American Pharmaceutical Review, April 2017


The race for the liquid biopsy is on. The industry is still looking ahead to what will undoubtedly be the next big thing in oncology screening, the biopsy blood test.

A liquid option is not only more appealing to patients, allowing those to get screened for cancer on a much more regular basis, but it will also enable those who are affected by the disease to progressively monitor their condition.1

Liquid biopsy options can be coupled with a tissue biopsy, though the ultimate goal of these tests is that they will be able to be used alone, and in a highly accurate way. The hope for liquid biopsy testing is that it will be able to deliver much higher results, and whether predictive or monitoring progress, stand out from the tissue biopsies we currently rely on via their (again, we hope) extreme accuracy.

Blood or Tissue

There is an industry-wide consensus that tissue biopsy extraction is not as efficacious for patient-health as the potential that liquid screening, which is a much less invasive option, offers. According to Guardant Health’s CEO Helmy Eltoukhy, who captured $100 million worth of funding in 2016 for the Guardant360 screening test, “In lung cancer, tissue biopsies cost $14,000 per patient and have a 19% complication rate, which is horrendous,” Eltoukhy expressed. The Guardant360 test, which was based off the results of a 15,000-plus person trial study, seeks out circulating tumor DNA in patient’s blood and is able to pinpoint the genetic mutation that codes for the corresponding cancer. This is where the industry is taking notice - of the genetic mutations that were confirmed in breast, colorectal, lung and other cancers through the Guardant360 test, 94-100% were also present in the patient’s solid tissue, meaning the cancer found in the blood mirrored that in tissue, in a hugely accurate way.2 This rate captures the true promise of replacing tissue biopsy, which is invasive, costly and not without error, with a routine blood test.

Indeed, that is the goal of Guardant, whose Project Lunar will focus on being able to detect five of the most common cancers early on, including breast, lung, ovarian, pancreatic and colon. In cancer in general, but especially in ovarian, lung and pancreatic, early-detection coupled with early treatment would be key to saving lives. “That’s the vision of Guardant,” explained Eltoukhy in the same interview. “An annual blood test at an annual physical examination that protects against cancer.”2

Although there are many players in the blood biopsy space, only Roche’s liquid oncology screening test has passed through the gates of the FDA, gaining approval in June of last year. This test, the Roche Molecular Systems’ cobas® EGFR Mutation Test v2, was the first of its kind to be approved. Again, even the FDA has insinuated that tissue biopsy methods are outdated, and there is an eagerness to approve other blood based tests which can prove their worth. Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health, stated in the press release for the Roche test that, “Approvals of liquid biopsy tests make it possible to deliver highly individualized health care for patients,” he said, continuing, “Liquid biopsies also have the potential to allow physicians to identify patients whose tumors have specific mutations in the least invasive way possible.”3

However, the cobas® EGFR Mutation Test v2 is not the Holy Grail in testing, it is merely the first. The test is inherently limited, as it is primarily used as an aid to see whether a patient has specific NSCLC mutations [exon 19 deletion or exon 21 (L858R) substitution mutations] in their blood. If these mutations are detected, this patient may be a candidate for receiving Tarceva treatment. If the test comes up null and no mutations are found in the blood, then a tumor biopsy must still be performed. Indeed, although the test is promising for what it offers - and what it means in terms of screening approvals - if a patient receives this testing it is likely because they cannot provide a tissue sample due to either not being well enough, or any other reason that a sample is not the primary go-to screening method.3

Limitations to Tissue

Although tissue sampling has been the standard in monitoring for and checking on cancer development and progression, as stated before, there are inherent limitations with tissue collection and one of the main downsides of which is time. As tissue sampling is such a laborintensive process, by the time a sample comes back to the practitioner, the sample might already be outdated. The median time of processing a biopsy sample is approximately 27 days for those who have received treatment and 12 days for those who are newly diagnosed, versus a 3-day turnover when dealing with a blood sample.1 Specialized tests for samples that must be treated more extensively, such as bone or breast tissue pack in extra time, as does any additional testing depending on how the pathologist orders the sample to be treated. Such testing examples include histochemical or immunohistochemical staining, flow cytometry, electron microscopy and genetic tests. A second opinion also embeds additional time into this process.1

Indeed, the tissue itself sampled likely does not tell the full story of the cancer, making all the time spent into analyzing it merely, what we can do, but not the best that we can do. According to a study titled, “Intratumor heterogeneity and branched evolution revealed by multiregion sequencing” pulished by the New England Journal of Medicine, a tissue sample is not indicative of the entire tumor landscape. The study found that 63% to 69% of somatic mutations were not detectable throughout all regions of the tumor. This study concluded that this does present significant challenges, especially for personalized medicine and biomarkers given that it is unlikely that a sample tells the full genetic story of the entire tumor. The study pointed out, “Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples.”4 This “underestimation” can mean the difference between life and death for many, and again indicates that a single sample is far from telling the full story of the cancer. An analysis of this paper indicates that a single biopsy is only capturing 55% of the mutations present on a tumor, with only 34% of those identifiable mutations distributed throughout the tumor.1

Adding insult to injury here is cost. Biopsies are not only invasive; they are expensive and may cause additional health complications for the patient undergoing treatment. Cost varies depending on where the tumor is, but typically reach the thousands of dollars level with, as stated previously, a single biopsy on the lung costing upwards of $14,000.2

How Liquid Biopsy Works

A liquid biopsy on the other hand, carries none of the baggage of surgical procedures. Labor, cost and time are significantly reduced. However, the ability to diagnose the stage of the mutation and track the cancer progression, including possible tumor shrinkage or the treatment response is greatly increased. As the blood drawn is highly specific to the patient, the patient-centricity problem undermined by collecting single tissue samples is seemingly solved.

Liquid biopsies are not limited to the blood, though this is greatly where the research is focused. Urine, saliva or cervical fluid may also be used, as genetic information is also present in these fluids. These biopsies are concentrated on finding the circulating tumor cells (CTC), cell-free circulating DNA (cfDNA), exosomes, extracellular vesicles (EVs) and micro RNA (miRNA), which are more or less present in the blood of those afflicted by cancer.1

CTC is emitted in the blood via tumor shedding, though it is incredibly hard to isolate and does not always indicate genetically cancerous cells. Circulating tumor DNA fragments are shorter in those with cancer and a greater number indicates malignancy. The challenge here is distinguishing the cell-free circulating DNA from the circulating tumor DNA and mutations. However, once ctDNA is analyzed, it can be used to identify the change in a tumor’s DNA and identify a disease early on; the presence of ctDNA can aid in confirming cancer initially and is therefore promising in early detection applications.1

Another option is studying exosomes, specifically in tumor cells. Tumor cells casts off thousands of exosomes, or vesicles, which carry RNA, DNA or protein throughout the body. These become concentrated in plasma and can be tracked from the original cell and used in distinguishing mutations. Exosomes are potentially useful because they can be analyzed and extracted from frozen biofluids. Research is also being devoted to MicroRNAs. MicroRNAs in a healthy individual consists of 22 nucleotides. This number will increase as cancer develops. The presence of tumor associated RNA, including tyrosinase mRNA and telomerase RNA in plasma and serum is an indicator of cancer and can serve as a tumor marker.5

An Open Field for Potential Players

All of this indicates that there is tremendous potential to get involved in liquid biopsy screening across the supply chain; and this is especially true for Contract Research Organizations (CROs). According to the 2017 Nice Insight Preclinical and Clinical Contract Research Survey, 47% of buyers indicate an annual outsourcing expenditure of over $51 million, with only 10% spending less than $10 million on their outsourcing.6 This indicates that there is money to be spent on clinical trials, and especially for a topic as hot as oncology research and development. Again, according to the same survey, 33% of respondents include oncology as their therapeutic area of focus.

This research coupled with a Frost & Sullivan sponsored “2015 Global Survey on Liquid Biopsy Adoption Trends” indicates that the stage is set for the technology, which is only gaining in popularity. According to the survey, reference laboratories “are the most faithful users of liquid biopsy technology” at 32.3%, expected to grow to up to 44.4%. The survey also indicates that 48% of “future users” intend to fully adopt liquid biopsy technology in the near future, with most believing that liquid biopsies will be used in conjunction with tissue samples.7

All in all, the market for liquid biopsy testing is growing and ripe for the taking, it is just a race to see who can get there - not just first - but best. The market is projected to be valued at over $10 billion by 20201 and with so many companies developing their own version of the technology, the first to the finish line will undoubtedly capture a remarkable market share, depending on how thorough the testing might be. There is potential for many firms to enter the liquid biopsy market in a niche way, from the contract research providers to the company who can patent a test for a particular mutation in relation to its corresponding therapy, as in the case of Roche.

As recently as March, OncoCyte announced the success of their 300-person trial in diagnosing lung cancer - these study details will be released at the American Thoracic Society (ATS) gathering in May of 2017. OncoCyte has already disclosed that their liquid biopsy test has confirmed a previous study by the Wistar Institute. In this study, the liquid biopsy had a 90% success rate in detecting malignancies in patients as well as a 62% accuracy rate in detecting benign lung nodules.8

This is just one in a string of examples of companies trying to come out on top in terms of their oncology screening methods. We are on the precipice of these tests becoming routine, within reach, and as easy as drawing blood. From Roche to Guardant to OncoCyte, the market is prime for the taking. The ultimate winner in this scenario will be the patient, more effective methods of cancer screening and diagnostic means prevention and the potential to save millions of lives.

References:

  1. Novella Oncology Liquid Biopsy Whitepaper, http://novellaclinical.com/content/ uploads/2016/09/Novella_Oncology_Liquid-Biopsy_Whitepaper.pdf
  2. http://fortune.com/2016/06/05/asco-guardant-liquid-biopsy/
  3. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm504488.htm
  4. https://www.ncbi.nlm.nih.gov/pubmed/22397650
  5. https://www.ncbi.nlm.nih.gov/pubmed/11708475
  6. 017 Nice Insight Preclinical and Clinical Contract Research Survey
  7. https://ww2.frost.com/news/press-releases/majority-users-identify-therapymonitoring-promising-liquid-biopsy-application/
  8. http://www.fiercebiotech.com/medical-devices/oncocyte-tees-up-for-lung-cancerliquid-biopsy-launch