Jeffrey S. Buguliskis Ph.D. Technical Editor Genetic Engineering & Biotechnology News
Predictive Diagnostic Tests Are Continuing To Advance Through The Use Of Novel Techniques and Cutting-Edge Technology
On a cold December day in 1971, Richard M. Nixon, the 37th president of the United States, signed a bill in front of a packed White House room and proclaimed that it was “an early Christmas present for the American people.”
That bill was The National Cancer Act. Outlined in the document were plans to create a new research infrastructure with enormous resources devoted to fighting the disease. The media quickly dubbed it “Nixon’s War on Cancer.”
However, Nixon was initially reluctant to partition money into a large public health bill and, in fact, originally planned to cut the budget for cancer research. Yet, with continued pressure, especially from individuals such as health activist and philanthropist Mary Lasker and her eponymous foundation, President Nixon made his case in front of the American people during his January 1971 State-of-the-Union Address.
“The time has come in America when the same kind of concentrated effort that split the atom and took man to the moon should be turned toward conquering this dread disease,” President Nixon declared. “Let us make a total national commitment to achieve this goal.”
Brimming with jubilation from having put two men on the moon just a few years earlier, political bluster knew few boundaries, and many pontificated about cancer’s cure by the time the bicentennial had rolled around. Now, more than 45 years later, the public continues to ask where the cure is and what is to show for the money that has been spent.
An Ounce of Prevention
By 2005, the war on cancer looked as though it was ready to raise the white flag—at least within the court of public opinion. Estimates had the National Cancer Institute (NCI) spending $105 billion in the 40 years since its inception while the overall death rate for cancer had only dropped 5% since 1950. By way of comparison, in the same time frame, heart disease death rates dropped 64%, and deaths from lung and bronchial illnesses such as pneumonia and influenza fell 58%.
However, just five years later, new data began to tell a different story, showing that death rates were 11% lower for men and 6% lower for women since the signing of the National Cancer Act. Certainly there were a number of reasons why deaths from cancer have been on a steady, albeit slow, decline over the past several decades, but the sharpest drop uncoincidentally coincides with the rise of genomic-based screening, which has become dramatically more affordable and clinically accessible.
“It is clear that better survival is associated with early detection when the cancer is at stage I or II, and surgical procedures can intervene,” says Graham Lidgard, Ph.D., CSO and svp of R&D at Exact Sciences. “The cancers that have screening programs have shown the most improvement in survival are cervical cancer, breast cancer, and colon cancer.”
Preventive medicine is inherent in the rationale that has thus far led to noticeable declines in cancer mortality rates. This approach requires a fundamental understanding of the underlying mechanisms of cancer. Conversely, early detection can be ignorant of the cause or development of the disease, and merely necessitates the employment of a particular method that correlates with the disease state. These two approaches are not mutually exclusive, however, and are often combined toward comprehensive healthcare strategies.
“We are already starting to see significant improvements in the early diagnosis field, and improvements in matching types of cancer to therapy,” Dr. Lidgard, states. “Early data from research suggests that we may be able to treat based on molecular information instead of the original cancer site.”
Traditionally, most early detection methods have utilized some form of imaging and/or measurement of a metabolic analyte. Over the past several years, the sensitivity of these techniques has exponentially improved and, due to advances in genomics, proteomics, and microfluidics, an entirely new range of predictive tests and biomarkers have emerged.
A Pound of Prediction
A generation of predictive markers has materialized by casting a wide net across the whole of cancer biology through the use of genome-wide association studies, transcriptomics, proteomics, and metabolomics. These fields attempt to capture large amounts of DNA, RNA, proteins, and metabolites from target organisms, with the hope that some subtle but critical information can be teased out of the minutiae. To follow this course of action efficiently, researchers are always on the hunt for ways to improve the manipulation and analysis of genomic sequences.
Within the past several years massive parallel sequencing, commonly referred to as next-generation sequencing (NGS), has begun to rapidly transition from its primary role as a purely analytical laboratory technique to an invaluable part of diagnostic clinical medicine. Decreases in equipment and technology costs, combined with dramatic increases in output speeds have allowed for the democratization of NGS, which is an essential step toward full integration with personalized medicine objectives.
“NGS continues to deliver new information as technology is constantly evolving and improving,” says Rita Shaknovich, M.D., Ph.D., group medical director and vp of hematopathology at Cancer Genetics. “This allows for significant advancements in predictive NGS-based cancer diagnostics through improved understanding and interpretation of test results.”
However, NGS is only as good as the biomarkers that have been identified to predict the probability of acquiring cancer. BRCA1 and BRCA2 are two quintessential examples of predictive diagnostic markers, as mutations in either of these genes increase a woman’s risk of developing breast cancer by 45-65% and ovarian cancer by 17-39%. Since their initial discovery almost two decades ago, the number of predictive biomarkers has grown exponentially. Furthermore, BRCA 1 and 2 mutations have shown to be associated risk factors for several other tumor types such as pancreatic and non-small cell lung cancer.
Extensive cancer studies and databases have been able to mine the genomes of thousands of patients searching for genes that contain single point mutations, called polymorphisms that are more prevalent in cancer patients. Though this approach has proved immensely successful in identifying new biomarkers, oncologists are always searching for faster more accurate diagnostic tests.
More recently, the use of circulating microRNAs (miRNAs) as a predictive tool have garnered a lot of attention due to their low cost, high stability, increased abundance, and minimal invasiveness. miRNAs are small pieces of non-coding RNA (roughly 20-22 nucleotides in length) that typically function as gene silencers and post-translational regulators of gene expression.
Previous evidence has found that levels of miRNAs increase within cancer cells and eventually make their way out to the systemic circulation. Since they are bound to proteins, miRNAs are highly resistant to degradation and can survive extended periods of time, which is a highly valued characteristic for molecular diagnostics.
One example where miRNAs are starting to gain real ground and are poised to be utilized as a clinical tool is for prostate cancer (PC). While the prostate specific antigen (PSA) protein marker is the current gold standard for diagnosing these tumors in males, the test suffers from a high rate false-positive and negative results, due to its low sensitivity.
Conversely, since isolated miRNAs signals can be amplified by techniques such as qPCR, this gives them a sensitivity and cost advantage over protein biomarkers like PSA. Moreover, recent studies found that a panel of five miRNAs was able to distinguish between PC and benign prostate hyperplasia—making them ideal for use as early cancer detection tools.
The Answer, My Friend, Is Flowing in the Blood
Having the ability to noninvasively detect metastatic disease before it has a chance to take hold within another organ of a cancer patient almost seems like science fiction. Yet, scientists and clinical researchers have developed liquid biopsies that are able to capture circulating tumor cells (CTCs). Identifying these cells are of extreme clinical value as they are thought to be the cause of metastatic cancer.
“I believe that the new technology on the horizon is the use of a blood test to secure cancer cells for analysis and from that analysis make therapy selections to determine which drug will be most effective for each patient,” explains Andrew Newland, founder and chief executive of Angle, a U.K.-based medical diagnostics company. “There are a lot of new targeted drugs, such as immunotherapies that can work well but only for a proportion of patients, about 30 or 40 percent, and you need to know which ones.”
Angle has developed a simple system for capturing and enriching CTCs from a patient’s blood sample for further analysis and identification. In collaborations with research groups from USC and the University of Vienna, the Angle system has aided investigators studying ovarian and metastatic breast cancers.
“What we have is a system so sensitive that a woman who didn’t even have any symptoms whatsoever, was able to predict her cancer,” stated Newland, referring to a particular case through the collaboration at the University of Vienna. “What we hope for over time is that this will translate into the ability for earlier detection of cancers.”
Being able to discern the right treatment or diagnose the appropriate disease is paramount to quality patient care. Whether it be through the isolation of genetic material or free-roaming cancer cells, the development of new microfluidic devices or the use of the old standby PCR machine, the future of successful cancer therapy, and by extension precision medicine, lies at the proverbial feet of predictive diagnostics.
This article was originally published in the October 2015 issue of Clinical OMICs. For more content like this and details on how to get a free subscription to this digital publication, go to www.clinicalomics.com.