How Liquid Biopsies May Help People With Lung Cancer

Detecting Circulating Tumor Cells and Cell Free DNA

cancer cells breaking away and moving
What is a liquid biopsy and how can these be used to monitor lung cancer?. Istockphoto.com/Stock Photo©vitanovski

* On June 1, 2016, the FDA approved a liquid biopsy test for detecting EGFR mutations in people with non-small cell lung cancer.  This is the first "blood test" approved for evaluating and treating lung cancer.

What is a liquid biopsy? Your oncologist may have mentioned this new method of evaluating lung cancer or you may have heard of this technique while researching your cancer online. What kind of procedure is this, when can it be done, what are the advantages and disadvantages, and where are we headed with this aspect of precision medicine for lung cancer?

What Is a Liquid Biopsy?

You may be familiar with conventional lung cancer biopsies. In order to diagnose a lung cancer, a sample of the tumor is obtained in some way. Then, as treatment proceeds, further biopsies may need to be done to see if the tumor has "evolved"-that is if it has developed new mutations which make it resistant to the current treatment.

Wouldn't it be nice if those traditional biopsies (at least some anyway) could be replaced with a simple blood test? For lung cancer, at least to monitor some people with a specific molecular profile, that wish is becoming a reality.

There is much we don't know when it comes to the potential of liquid biopsies for monitoring lung cancer diagnosis and treatment, but we'll share some of what we know today. 

At present in the United States, all liquid biopsies are considered investigational for the diagnosis and management of lung cancer and should not be used alone to guide diagnosis or treatment monitoring of this type of cancer.

Types of Liquid Biopsies

How could a blood draw help to monitor a cancer? How do the cells get there? It's helpful to begin by talking about exactly what doctors look for in a liquid biopsy (blood) sample from someone with cancer. We know that tumor cells, and more often parts of tumor cells, frequently break off from a tumor and enter the bloodstream.

This doesn't mean that a tumor is metastatic and fragments of cancer cells may appear in the blood in even the earlier stages of cancer. In research thus far, scientists have been looking for one of the following: 

  • Circulating tumor cells (CTCs) - This refers to tumor cells which can be found in the bloodstream of some people with cancer. So far CTCs are more important in cancers other than non-small cell lung cancer and are used primarily for determining the prognosis of those cancers. There is some evidence that CTCs may help with small cell lung cancer and, in one study, 85 percent of patients with small cell lung cancer had CTCs. Evaluation of these CTCs in small cell lung cancer patients appears to be predictive of overall survival.
  • Cell-free (circulating) tumor DNA (ctDNA) - Unlike whole tumor cells which are less commonly found in the blood, these samples may detect fragments of tumor cells which have broken off from a tumor and are shed into the bloodstream. This may occur from either the primary tumor or metastatic tumors. This ctDNA was found in one study to be present in 82 percent of cancer patients with non-brain solid tumors. It was found in tumors of all stages but was more likely to be found with higher stages of cancer.
  • Tumor RNA in platelets - You've probably heard less about tumor RNA in platelets than CTCs and ctDNA, but this is another exciting area under the heading of liquid biopsies. Platelets are known for their ability to take up RNA from tumors and may play a role in the spread of cancer.

Thus far, FDA approval has only been given for the use of CTCs as a measure to estimate prognosis (and now ctDNA to detect EGFR mutations) but the use of ctDNA and tumor RNA in platelets will likely provide more assistance in monitoring cancer as time goes on.

Liquid Biopsy vs. Conventional Tissue Biopsy – Why the Excitement and What Could it Look Like?

You may be wondering why there is so much excitement in the air over the possibility of following some cancers with liquid biopsies. We will list out some possible advantages and disadvantages below, but let's first compare an example of how lung cancer could be monitored and treated with and without the use of these biopsies.

How Could Lung Cancer Management Change at Diagnosis?

Imagine that you are newly diagnosed with non-small cell lung cancer. Ordinarily, the diagnosis is made using conventional lung cancer biopsies with tissue taken by either:

  • A needle biopsy
  • An endobronchial ultrasound and biopsy (a needle inserted into a tumor through a bronchial tube during a bronchoscopy)
  • An open lung biopsy (either a thoracoscopy, in which a lighted instrument is inserted through small holes in the chest, or a thoracotomy, involving an incision through the chest wall to access the lungs)

These current biopsy techniques all carry the risk of infection, bleeding, the collapse of a lung (pneumothorax), and of course pain.

Once the tissue is obtained, it is sent for the pathologist to look at under the microscope and also for special tests looking for specific genetic abnormalities in the tumor cells. This gene (or molecular) profiling often takes several weeks (often five to six) before results are available. If a genetic abnormality (such as an EGFR mutation) is found, treatment can be started with a targeted drug, such as the tyrosine kinase inhibitor Tarceva (erlotinib.)

With a liquid biopsy technique, instead of doing an invasive biopsy such as a needle biopsy to obtain tissue for gene profiling (specifically gene mutation testing for the two mutations the test can currently test for), a simple blood draw could be done - a much less invasive test. And instead of waiting weeks for the results, rapid plasma genotyping could give results in around three days. So at the time of diagnosis, patients with an EGFR mutation could have the mutation discovered not only through a much less invasive test but could be started on a therapy to address that mutation in just a few days. (We are not yet there with the technology to "find" other genetic abnormalities such as ALK rearrangements and ROS1 rearrangements.)

How Could Monitoring Lung Cancer Change?

Even more exciting perhaps is the potential for using liquid biopsies to monitor people who are already being treated with a medication targeting an EGFR mutation.

At this time, once someone is started on an EGFR inhibitor such as Tarceva, the course of their disease is monitored by doing periodic CT scans to watch the growth of the tumor. We know that virtually every tumor will develop resistance to these drugs in time, but that period of time varies considerably between different people. How can you know when that time has come? Traditionally, we learn that at tumor has developed resistance when a scan (such as a CT scan or PET scan) shows that the tumor has begun to grow again. Most of the time (unless symptoms suggest a cancer is worsening) patients learn that their medication has stopped working when they receive the results of a scan which shows a tumor growing again.

At that time, the medication is stopped and people are again faced with doing another biopsy to evaluate the tumor to look for the changes which made it resistant. As noted above, conventional lung biopsies carry the risks of a more invasive procedure, and again, it takes weeks without treatment to know the results and understand where to go next.

In contrast, with a liquid biopsy done periodically, doctors would be able to tell much sooner if a tumor has become resistant to a medication. It's been found in studies that these changes show up in ctDNA long before changes related to resistance show up on a CT scan. During this period of time - between when a blood test shows resistance and it is found on a CT scan - people would be using a medication which is no longer effective and coping with side effects of a drug which isn't needed. It also means a longer period of time before they could be switched to an effective therapy.

With the liquid biopsy results showing resistance, the tumor sample (from a liquid biopsy) could be evaluated and the patient could then be changed to a next generation medication targeting that gene mutation or possibly another type of therapy, such as chemotherapy or immunotherapy.

Tumor Heterogenicity and Liquid Biopsies

Another potential advantage that a liquid biopsy could have over a conventional lung cancer biopsy is related to tumor heterogenicity. We know that lung cancers are heterogeneous, meaning that different parts of the tumor (and especially different tumors such as the primary tumor and a metastasis) may be somewhat different in their molecular characteristics. For example, a mutation present in cancer cells in one part of the tumor may not be present in cells in another part of the tumor. To understand this, it's helpful to realize that cancers are continually changing, developing new characteristics and mutations.

A conventional biopsy is limited in that it samples only one specific area of tissue. A liquid biopsy, in contrast, may be more likely to reflect the characteristics of the tumor as a whole. This has already been seen in studies, in which an actionable driver mutation may be detected by a liquid biopsy that would otherwise be missed on a tissue biopsy.

Advantages of Liquid Biopsy Over Conventional Biopsy

To truly understand the excitement, but also the possible limitations of liquid biopsy sampling, it can help to list out some of the possible advantages and disadvantages of the procedure.

  • The results of a liquid biopsy are closer to "real time." In other words, they may allow for earlier evaluation of efficacy and resistance of a tumor during treatment. When a tissue biopsy is done, results of molecular profiling (gene profiling) on the tumor usually requires several weeks (often five to six) whereas gene mutation testing on a liquid biopsy specimen takes only around three days. This is time during which specific treatment could be used or during which a next generation targeted drug could be used if the tumor is found to be resistant. 
  • The liquid biopsy procedure itself is more rapid than a conventional biopsy.
  • Liquid biopsies are less invasive.
  • Some tumors are in areas which are difficult to access in order to do a conventional tissue biopsy.
  • Some tumors and metastases are not ideal samples for doing gene profiling - for example, bone metastases
  • Liquid biopsies allow for tumor heterogenicity. As noted above, most tumors are heterogeneous. A liquid biopsy may be able to give samples more likely to represent the tumor as a whole in contrast to a conventional biopsy sample which would be representative only of the cells in that particular part of the tumor.
  • It's likely that liquid biopsy techniques will eventually be less expensive than conventional biopsies.
  • Liquid biopsies carry a lower risk of complications than those of conventional biopsy techniques, such as the risk of infection, bleeding, and collapse of a lung (pneumothorax.) These complications not only reduce quality of life but can result in treatment delays as well (and the consequences of delays could mean tumor progression.)
  • Liquid biopsies are less painful.
  • If a biopsy needs to be repeated due to insufficient tissue, it is much easier to repeat a blood draw than redo a conventional biopsy.
  • Advancement of the science of cancer. By observing the results of liquid biopsies done more frequently over time, researchers can learn more about how tumors change genetically over time.
  • Liquid biopsies may pick up mutations that are missed on tissue sampling.
  • Liquid biopsies - if they detect resistance sooner - could help spare unnecessary treatment (and any side effects that go with that treatment) while maximizing the amount of time someone is using effective treatment.
  • Liquid biopsies could theoretically decrease the amount of radiation given due to the current need for frequent scans to monitor progress.  

Disadvantages of Liquid Biopsy

At this time, there is much to learn about liquid biopsies.They are also currently limited to detecting gene mutations such as those in EGFR (although there's talk that they may soon be able to be used to detect translocations and other changes.) In most types of lung cancer, the circulation of cancer cells or cancer DNA occurs only in a relatively small proportion of lung cancers and is influenced by the type and stage of the cancer.  A negative result from a liquid biopsy does not mean that cancer is not present in the body.

Current Status of Liquid Biopsies for Lung Cancer

Liquid biopsies are being used primarily for research in the United States, although some oncologists are using these to detect or monitor patients with EGFR mutations.  That said, a liquid biopsy test - the first test of its kind for lung cancer - was approved on June 1, 2016, for evaluating EGFR mutations in patients with non-small cell lung cancer.  

At least one major cancer center is now offering the test along with rapid plasma genotyping for all patients with non-small cell lung cancer either at the time of diagnosis or after a relapse/recurrence of lung cancer.

In Europe, they are currently being used for people with non-small cell lung cancer to evaluate for EGFR mutations and are considered necessary to determine if people are candidates for treatment with a tyrosine kinase inhibitor.

What's Holding Us Back?

It can be confusing when learning about liquid biopsies, as to why this technique is not yet done widely. What we don't yet know is how well liquid biopsies will fulfill two requirements: accuracy and reliability. It has to be determined that liquid biopsies can provide the same information (or better) than tissue biopsies and consistently deliver that information.

The Future

It's hard to know exactly what the potential of liquid biopsies is at this stage of the research since they are so new. Eventually, it's hoped that the technique will aid not only in estimating prognosis and monitoring for resistance but as a screening tool for the detection of cancer - though that is still a ways off. One way or another, it is an exciting aspect of cancer research in the era of precision medicine.

Sources:

Bettegowda, C., Sausen, M., Leary, R. et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Science Translational Medicine

Imamura, F., Uchida, J., Kukita, Y. et al. Monitoring of treatment responses and clonal evolution of tumor cells by circulating tumor DNA of heterogeneous mutant EGFR genes in lung cancer. Lung Cancer. 2016. 94:68-73.

Jiang, T., Ren, S., and C. Zhou. Role of circulating-tumor DNA analysis in non-small cell lung cancer. Lung Cancer. 2015. 90(2):128-34.

Karachaliou, N., Mayo-de-las-Casas, C., Molina-Vila, M. et al. Real-time liquid biopsies become a reality in cancer treatment. Annals of Translational Medicine. 2015. 3(3):36.

Mahaswaran, S., Sequist, L., Nagrath, S. et al. Detection of mutations in EGFR in circulating lung-cancer cells. The New England Journal of Medicine. 2008. 359(4):366-77.

Sacher, A., Paweletz, C., Dahlberg, S. et al. Prospective Validation of Rapid Plasma Genotyping for the Detection of EGFR and KRAS Mutations in Advanced Lung Cancer. JAMA Oncology. Published online April 7, 2016.

Santarpia, M., Karachaliou, N., Gonzalez-Cao, M. et al. Feasibility of cell-free circulating tumor DNA testing for lung cancer. Biomarkers in Medicine. 2016. 10(4):417-30.

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