Trends in Cancer Diagnostics

Improving cancer diagnostics complements efforts to develop novel therapeutics

            Cancer is a difficult disease to cure for a variety of reasons (as discussed in an earlier post). It is a highly dynamic disease involving rapidly evolving tumor cell populations. These tumor cells often possess a diversity of mutations that each require a different targeted treatment. Furthermore, tumors frequently originate from a single cell that divides uncontrollably. In the case of certain cancers (like that of the pancreas), detection often comes too late for effective treatment because symptoms only occur once a tumor reaches a certain size.

            In addition to developing hundreds of targeted cancer therapeutics, the field of oncology has also focused efforts on improving early diagnostic tools. The hope is that better prognostic outcomes will result from detecting cancer in earlier stages, especially before metastasis occurs. Here, I review the principle cancer detection assays currently in clinical use and discuss their advantages and disadvantages.

Phenotype-based diagnostics

            Some diagnostic approaches depend on the phenotype—or the gross morphology—of a tumor or cancer cells. These methods include 1.) diagnostic imaging and 2.) histology.

Diagnostic imaging

            A variety of biological imaging techniques have been developed to identify tumor masses once they have formed (Figure 1).  These include Magnetic Resonance Imaging (MRI), Positron Emission Tomography/Computed Tomography (PET-CT), ultrasound, and X-ray imaging.

Fig1
Figure 1. MRI is a diagnostic imaging method used to identify tumors.
This MRI image of a patient’s head reveals the location of a primary central nervous system lymphoma (high-intensity white areas in the center of the image).
Image credit: Steven Fruitsmaak

The main advantage of these techniques is that physicians typically do not need to have any foreknowledge of the specific location or type of tumor being screened.  Some of these methods can be used to scan the whole body, such as MRIs and PET-CT scan, allowing physicians to effectively assay for metastasis. However, these tests have varying levels of accuracy.  The PET-CT scan is arguably one of the most accurate imaging methods because it involves the use of a radioactive tracer molecule that preferentially accumulates in tumors.

 

            Unfortunately, not all of these imaging methods are as accurate as the PET-CT scan, and they display varying frequencies of false-negatives and false-positives.  Moreover, some of these imaging tests are disadvantageous because they are mutagenic, increasing a patient’s lifetime risk of developing cancer in the future. This includes the radioactive tracer used in PET-CT scans and X-ray-based techniques (such as mammography).  Some of these tests are quite expensive, requiring highly trained staff to administer and interpret the results (Figure 2). They also cannot be performed on all patients.  MRIs, for example, often cannot be used effectively on children or people suffering from claustrophobia because movement in the machine blurs the images. MRIs have decreased effectiveness in patients with metal implants, such as a hip replacement or a pacemaker, because the metal may cause image distortions or heat up/shift in the tissue because of attraction to the magnet in the apparatus. Some patients can even have allergic reactions to contrast agents used for some of the imaging methods like PET-CTs and MRIs.

Fig2
Figure 2. Teleradiology: An emerging trend in cancer diagnostic imaging.
To reduce costs, many hospitals are outsourcing imaging diagnostics as part of the growing field of teleradiology. Image credit: MedIndia

Histology

            Another phenotype-based method for diagnosing cancer is to obtain a piece of the tumor (a biopsy) and examine the cells under light microscopy (histology; Figure 3). The primary advantage of this approach is that it is typically considered the “gold standard” method for diagnosing cancer.

Fig3
Figure 3. Histological analysis of tumor biopsies.
Cancer cells have characteristic morphologies that pathologists assess using histological stains and visualization under a microscope.  This is considered the “gold standard” method for cancer diagnostics.  Image credit: Dr. Wayne LaMorte, Boston University School of Public Health

It enables the physician to stage the diseases by examining, for example, how far into a tissue the cancerous cells have invaded.

            The most obvious disadvantage of biopsy/histology-based cancer diagnostics is that it requires surgical intervention. This can be expensive, especially if a patient does not have medical insurance.  Biopsies increase the risk of surgical complications and of spreading the cancer to other tissues by breaking apart the tumor.  Biopsies also require fore-knowledge of the location of the tumor, which does not permit high-throughput screens for early-stage tumors that are suspected to be hiding somewhere in the body.  Furthermore, biopsies only give a binary diagnostic answer (yes or no). They do not provide information about the mutational heterogeneity of a tumor and, thus, which therapeutic(s) should be prescribed.

Biomarker-based diagnostics

            To overcome many of the disadvantages associated with phenotype-based cancer diagnostics, researchers have been developing methods for identifying cancer using “molecular signatures.” These signatures are composed of biomarkers associated with different types of cancer. Biomarkers include any of the three main biological molecules (DNA, RNA, and protein), in addition to small molecule metabolites (such as volatile organic compounds [VOCs]). These biomarkers are either released by cancer cells themselves or, in the case of metabolites, they are released as a result of altered metabolism in healthy cells. Biomarker assays work by detecting mutations, modifications, or (in the case of metabolites) the simple presence or absence of these biological molecules. Using this information, improved diagnoses, prognoses, and personalized treatments can be delivered to patients.

            To perform a biomarker diagnostic assay, biological samples must be obtained from a patient.  Samples extracted as a biopsy during surgery or during an outpatient procedure are often sent off for biomarker analysis.  Samples can also be obtained through less invasive means. For example, “liquid biopsies” are now feasible, and they can be performed on various biological fluids, such as blood (e.g., GuardantFreenomeGrail), urine (e.g., TrovageneUroSEEK), saliva, cerebrospinal fluid, and pleural secretions.  Companies like Owlstone Medical are even developing technologies for “breath biopsies.”

            Most of biomarker diagnostics work in one of three ways.  Some involve sequencing the DNA or RNA obtained from a biopsy using various next-generation sequencing or genotyping technologies (Figure 4).

Fig4
Figure 4. A list of sequencing- and genotyping-based technologies currently used in cancer detection assays. Modified from Siravegna, et al., 2017: Nature Reviews Clinical Oncology  

Others involve chip-based biosensors. Of these chips, there are three basic designs that allow the detection of minuscule amounts of nucleic acids or proteins. They all involve a “biorecognition” molecule bound to the surface of a material known as the “transducer.”  When the cancer biomarker in the patient’s sample binds the biorecognition molecule, the transducer converts this interaction into a measurable readout: typically, an electrochemical, optical, or mass-based signal (Figure 5).  The third type of assay is used for breath biopsies. It deploys similar technology as alcohol breathalyzers, which measure the mobility of exhaled volatile metabolites using a technique called Ion Mobility Spectrometry (Figure 6).

Fig5
Figure 5. Three types of chip-based biosensors. In these assays, the target biomarker can be a nucleic acid, such as DNA or RNA (left), or it can be a protein, such as a cell membrane receptor (middle) or secreted protein (right).  The target binds to “bait” bound to the chip, which then initiates a response in the transducer. The transducer’s response can be an electrochemical, optical, or mass-based signal, which is read and interpreted by a physician. Image credit: Jayanthi, et al., 2016: Biosensors and Bioelectronics.

 

 

            Ultimately, biomarker diagnostics have a number of key advantages over phenotype-based assays. Many biomarker methods are highly sensitive, allowing the detection of cancers in much earlier stages of the disease. The information they provide gives physicians the opportunity to tailor treatments to each patient: an approach called precision medicine. Given the improvements in next-generating sequencing technologies in recent years, many of the sequencing-based assays in particular are less expensive than others involving surgical procedures or full-body imaging.  Likewise, the ease of obtaining samples for liquid and breath biopsies allows the close monitoring of cancers for mutations, recurrence, or metastasis over time. Many of these biomarker assays can also be readily adapted to test for new cancer biomarkers as we learn more about these diseases.

Fig6
Figure 6. Breath biopsy technology.  Owlstone Medical has developed a technology called Field Asymmetric Ion Mobility Spectrometry (FAIMS), which identifies biomarker metabolites associated with cancer by measuring the speed at which these small molecules move. Image credit: Owlstone Medical

     Unfortunately, biomarker diagnostics do have some downsides.  The first disadvantage is that these methods rely upon our existing knowledge of which biomarkers are associated with different types of cancer.  Some biomarkers may only be associated with a given cancer under certain circumstances, which might be influenced by the patient’s genetics. Furthermore, some biomarkers may not necessarily be cancer-specific if the gene or protein being assayed is also expressed in other tissues where it plays roles in normal physiological processes. Thus, we are limited by our current understanding of cancer biology and an imperfect set of biomarkers currently on hand for assay development.  The second key disadvantage of biomarker-based diagnostics is that these tests do not necessarily yield precise spatial information like imaging methods can.  In a blood biopsy, for example, the physician may only know that mutated DNA or proteins are present. The assay does not necessarily reveal where the cancer is located in the body.

The future of cancer diagnostics

            Going forward, the field of cancer diagnostics should continue to utilize both phenotype-based and biomarker-based assays, since each have their own clinical advantages and limitations.  New innovations in these diagnostic assays, along with the continued development of targeted therapeutics, afford patients the hope that cancer will one day become a chronic, but entirely treatable, condition.

By: Sarah A. Elliott, Ph.D.

 

Featured image credit: Prostate cancer cells, 2017 Nikon Small World Photomicrography Winner, James E. Hayden, FBCA, RBP

 

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