Liquid Biopsies With Non-Small Cell Lung Cancer

A liquid biopsy, also referred to as rapid plasma genotyping or the "blood test for lung cancer mutations" is a new way to detect genetic changes in lung cancer cells that may respond to treatment with targeted therapies. Traditionally, a tissue biopsy has been required to test for these changes, a process that can be uncomfortable and sometimes lead to complications such as a pneumothorax. In some cases, the location of the tumor or metastases can make a biopsy very challenging. A liquid biopsy allows doctors to draw a blood sample (a simple blood test) to look for the presence of circulating cell free DNA (cfDNA) from the tumor in plasma to guide treatment with targeted therapies.

Though there are advantages and disadvantages to both methods, a 2019 study found that a liquid biopsy was as effective as a tissue biopsy in detecting the presence of all relevant (treatable) mutations and other genetic changes in people with non-small cell lung cancer. This finding was very exciting as the response rate to targeted therapy is higher than that to either chemotherapy or immunotherapy.

First approved in 2016 for detecting EGFR mutations, liquid biopsies are now used to detect a wide range of potentially treatable mutations via next generation sequencing.

Types of Liquid Biopsies

Many people wonder how a blood test could help to monitor cancer, or how the cells get there in the first place. 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 much 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)

CTCs refer to tumor cells that 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 people with small cell lung cancer had CTCs. Evaluation of these CTCs in small cell lung cancer patients appears to have predictive value in estimating overall survival.

Cell-Free (Circulating) Tumor DNA (cfDNA)

Unlike whole tumor cells, that are less commonly found in the blood, these samples may detect fragments of tumor cells that 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 solid tumors other than brain cancer. It was found in tumors of all stages but was more likely to be found with more advanced stages of cancer. The detection of cfDNA is currently the method used when evaluating non-small cell lung cancer.

Tumor RNA in Platelets

Tumor RNA in platelets is discussed less often 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.

Liquid Biopsies and Lung Cancer

Liquid biopsies are now used routinely often in combination with tissue biopsies to assess the presence of targetable genetic changes, but as with many rapidly adopted tests, there has been some controversy, and it's common for the accuracy of liquid biopsies to be questioned relative to tissue biopsies.

Comparison With Tissue Biopsy

A 2018 study published in the Journal of Clinical Oncology found that the results of genetic testing on liquid biopsy specimens correlated closely with results on tissue biopsy with a concordance rate of 56.6 percent. When positive for genetic alterations, the results of a liquid can be used to guide immediate therapy, but if negative, further testing is needed.

If a genomic alterations was detected on liquid biopsy, it was also found and tissue biopsy 89 percent of the time and vice versa. Concerning those people for whom driver mutations were found on liquid biopsy, 96 percent were also found on tissue biopsy leading to treatment with a response in 21.9 percent. A clear advantage to liquid biopsy was that the results were returned in 9 days, vs. 20 days for tissue.

Role in Diagnosis

At the current time, tissue biopsies remain the standard of care in the initial diagnosis of lung cancer and allow pathologists to analyze complete cells within tumors rather than fragments of DNA alone. Along with the initial tissue biopsy sample, however, some oncologists send off both tissue and blood samples (liquid biopsy samples) for genomic sequencing.

In Management

Liquid biopsies have become mainstream in the management of non-small cell lung cancer, and either a liquid biopsy, tissue biopsy, or both may be ordered when a cancer progresses.

It has been hoped that at some time in the future liquid biopsies may be used routinely to detect resistance to a targeted therapy before it can be seen on imaging studies, but we aren't quite there yet (see below).

Liquid Biopsy vs. Conventional Tissue Biopsy

Knowing some of the differences between a liquid biopsy and a conventional tissue biopsy can help people understand the excitement oncologists expressed when this type of biopsy first became available. Differences in these two methods can be broken down into several areas.

Safety and Invasiveness

A liquid biopsy requires a simple blood draw, similar to a blood draw you would have to check a complete blood count.

In contrast, a conventional lung cancer biopsy is an invasive test. Tissue may be obtained via:

  • 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 tissue biopsy techniques all carry the risk of infection, bleeding, the collapse of a lung (pneumothorax) in up to 10 percent to 20 percent of people, and of course, pain.


Tumors in some locations may be difficult to reach to biopsy and some metastases, such as bone metastases, are not ideal for testing.

A liquid biopsy may be particularly advantageous when a tissue biopsy results in insufficient tissue. It is much easier to repeat a blood test than repeat a tissue biopsy.


A liquid biopsy can lead to more rapid results in more than one way. A blood test can be scheduled quickly and easily, with results immediately sent off for testing. In contrast, when performing a tissue biopsy there is often a delay of a few days before the biopsy is scheduled, and when the results are obtained they may not immediately be sent off for testing.

Results from a liquid biopsy may be returned in two weeks or even less, while those from a tissue biopsy make take up to four weeks (for next generation sequencing) depending on how rapidly the sample is sent and where the test is performed.

Tumor Heterogenicity

Another potential advantage of liquid biopsies is with regard 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.

Possible Future Roles of cfDNA

There are two areas of lung cancer management in which cfDNA may play a greater role in the future.

Management: At the current time, regular CT screens are used to monitor for the progression of tumors. In theory, regular blood tests might detect resistance to a targeted therapy (resistance mutations) before evidence of progression is seen on a CT scan. This would theoretically allow physicians to change therapies to an effective therapy as early as possible while avoiding the radiation related to repeated scans. At the time, the cost of repeated blood tests and next-generation sequencing is prohibitive, but will likely be more feasible in the future.

Early Detection: There is also hope that liquid biopsies may someday be used in the early detection of lung cancer, by detecting cfDNA from tumor cells before a tumor is seen (or as a way to replace CT screening). Since small tumors are less likely to result in cfDNA in the blood, this method of screening is a ways off.

A Word From Verywell

The science related to liquid biopsies and genomic sequencing is changing rapidly, making it challenging for oncologists, especially those who treat a wide range of cancers, to stay abreast of the changes. At the same time, there is usually a period of skepticism surrounding new diagnostic tests and therapies. With liquid biopsies offering an easier way to study how cancers change over time, it's expected that change will happen every more rapidly.

With non-small cell lung cancer, especially lung adenocarcinoma it's more important than ever to be your own advocate in your care, to consider getting a second opinion (preferably at one of the National Cancer Institute-designated cancer centers), and to educate yourself on the treatment and management of the disease. An excellent way to stay abreast of the latest research while getting and receiving support from people facing similar challenges is to take an active part in the lung cancer community.

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