Liquid biopsy: the time is even more right!

Dec. 19, 2015

Editor’s note:  Almost one year ago, in the February 2015 issue of MLO, Dr. Arnold and Mr. Trivedi published the article, “Liquid biopsy: the time is right.” We asked them for an update for publication in this issue, and we are pleased to share their response with readers.

Precision therapies that target alterations around the EGFR and ALK gene have radically impacted the way we care for a large subset of lung cancer patients. The movement in personalized medicine is well on the way to transforming many cases of cancer into a relatively manageable chronic disease. However, due to challenges related to obtaining sufficient biopsy material, clinicians who adhere to conventional diagnostics cannot know the molecular status of a large number of their patients with a lung cancer diagnosis. They are not able to monitor the effectiveness of chemotherapy, and they do not have the tools to determine whether the patients are eligible for clinical trials. Liquid biopsy is primed to change that.

Limited tissue availability

Today, there are a number of drug therapies for lung cancer, either on the market or in clinical trials, which require a companion diagnostic test to identify eligible patients. These biomarkers include EGFR, ALK, ROS, BRAF, and PDL-1 for lung cancer patients. The challenge is to identify patients who qualify for these companion therapies when tissue is available in limited abundance. And therein lies the problem: tissue availability is very often limited. Some recent examples:

  • In 2010, the International Working Group on Multidisciplinary Lung Adenocarcinoma Classification estimated that only 57 percent of such biopsies had sufficient tissue for genomic analysis after initial pathology diagnosis and staining.1
  • In the Lung Cancer Mutation Consortium study of 14 U.S. academic centers, one oncogenic driver mutation could be tested in 91 percent of tissue specimens, but the ten desired target gene alterations could only be measured in 66 percent of them.2
  • In a study of advanced breast cancer, yield for molecular testing was only 36 percent for biopsy samples from bone, the most common site of breast cancer metastasis.3

When tissue biopsies have insufficient tumor cell content or are QNS (quantity not sufficient) for genomic analysis, formalin-fixed paraffin embedded (FFPE) material or slides for tissue-based next generation sequencing are often unavailable or unobtainable, or maybe outdated because they no longer reflect the current genomic status of the tumor.

Liquid biopsy as a feasible strategy

It is in this context that interest in the kind of diagnostic now commonly known as “liquid biopsy” has been growing substantially in recent years—and, indeed, during the year since we last addressed readers of MLO. What most recommends liquid biopsy is that it circumvents the problem of tissue availability. A liquid biopsy has the ability to detect solid tumor material from a simple blood draw. This is accomplished by either evaluating circulating tumor cells (CTCs) that are derived from lesions in the body that enter the blood stream or by evaluating circulating tumor DNA, where fragments of DNA from a tumor cell are shed into the blood stream. Either approach can give clinicians the ability to interrogate tumor material that may not otherwise be accessible for analysis. The good news for patients is that it is not an either/or scenario. CTCs and ctDNA can be complementary to one another, and both of these components may allow testing of a patient’s eligibility for targeted therapies.

This technique has generated significant interest and excitement—particularly in the clinical realm. Until recently, evaluating CTCs and ctDNA was seen primarily as an academic endeavor and not something ready for mainstream commercialization. Part of the challenge is that tumor material in the blood might be present only in small quantities when compared to the total genomic content produced by normal blood cell populations. Therefore, effectively capturing and assaying these rare components has been seen as a major obstacle. But recent progress in this area has indicated that tumor cells even in minute proportion can provide a noninvasive, ongoing picture of a patient’s cancer. Clinical oncologists are now using liquid biopsy to gain real-time insight into how best to treat a patient’s cancer.

Lung cancer applications

Lung cancer is one of the diseases that most requires a liquid biopsy approach. According to the National Cancer Institute, it is estimated that 220,000 patients are diagnosed with lung cancer each year, and approximately 20 percent to 25 percent may not have enough tissue to interrogate for one of the many targeted therapies available today.4

The recent approval of Tagrisso (osimertinib), a new treatment option for metastatic lung cancer patients whose tumors have a specific epidermal growth factor receptor (EGFR) mutation (T790M) and whose disease has gotten worse after treatment with other EGFR-blocking therapy, is a case in point. Currently, to qualify for this breakthrough drug, patients would need repeat biopsies as they are progressing on current therapy. That means that the tumor burden has substantially increased, and the performance status of the patient may put them at high risk for side effects and co-morbidities if a repeat biopsy is obtained during a surgical procedure. However, a simple blood draw consisting of 10ML of fluid can identify the presences of the tumor alteration. In this case, a liquid biopsy can address a growing unmet need for patients who need re-biopsies because their cancer is starting to progress as they are not responding to their current therapy.

Liquid biopsy is a drastic change from prior technologies that have been available on the market. But liquid biopsy is not just about counting the amount of tumor material in the blood (enumeration). Although other available systems evaluate and measure intact CTC to give a prognosis of overall survival, the potential predictive value of biomarker analysis on this sample type creates a much larger value proposition for qualifying patients for targeted therapy options. Evaluating biomarkers as “predictors” has the potential to help guide treatment decisions. In a sense, the ultimate potential of a liquid biopsy will allow us to understand specifically what kind of molecular changes are happening in the tumor in real time—a very big step beyond where CTCs are today, clinically.


  1. Rosen S. World Market for Cancer Diagnostics, 5th Edition, Precision and Personalized Medicine Arrives. Kalorama Diagnostics. New York: 2013
  2. Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs.JAMA.2014;311:1998–2006.doi:10. 1001/jama.2014.3741PMID:24846037.
  3. Amir E, Miller N, Geddie W, et al. Prospective study evaluating the impact of tissue confirmation of metastatic disease in patients with breast cancer. J Clin Oncol. 2012;30:587–92.doi:10.1200/JCO.2010.33.5232PMID:22124102
  4. American Cancer Society. What are the key statistics about lung cancer? Accessed December 5, 2015.
Lyle Arnold, PhD, serves as Senior Vice-President of Research & Development and Chief Scientific Officer for Biocept, Inc.
Raaj Trivedi serves as Vice President, Commercial Operations, for Biocept, Inc.