Constantine:Liquid Biopsy for Cancer Treatment

Based on the DC comic, ‘Hell-Blazer’, the 2009 film ‘Constantine’ tells the life story of John Constantine (Keanu Reeves) who was born with a gift- or as he calls it a ‘curse’. As a suicide survivor, he is haunted by his horrific memory spent in Hell when he is pronounced dead for a full 2 minutes, gives Constantine his current ambition to use this supernatural ‘talent’ to hunt down demons and earn his spot in Heaven. Having smoked 2 packs of cigarettes since the age of 15, Constantine discovers that he has less time on earth than he thought. It is without a doubt that if current breakthroughs in cancer treatment with liquid biopsies, that our protagonist would have more time to earn his way into God’s good graces and ultimately into Heaven.

INTRODUCTION:

Over a century has passed since the discovery that tumors shed molecules and cells into the fluids throughout the body. Even more recently, it was discovered that analyzing these very same molecules and cells reveal similar information that tissue biopsies have given to the world. Researchers from diverse backgrounds have worked relentlessly to develop, refine, and establish clinical uses for liquid biopsy tests. [A]

These dedicated individuals have been continually exploring new approaches to enhance the benefits of current cancer treatments. One of these approaches has been focused on enhancing the main form of treatment-using just tissue biopsies. This procedure is known as ‘liquid biopsy’. It relies on analyzing bits of tumor material (molecules and whole cells) found in circulating blood, various body fluids, urine, cerebrospinal fluid, and or even saliva. These liquid biopsy tests analyze the many and various types of tumor material like DNA, RNA, proteins, exosomes, and whole cells. [A]

Majority of bodily fluids are easy to access and are therefore the most common procedure for collecting sample(s). This key feature makes liquid biopsies our greatest weapon in treatment of cancer as it can be used in various important applications where with tissue biopsies it would be much more difficult to conduct. Liquid biopsies are being used to monitor cancer development, track an individual’s response to treatment, or serve as a form of surveillance method for those who have completed their treatment but remain at high risk of their disease returning. [A]

 

 

Majority of bodily fluids are easy to access and are therefore the most common procedure for collecting sample(s). This key feature makes liquid biopsies our greatest weapon in treatment of cancer as it can be used in various important applications where with tissue biopsies it would be much more difficult to conduct. Liquid biopsies are being used to monitor cancer development, track an individual’s response to treatment, or serve as a form of surveillance method for those who have completed their treatment but remain at high risk of their disease returning. [A]

Increasing treatment options for patients increases their chances of winning the battle against cancer. It is studies such as these where scientists make discoveries that lead to more precise robust analysis of circulating molecules, cells, and everything in between. The recent observations that have been made is dictating the variety of technology emerging and exciting clinical potential for liquid biopsy approaches. [A]

Routine pre-screening processes should include liquid biopsy tests for people visiting their primary care physician. This minor yet pivotal addition can detect early-stage cancer and possibly save countless lives. There are high risk individuals who were born with hereditary cancer syndromes and will most likely have no conscious awareness of this until it is too late. The hope for the future is to use liquid biopsy tests along with existing technology to help detect and personalize treatment to the road of recovery.

BACKGROUND INFORMATION:

When a patient has a suspicious lump or symptoms, one of the first things a physician may do is perform what is known as a ‘tissue biopsy’. This procedure collects cells from the body for closer inspection. Examining the appearance of the cells under the microscope can determine A) presence or absence of cancer, B) the type of cancer detected, and C) give physicians the necessary clues for a starting point in constructing a patient’s prognosis. Tumors release pieces of DNA into the bloodstream that can be analyzed to obtain important information that may inform patient care. The molecular analysis of a tissue biopsy can give physicians the necessary information to create personalized treatment for each unique potential cancer patient.

Most cancer types have unknown specific DNA mutations and/or well-established biomarkers that allow scientists to identify then track the disease with ctDNA. Many studies use liquid biopsy tests to detect ctDNA in samples of blood collected from patient’s months before they were diagnosed with cancer by traditional methods, like imaging techniques. But, just because ctDNA is in the blood, this does not always mean that this ctDNA represents the DNA from the tumor.

Tumors are heterogeneous, meaning that their DNA mutations vary between cancer cells in a tumor. Even when diagnosing the same cancer type, DNA mutations in cancer patients vary case by case. This makes identifying ctDNA biomarkers incredibly difficult to treat let alone cure. It is unknown whether ctDNA is released from the whole tumor or only certain parts of it.

Typically, biomarkers are used to track advanced pancreatic cancer, but they are considered unreliable for early detection. The technology for detecting ctDNA in body fluids has improved dramatically, but the understanding and knowledge needed to identify the appropriate biomarkers of numerous forms of cancer have not.The earlier the detection the more successful a patients’ outcome, but tissue biopsy tests are very difficult for patients.

These tests are invasive, high risk, and painful. The process involves a large needle, known as an ‘endoscope’ and in some cases, open surgery is also needed. Then there are those cases in which patients cannot even have a tissue biopsy performed on them because of the location of the tumor(s) and/or other health conditions. Unfortunately for cancer patients today, this is the most effective approach modern science has in the detection and method in obtaining information about cancer.

 “John Constantine: Detective. What if I told you that God and the devil made a wager, a kind of standing bet for the souls of all mankind?

Angela Dodson: I'd tell you to stay on your meds.

John Constantine: Humor me. No direct contact with humans. That would be the rule. Just influence. See who would win.

Angela Dodson: Okay, I'm humoring you. Why?

John Constantine: Who knows. Maybe just for the fun of it. No telling.

Angela Dodson: Oh, so it's fun? It's fun when a man beats his wife to death? It's fun when a mother drowns her own baby? And you think the devil is responsible? People are evil, Mr. Constantine. People.

John Constantine: You're right. We're born capable of terrible things, but then sometimes something else comes along and gives us just the right nudge.

Angela Dodson: Well, this has been real educational, but... I don't believe in the devil.

John Constantine: You should. He believes in you.”

 RESEARCH:

Since ctDNA-based liquid biopsies are non-invasive and can be easily repeated, this makes them our greatest weapon against cancer. They carry the potential to become the most effective tools in monitoring patients’ status pre- and post-treatment. By tracking patients’ response to treatment, clinicians will be able to adjust aspects of treatment accordingly.

Mark Roschewski, M.D., of NCI's Cancer Research Center and his colleagues found that alterations of ctDNA were linked to positive responses in chemotherapy. Scientists realized that patterns of ctDNA were detecting tumors during their growth periods much quicker than CT scan(s) were. This revealed the level of sensitivity liquid biopsy tests have compared to our current imaging techniques such as CT scans.

 This potential alternative tested ability of liquid biopsy to test the track treatment responses in patients with lymphoma. They were able to detect these changes in ctDNA levels in patients within 14 days from the start of immuno-therapy treatment. With early detection, patients’ odds of beating cancer increase. Especially with the fact that only a small portion of individuals respond to immuno-therapy. From another division of NCI, a division of cancer treatment and diagnosis, Brian Sorg, Ph.D, used this new information to help track the development of drug resistance during treatment. 

When looking at many of lung cancer patients’ responses to treatment, which includes a class of drugs known as ‘tyrosine kinase inhibitors’ that help the body develop resistance to treatment. This resistance lasts from 1 to 2 years.

These results led to further studies which analyzed ctDNA mutations of lung cancer patients who during treatment became resistant to ‘tyrosine kinase inhibitors’. These individuals, roughly 80% of participants, developed the genetic mutation that caused this resistance. However, to really determine whether liquid biopsy test(s) can truly identify the tumors with this mutation as well as those who will most likely benefit from which treatment.

Liquid biopsy tests have the added advantage of providing molecular information about the cancer, which can change during and after treatment. Precision Medical treatments could also benefit from ‘ctDNA-based liquid biopsies’ by identifying unique molecular characteristics of cancer that is developing and growing inside of patients'. 

Cancer Center of UC San Diego Moores has analyzed 168 blood samples from patients each with a different type of cancer -locating in the brain, breast, lung. They discovered that in 58% of the participants at least one cancer related ctDNA mutation. Most of these patients, a Food and Drug Administration (FDA)–approved drug was available to treat cancers with that mutation. 

There also exists many other studies which demonstrate the practicability of ctDNA-based liquid biopsies applied on a large scale to identify DNA mutations in patients' cancers. Investigators used Guardant360 to detect mutation in ctDNA of over 15,000 patients. The Guardant360 is a test which can analyze 70 cancer-related genes in a blood sample. Most of these patients had genetic mutations identified by the liquid biopsy test. This observation was consistent with the genetic mutations found by tissue biopsy test.

Currently there are many liquid biopsy tests available but still need to be tested for possible risks or side effects and what possible clinical benefits might be seen in patients. The FDA officially approved a type of liquid biopsy test in 2016 which detects the EGFR gene mutation(s) in ctDNA in lung cancer patients. This test is better known as the ‘EGFR Mutation Test’ or ‘Cobas’

It was created with the intention of identifying good candidates for ‘erlotnib’(Tarceva) and ‘osimeritinib’(Tagrisso) treatments. These treatments are targeted therapies that attack cancer cells with EGFR mutations. However, the test can produce a false-negative test result, the FDA has recommended a tissue biopsy if the liquid biopsy is negative (meaning it does not detect an EGFR mutation).

CONCLUSION:

The field of cancer research has seen much progress, but now there exists a possible solution by combining tissue and liquid biopsies. First, a tissue biopsy could be used to identify unique biomarkers for an individual’s tumor, then liquid biopsy tests could be used to track those biomarkers. However, it is critical to note that ctDNA itself may not be the best source of information regarding clinical decisions.

As of right now, it is the risk of ‘over treatment’ in early cancer development that gives scientists and researchers their greatest concern. There were instances in these studies where ‘liquid biopsy tests’ revealed cancerous DNA when no cancer was present producing false-positive test results. These tests can detect early-stage tumors that will grow so slowly that in many cases will have no harm let alone effect on the individual if the tumor grows at all.

“Satan: Hello, John. John, hello. You're the one soul I would come up here to collect myself.

[claps giddily]

John Constantine: So, I've heard.”

There the potential in ctDNA-based liquid biopsies is there, but limitations are also present when using this treatment method. Scientists are also unsure of whether mutations found in ctDNA are ‘driver’ mutations which play the major role in cancer’s biology. They could instead be the ‘passenger’ mutations, where the alterations that occur along with the development of cancer but have no control of its growth.

To really determine that finding ctDNA in a patient’s blood can be an accurate marker for early-stage cancer, possibility of this detection to authorize treatment(s) and if this innovative treatment improves patient outcomes, more prospective cohort studies are needed. 

The NCI supports the initiative to develop and validate the possible technologies that liquid biopsy has to offer in detecting early-stage cancer. The organization also supports advancing the development in distinguishing cancer from benign conditions and to quickly identify slow growing cancers. A major aim of the initiative is to create a public–private partnership that brings engineering and clinical experts together to accomplish these goals.

 [Gabriel holds Constantine helpless]

“Gabriel: You're handed this precious gift, right? Each one of you granted redemption from the Creator - murderers, rapists, and molesters - all of you, you just have to repent, and God takes you into His bosom. In all the worlds in all the universe, no other creature can make such a boast, save man. It's not fair.

[leans closer]

Gabriel: If sweet, sweet God loves you so, then I will make you worthy of His love. I've been watching for a long time. It's only in the face of horror that you truly find your nobler selves. And you can be so noble. So, I'll bring you pain, I'll bring you horror, so that you may rise above it. So that those of you who survive this reign of hell on earth will be worthy of God's love.

John Constantine: Gabriel, you're insane!

Gabriel: [smiles] The road to salvation begins tonight. Right now.

[Gabriel blows, sending Constantine crashing through the door]”

 

Many researchers agree that studies which analyze the effect(s) of liquid biopsy tests for clinical outcomes are needed before they can be used on actual patients. Since October of 2017 clinical trials by Stanford University and NCI teams have already started to evaluate an overall survival rate of patients (specifically adult patients with metastatic solid tumors) who will be the recipients of this targeted therapy.

Links:

[A] https://www.cancer.gov/news-events/cancer-currents-blog/2017/liquid-biopsy-detects-treats-cancer

[B] https://www.theguardian.com/science/2017/jun/04/cancer-detection-liquid-biopsies

 

*Please note! These images are not mine. They were found on various tumblr, pinterest, google image sites! If any are yours’ please let me know so that I can give you credit for them! Also the people in the images have no relation to the diseases, illnesses, or cancers I write about. Thanks so much & enjoy~

*Quotes by: www.imdb.com/title/tt0360486/quotes 

*Screen caps by: www.cap-that.com/constantine/?page=54