of price, but haven’t produced many good results in terms of correlative studies,” he contended. “However, advances in sequencing have been so dramatic and at the same time the cost has come down so much. We also believe mutations are such an important part of the cancer process and we know drugs can target certain mutations, that there’s a higher level of enthusiasm for sequencing.” Sidransky is professor of otolaryngology and director of head and neck cancer research at Johns Hopkins University School of Medicine in Baltimore.

In contrast, Tsongalis believes the critical and specific roles microRNA plays in many different cellular processes ultimately could go a long way towards explaining the pathology of cancer and providing targeted therapy for individual patients. “Micro RNAs are small molecules with a big punch. Their size alone gives them a huge advantage over traditional gene expression profiling, as they are less susceptible to degradation,” he explained. “They also have an inherent specificity for cell/tissue type and disease that I have not seen in other biomarkers thus far in my career.”

Still other experts believe that cancer pathology is so complex that only combinations of genetic, metabolomic, and proteomic testing will solve the many mysteries of the disease. “There had been keen enthusiasm that RNA profiling or messenger RNA testing by PCR methods could be used to characterize the best way to treat everyone’s cancer, but that’s kind of played out mostly to a negative,” said Jeffrey Ross, MD, Cyrus Strong Merrill professor and chair of pathology and laboratory medicine at Albany Medical College in Albany, N.Y. “But as we look to the future, next generation sequencing must be combined with testing for other important biomarker pathways and epigenomic changes to enable us to get a good enough picture of the cancer to successfully and efficiently target therapies.” Ross also is interim head of pathology and molecular diagnostics at Foundation Medicine.

Chin believes that as researchers, aided by computational biologists, are better able to distinguish signal from noise inherent in massively parallel sequencing, eventually all the impressive heterogeneity of cancer will not be quite so daunting as it is today. “Systematic multi-dimensional characterization of the cancer genome is uncovering hundreds to even thousands of things wrong in any one tumor, and these errors appear to be random, making it difficult to discern the drivers we would want to develop drugs against. However, I think that once we understand the biology better, we’ll be able to come up with rules for helping us interpret the complex wiring in cancer just like rules in physics. Once we can articulate these rules, we’ll be able to better predict behavior and response to target therapies; however, we’re not anywhere near that now.”

Getting near the point of developing cancer behavior rules will require closer collaboration between different disciplines of cancer research, Chin adds. “The germline and somatic communities have evolved separately without talking to each other; however, as a biologist, I would bet that the behavior of a tumor is not solely dictated by somatic changes in the cancer genome. It’s absolutely going to be influenced by germline susceptibility,” she contended. “So those communities and data need to be integrated in a way they haven’t been before.”

Groundbreaking Drugs and Diagnostics

As the cancer research enterprise charges ahead, two recent developments have buoyed patients, oncologists, and researchers alike about the potential of personalized medicine in cancer. Under its priority review process for drugs that may offer major treatment advances or treatment when no adequate therapy exists, the FDA on August 17 approved Roche’s vemurafenib to treat patients with metastatic or inoperable melanoma whose tumors test positive for the BRAF V600E mutation. FDA coupled approval of the drug with a companion diagnostic, the Roche cobas 4800 BRAF V600 mutation test. In a clinical trial of 675 late-stage melanoma patients with the BRAF V600 mutation who had not previously received treatment, the median survival had not been reached in patients randomized to vemurafenib, versus 8 months in those assigned to dacarbazine, another anti-cancer therapy.

Less than 2 weeks after the vemurafenib approval and also under its priority review process, FDA approved Pfizer’s crizotinib, a drug to treat late-stage NSCLC, along with Abbott’s Vysis ALK Break Apart FISH Probe Kit to detect abnormal anaplastic lymphoma kinase (ALK) gene expression. In two clinical trials involving 255 patients with late-stage, ALK-positive NSCLC, the objective response rate in one trial was 50% with a median response duration of 42 weeks. In the second trial, the objective response rate was 60% with a median response duration of 48 weeks.

A New Drug Development Paradigm

Co-approval of these drugs and diagnostics—the first in which patients were tested for the genes prior to enrollment in clinical trials assessing the drugs—signals a sea-change in how drug companies approach drug development and how FDA views approval of drugs and companion diagnostics. In July FDA issued draft guidance on in vitro companion diagnostic devices clarifying that in instances where a companion diagnostic is essential for the safe and effective use of a therapeutic, the agency should approve both products contemporaneously for the intended use.

Also this year, the Industry Pharmacogenomics Working Group, a voluntary and informal association of pharmaceutical companies engaged in research in the science of pharmacogenomics, issued a white paper on prospective-retrospective biomarker analysis. The group recognized that while prospective development of drugs and biomarkers is ideal, it often is not feasible or even apparent at the start of a discovery process. So the committee proposed a set of conditions for conducting prospective-retrospective analysis along with a decision tree for generating robust scientific data from samples collected from an already completed trial.

This kind of dialogue will be critical as the pharmaceutical industry moves away from general cytotoxic agents to targeted therapies that are effective in much smaller patient populations. For example, only 7% at most of NSCLC patients have the ALK gene abnormality and would be eligible for crizotinib. “Developing drugs is so expensive that the industry can’t afford any longer to take a drug to Phase 1 or 2 clinical trials and find out that it’s not working like they hoped. It’s clear that the biomarker or markers should be embedded in the process very early,” said Dan Theodorescu, MD, PhD, Paul Bunn chair, professor of urology and pharmacology, and director of the University of Colorado Comprehensive Cancer Center. “In my opinion, even Phase 1 trials should be biomarker-driven for patient selection and prediction of response.”

Ross predicts that the pharmaceutical industry will embrace co-development of companion diagnostics and targeted therapies that reach smaller populations because it will not only speed the pace and decrease the risk of drug development, but also enable pharmaceutical manufacturers to realize sizable revenues. “Developing drugs is very expensive, so the pharmaceutical companies want to know what drugs to kill early and get out of the way so the ones that are most likely to work will get all the resources. The way to do that is to have a single or multiple biomarkers of efficacy and toxicity. A lot of these drugs will be financial blockbusters even though they’re only treating a small percentage of patients. That’s because they’ll generally be approved at a fairly high price per dose and patients will stay on them for longer periods of time.”

Labs Vital to Personalized Medicine

Even as the scientific and regulatory ground continues to shift, clinical labs have a vital role in working with clinicians and researchers to evaluate, implement, and make the best use of personalized medicine tests in cancer. Mary-Claire King, PhD, recipient of the Wallace H. Coulter Lectureship Award, and plenary speaker at AACC’s Annual Meeting, challenged laboratorians and AACC to carefully consider how complicated molecular tests will be implemented. “Who’s going to take responsibility for vetting these new tests? I’m really concerned about this class of testing getting into the hands of people who don’t know what they’re doing,” she said. “Competence in carrying out the test is one issue, but another is the quality of the test. I hope your organization will think carefully about the application of very deep sequencing testing tools and how they might best be brought under proper regulation so that they’re useful to patients.” A professor of genome sciences and of medicine at the University of Washington in Seattle, King discovered the BRCA1 gene locus in hereditary breast cancer, and her lab is employing sophisticated molecular analysis to explore the interplay of genetics and environmental factors in breast and ovarian cancer.

Samir Hanash, MD, PhD, urged laboratorians to consider their capabilities, test menus, and policies around the use of molecular diagnostics in cancer. “Are they going to be in a position to do the whole genome every time a patient comes in with a tumor? If the answer is yes, then the question becomes how to do it in a way that meets the requirements for a robust assay used in a clinical setting. If they’re not in a position to do that, and can only run a limited set of assays, then labs need to figure out what this limited set of assays is going to be based on the type of patients they see at their hospital and based on the resources they have available,” he said.

Hanash, who is program head of molecular diagnostics at Fred Hutchinson Cancer Research Center in Seattle, added that many organizations, including his own, are in the middle of this somewhat ill-defined process. “We’re all more-or-less in the same boat trying to figure out how to navigate this. There are no clearly accepted guidelines for determining what type of molecular profiling will provide the most benefit to patients. We’re basically in unchartered territory.”

Yousef also urged labs to take an active role in evaluating technology and deciding which tests and methods to implement. “Laboratorians should be active participants in choosing the tests to be implemented and judging how efficient it will be from different aspects, including the feasibility of the technique. Unfortunately, the current situation often is that the lab just gets a request from a clinician to run a new test and there’s not an organized process to decide which test to do and how to perform them.” The driving principle in this process should be clinical benefit, according to Richard Schlisky, MD, professor of medicine and deputy director of the Comprehensive Cancer Center at the University of Chicago. “The technologies will forever be changing, so from the clinician’s point of view, after the test’s sensitivity, specificity, and analytical validity have been established, the most important question to answer is, what information am I going to get from this test that will enable me to improve the management of my patient?”

Ross suggested that even though many labs may not adopt techniques like massively parallel sequencing, they still will play an important role in the implementation of tests used to personalize cancer therapy. “Most are never going to be personally providing these tests, so it’s going to be a send out. There’s always a tendency in this circumstance to walk away and say, if I’m not doing it, I’m not responsible for it. However, I’d offer that anything that’s used to make a personalized medicine decision on a patient is their responsibility. If it’s not done in their facility, then they’re responsible for the send-out cost, and for figuring out which labs have the best analytical performance and turnaround times.”

Schlisky urged laboratorians and test developers to think carefully about how test results are reported to clinicians. “Oncologists are very busy, they see lots of patients, their patients are complicated, and they like a simple test result that is clearly linked to a specific clinical action. So the best test for many is a binary, positive-negative test. As you get into things like a recurrence score that’s a continuous variable, that’s a little more complicated, but you can still figure it out. What they don’t want is an algorithm they have to figure out, where if this gene is high and another is low, is that a good or bad thing?”

Yousef emphasized laboratorians’ educational role in implementing personalized medicine tests. “Labs need to be active participants on a regular basis in teaching clinicians about the various tests and how they can improve patients’ survival, because the tendency of clinicians is, if they don’t understand a test, to just ignore it.”

A Bright Future

If experts see many challenges ahead in fully realizing personalized medicine in cancer diagnosis and management, they also are quite bullish on the future of the field, Schlisky among them. “I can easily envision a day when patients with cancer show up at their doctor’s office and have a few simple blood tests done that will help the doctor refine their prognosis, select optimal therapy, and get insight into whether their genetic constitution puts them at risk for side-effects from those therapies.”

Randox Molecular Diagnostics (MDx) offers a range of Molecular Arrays and assay formats, providing diagnostic, prognostic and predictive solutions for a range of conditions including colorectal cancer, sexually transmitted disease and respiratory infection, with many more applications currently in development. The versatility of the Randox multiplex PCR and proprietary Biochip Array Technology is exemplified by the broad range of array formats available.

Personalised cancer medicine based on genetic profiling of individual tumours is regarded as the treatment strategy of the future. Evidence now indicates that in addition to KRAS mutational status other molecular alterations such as BRAF and PIK3CA mutations, which can co-occur in a single tumour, could preclude response to anti-EGFR therapy. As such Randox Molecular Diagnostics will be soon launching a rapid assay for the qualitative detection of mutations within KRAS, BRAF and PIK3CA genes from tissue DNA (biopsies or FFPE) to aid in the selection of patients for anti-EGFR therapy.


American Association for Clinical Chemistry

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