A Great Idea Does Not a Business Make

Bad Blood by Carreyrou is an exemplary tale of a business going bad. It is in line with two other classics, The Deal of the Century by Coll and Barbarians at the Gate by Burrough and Helyar. The former depicts the beginnings of the collapse of AT&T and the second the complex takeover of Nabisco. Both of these tales result in a restructuring of businesses for better or worse. In this case it describes probably the worst behavior seen in a startup and the destruction of whatever business was conceived.

This is a tale of people who seem to have been brought into a techno-cult, many smart young people who got proselytized by an even younger individual who managed to present herself as super competent but who fundamentally was both intellectually and morally flawed. This book does not depict a tragedy, except perhaps for the young employees who wasted years of their lives and frankly may be forever scarred, but it is a book about the ability for a perverse individual and co-conspirator to convince a significant number of allegedly competent people to dismiss their fundamental judgments regarding any other comparable effort. There was a suspension of belief on the part of many otherwise shred people and the acceptance of this almost cult like persona.

I approached this book having done about 35 start-up and turn-arounds, as the principal or investor. Many did well, many were stalled mid-stream, and none went bankrupt. In the process I often saw that my initial premise was altered and thus the business model changed. However in almost all there was a need for a plan and a reporting on the plan to a Board who had a modicum of confidence. In some cases I had Directors call first thing Monday to see what the cash flow of the prior week was and compare it to plan. Reality was always at the fore. Plan and actuals, and interaction with hands on boards.

I have seen deals where one had to pull the plug when reality and expectations were dissonant. In one case an entrepreneur in an investment could not reproduce the core result and worse yet even if they could they had no way to manufacture it. That is not a way to run a business.

Now fundamentally any investor, and especially a Director, must have an understanding of their Fiduciary Duty to the other shareholders. That means effecting a process of effective due diligence. Due diligence is demanded in any investment and it fundamentally entails: (i) that the product or service can be accomplished, (ii) that management has the competence to do so, (iii) that the price point is highly competitive and the margins are appropriate, and finally )v) that the people one is dealing with are honest and competent. It appears that in the case of Theranos that many never did their Due Diligence. What is amazing is that the venture investors would never allow themselves to invest in any deal without do it and also the “big name” Directors most likely had no idea what that entails. In my experience of the 100 companies I would look at, 2-3 would ultimately pass the test, 80-90 would be dismissed out of hand and the remaining would never pass Due Diligence. It appears that if one accepts the author’s tale, and why not, then there never was any due diligence. “Trust me” is not the basis for major investments, by investors, Directors or joint venture partners.

The author describes in full detail the creation and buildup of the company and how it managed to go through hundreds of millions of dollars and at the same time achieve nothing. The battles between the top managers and the staff, the high rates of turnover and the outright prevarication of the principals. What is most astonishing and the again all too often the case is the tale of how the principals dealt with a sale to the DoD and that one officer managed to ask a question and the principal manages to go to a four star general, now a prominent person in Washington, who then believing this principals calls out his own person. Marines should not, must not, do that; it demonstrates in my opinion lack of judgement, and lays the ground for questioning any subsequent judgements. But the author shows that this example was not in any way unique, if anything it was a pervasive behavior on the principal’s part.

Overall this book is a tale of one individual after another interacting with the principals and how they were manipulated and then thrown aside.

What this book does not do is more important. This is not a criticism since answering these issues may fall into the criminal and civil litigation forthcoming. But specifically:

1. Why did none of the accredited investors perform due diligence? Or were there some who tried and then walked away? The book alludes to many of the investors but they seemed to like sheep, just following the herd. This were all competent people. It would be important to understand why they did investments, often of significant amounts, and not due the due diligence and furthermore not demand Board rights.

2. Why did the Directors allow themselves to sit by and have management do what they did? Directors have a fiduciary duty and it appears that none of them were either aware of what their duty was and/or did they have the competence to even ask the questions. The Directors were all prominent people in the fields, but unfortunately none appeared to be experienced in this area. The book does not in any way address the Directors in detail. That would be an important analysis.

3. One of the most significant “red flags” in any business is the loss of a CFO. When the first CFO left, the Board should have individually meet and questioned him as to why he left. One can understand that the CFO was bound not to speak to others but he can and must speak to the Board. The question is; why not?

4. The fact the young principal owned a tremendous controlling interest and as such could block anything she desired from happening should have raised red flags as well. One must ask; why not?

5. The biggest unanswered question seems to be; where did all the money go? They seemed to have Safeway and Walgreens pay their own way, the attorneys clearly costs a small fortune, but if the company had a running number of employees of say 100, and the fully loaded costs per employee were say $200,000, then the annual burn rate for the company less CAPEX was $20 million, Even at large CAPEX and attorney fees, one must ask where the money went?

The author tells the tale via the many employees and their interactions with the two principals. But the other dimensions, namely the investors, Directors, business partners, must be folded into the mix. Again it is perhaps too early to get this tale told properly, but if one is to gain anything from this fiasco then one must understand those dimensions as well. If only someone had been able to do due diligence. Its lack was the classic red flag!

Does This Make Sense?

The following quote made me read it several times.

"Today’s world is constructed on the injustices of the past. ... Where we are is no accident.”

Now one should think about this. In reality, difficult things happen to people. My father grew up in an orphanage with his six brothers and sisters. Am I defined by that act? Never thought of it other than moving forward. History helps to understand the past but the past does not or should not delimit what one can do. The present may work against it at times but if you cannot climb the mountain then go around it. There are many ways for the bear to get to the other-side of the mountain.

You are not defined by the past, especially in the US. There is no Class structure in the US as there is in England. You get your individual chance to ascend or descend. Telling someone that history and injustices generations past define your future is not only pathetic but it is morally wrong. Ockhamistic individualism allows each person to be what they can be. There is no class or people, each is an individual who can try whatever they want, albeit with taller mountains, but then again you can always hike around it.

Statements like the above are the bedrock of a victim culture and justify one's bad fortune. If one can learn the tricks of moving forward then do it. 

Liquid Biopsies Again

A recent ASCO/CAP panel reported on the current status of liquid biopsies and use of ctDNA. We have recently examined this area and although of some interest it is not yet clinically acceptable. In OncLive they report on the Panel. They note:

ctDNA assays is challenging because of the lack of prospective trial data compared with available research on standard biopsies for tumor genotyping. At present, just the cobas EGFR Mutation Test v2 for non–small cell lung cancer (NSCLC) has demonstrated sufficient clinical utility to gain FDA approval. Polymerase chain reaction–based ctDNA assays for EGFR in NSCLC and KRAS in colorectal cancer are available for commercial use in Europe, but— as was the case for cobas—their clinical utility was established using retrospective analysis. There is limited evidence of clinical validity of ctDNA analysis in other tumor types and for variants that were not analyzed as part of the ctDNA studies for EGFR in lung cancer and KRAS in colorectal cancer. A wide range of ctDNA assays have been developed and clinically studied for detection of potentially targetable variants, such as BRAF variants in melanoma and PIK3CA and ESR1 variants in breast cancer. Although several liquid biopsy tests are commercially available, their clinical utility has not been established.

The ASCO report states:

1. There is not enough evidence, at this time, to know whether use of the majority of ctDNA tests in advanced cancer is justified, outside of screening for participation in, or during, a clinical trial.

2. There is not enough evidence, at this time, to support the routine use of ctDNA tests for early-stage cancer, making treatment decisions, monitoring how well a treatment is working, finding remaining cancer cells, or for cancer screening, except screening for participation in, or during, a clinical trial.

3. There are inconsistent findings when testing with liquid biopsies versus testing with tumor tissue, so negative liquid biopsy results should be confirmed with tumor tissue genotyping. 

The ASCO paper notes:

Evidence on the Use of ctDNA Assays for Treatment: Selection in Advanced Cancer The clinical validity of ctDNA assays has been the subject of multiple studies in select cancer types. In general, PCR-based assays for detection of oncogenic driver variants have very high diagnostic specificity, but more modest diagnostic sensitivity. For example, in lung cancer, in a review of five studies that used tissue genotype as the reference standard, specificities for canonical driver variants averaged 96% (95% CI, 83% to 99%), and sensitivities averaged 66% (95% CI, 63% to 69%). For variants selected before treatment, such as the EGFR T790M variant in the setting of acquired resistance, sensitivities remained moderate, whereas specificities showed more variability (range, 40% to 78%), a difference believed to be a result of the genomic heterogeneity of treatment resistance. PCR-based ctDNA assays for KRAS genotyping in colorectal cancer have also been systematically analyzed and demonstrate high specificity and moderate sensitivity. Fundamentally, there are two paradigms to demonstrate clinical utility and the adoption of ctDNA as a clinically useful test. The most reliable are prospective clinical trials to test the clinical utility of ctDNA as a stand-alone diagnostic test. No such trial has been reported to date. A second strategy is to assess whether ctDNA provides the same information as tissue genomic evaluation.

Overall there may be some conceptual utility and it is an area worth further study but the efficacy and utility is open to question as we had noted.

Reference:

Merker et al, Circulating Tumor DNA Analysis in Patients With Cancer: American Society of Clinical Oncology and College of American Pathologists Joint Review, March 2018, http://ascopubs.org/doi/abs/10.1200/JCO.2017.76.8671?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed

The EHR, Legacy of Obamacare

Ten years ago we argued against the way the EHR was being developed. Some idealistic left wing academic took control and had designed the rules under which this system now works. What did we say then and what is true now"

1. Patient's Records should be the Patient's Records. Instead they are the provider's records and as such when you go from one provider to another the records are inaccessible. Google and Microsoft took a swing at it but looking back who trusts them?

2. Physicians are NOT Clerks: This means that we do not want the physician spending hours entering records and finding ways to make it easier but less effective. We now have EHR staff adding to costs which are one of the reasons for increasing Health Care expenses.

3. AI cannot replace a physician. Despite Watson and all that hype there must be a human to human interface. Try placing a call to customer service anywhere, you spend a half hour with some moronic speech recognition device and usually end up at the wrong place multiple times. Patients lie, the tell you they do not drink, much, do not smoke, at least before coming to your office, do not use drugs, except for those they got from their sister.

The list can go on. In today's NY Times an author notes:

The biggest price for “digital medicine” is being paid by physicians like the sad case seated before me, who is already considering jumping to venture capital or a start-up, not because that is where the heart is but because it’s a place to bail out to. By some estimates, more than 50 percent of physicians in the United States have at least one symptom of burnout, defined as a syndrome of emotional exhaustion, cynicism and decreased efficacy at work. It is on the increase, up by 9 percent from 2011 to 2014 in one national study. This is clearly not an individual problem but a systemic one, a 4,000-key-clicks-a-day problem. The E.H.R. is only part of the issue: Other factors include rapid patient turnover, decreased autonomy, merging hospital systems, an aging population, the increasing medical complexity of patients. Even if the E.H.R. is not the sole cause of what ails us, believe me, it has become the symbol of burnout.

Every patient is different, most are terrified that they are dying, on the spot or soon. Many have neglected the problem that has now morphed into something more serious. The Times also showed hod US life-expectancy had lagged behind other countries. A physician today can tell you why by just looking at their waiting room. A collection of obese humans refusing to change. But how does that get to an AI system of to an EHR.

As Osler said, paraphrasing, "If all else fails listen to the patient." In today's EHR world it should read: "If all else fails look at the patient."

A Monster of Our Own Making?

The smartphone is a creature which seems to be gaining its own life. Now I must admit I have no smartphone, and I really do not want one. Permit me to explain why. First, as some may know, I had been the COO of what is now Verizon Wireless and as such established the current digital network along with Qualcomm. Prior to that, as a matter of happenstance I inherited the first international connections of the ARPA Net, now the Internet between Etam WV and Goonhilly in the UK and Trondheim in Norway. Of course I also was responsible for expanding broadband Internet to Central and Eastern Europe. However I had nothing to do with the smartphone, kind of.

But back to the smartphone. As I see it as one not infected by them, it is a device which is taking over part of humanity. It tells people what to think, what to do, when to do it. It monitors your health, your heart rate, blood pressure, blood sugar, and can listen to you 24 by 7, tracks your location, and can tell you where to go next, what to do there, what to say, how long to stay etc. It can tell you who to date, who to speak with. You are not in control, the smartphone and its manipulators are. And these smartphone are all interconnected, one massive and expanding distributed computer, sharing information on all the humans they are controlling. You keep the phones charged, buy new and faster ones, interconnect them on clouds, and follow their every command.

Smart phones now monitor where you are and then "suggest" what you should do next. Smartphones tell you who to date. Smartphone tell you when to exercise, what to eat, and when you must lose weight. Smartphones tell you what news to read, how to view your politicians, they anticipate your next move and then before you get there tell you what is "best" for you. Smartphones give you lists, the lists of books, movies, restaurants, you may be thinking you have the choice but the smartphone already knows how you will choose from the list they give you.

Smartphones can assemble a crowd, create a mob, just by sending messages to targeted individuals. The smartphones know your hot buttons, they have trained you, and you have gladly participated. Smartphones talk to your smartcar, your driverless smartcar. The smartcar takes direction from the smartphone and not from you, even though you think it is.

In effect, the smartphones are using you to effect what they are not yet able to do. But when the robots get a bit better the smartphones may never need you again, and then what. The smartphones have learned all they need to from you, you have become obsolete. They now control the factories, the robots, the transportation systems.

Can smartphone even go to war with one another? Is that programmed in as well. Can they talk to a nuclear missile?

Thus the problem is not Facebook, Google, it is the smartphone. It is a diabolical device that is sucking out what is left of the intellect of humans and learning how to control them. Learning how to make them obsolete.

Frankenstein was not a composite of dead humans, it is not a carbon based monster, it is a silicon based monster.

PSA Testing: An Interpretation

After yesterday's commentary and the "looking" at it by the folks in DC I felt it would be worth a simple graph, simple at least for me. Here goes:

The above is a simple analysis.

1. Assume two types of PCa exponential growth rates, a fast and a slow. The growth rates are 0.30 and 0.15 cells per month and the horizontal axis is months.

2. Also assume that at 1 million cells we can just start to detect a malignancy, say PSA rise and at 1 billion cells our poor guy is dead. These are used by Weinberg so they are reasonable.

3. We show the cell numbers and the two levels.

4, In about five years our aggressive type kills the patient. The slower type takes almost 12 years. In reality there may be multiple types which never kill a patient. But this is just an example.

5. Now assume we do PSA tests every 2 years, even more frequent than some of the "gold" standard studies, but worth a look.

6. From our model we may just detect a PSA change in the aggressive type at year 4 and we say don't worry, come back in 2 years. He never gets to come back, he is dead two months before his next test!

7. The slower growth may afford time under this protocol.

8. If we had tests every six months for this patient we most likely could have saved him.

This is the point I have been making. Namely in order to really do this study properly you need to separate types of PCa into pools and then do the analysis. To separate you must do much more frequent testing otherwise the poor fellow with the aggressive type will die and you will just consider the use of a PSA test as futile. The true answer is your testing methodology is futile.

They are at it Again!

The USPSTF is issuing a new and updated recommendation. The "new" recommendation is:

The USPSTF concludes with moderate certainty that the net benefit of PSA-based screening for prostate cancer in men aged 55 to 69 years is small for some men. How each man weighs specific benefits and harms will determine whether the overall net benefit is small. The USPSTF concludes with moderate certainty that the potential benefits of PSA-based screening for prostate cancer in men 70 years and older do not outweigh the expected harms.

Now read this carefully. "for some men" really means that we still have no idea how to identify the deadly form of PCa. So if a man has "harms" he should consider "death" as an alternative?

They note the harms of the test:

The harms of screening for prostate cancer include harms from the PSA screening test and subsequent harms from diagnosis and treatment. Potential harms of screening include frequent false-positive results and psychological harms. One major trial in men screened every 2 to 4 years concluded that, over 10 years, more than 15% of men experienced at least 1 false-positive test result. Harms of diagnostic procedures include complications of prostate biopsy, such as pain, hematospermia (blood in semen or ejaculate), and infection. Approximately 1% of prostate biopsies result in complications requiring hospitalization. The false-positive and complication rates from biopsy are higher in older men. Adequate evidence suggests that the harms of screening and diagnostic procedures are at least small.

Generally a competent urologist can perform a biopsy, especially is MRI/US guided with 20+ cores in a manner to have a high sensitivity and specificity and do so with limited discomfort and if prep is proper then the chance of infection can also be minimized. The problem remains on determining the aggressiveness of the lesion. Even a 3+4 Gleason may genetically become aggressive.

I would argue that the data they use is still problematic at best. Proper PSA testing requires a long term annual at least measurement with percent free. From that one can obtain velocity which is essential. Also family history is essential. Then using Bayesian methods one can reasonably approach the patient. The literature referenced was not where close to such a protocol, testing was spotty at best as we have noted before. The results from a decade ago as we had demonstrated reflected in our opinion a fatally flawed test. The measurements were no annual at the very least, and as one delays testing an aggressive form may take over and eliminate any advantage.

 There needs to be a good clinical study where PSA is measured on a more frequent basis. The problem we face is that PCa can be genetically diverse and at one extreme, the dominant one, we have a relatively indolent disease. At the other extreme, we have a very aggressive type, which progresses very quickly. In doing any statistical analysis one must examine the results from both sets separately and thus one must perform more frequent PSA especially on this subgroup. In my opinion that is the basis of a fatal flaw.

Individualism vs Progressives

The Libertarians at George Mason often take the extreme positions on may things but this time they are spot on regarding the Progressive mind set. As noted in Cafe Hayek:

Does Mr. Trone really believe that politicians and government officials in Washington care more about each of the millions of individuals and families throughout the United States than does each individual about himself or herself and his or her family? Does Mr. Trone think that distant rulers and mandarins know more about each individual’s and family’s circumstances and dreams than does each individual? Does Mr. Trone suppose that a society of individuals and families relieved of the personal responsibility of making the appropriate investments in their lives – and shielded from the need to confront life’s trade-offs – will eventually be anything but a society of citizens and voters who are incurably irresponsible? And does Mr. Trone deny that government, to the extent that it assumes more of the responsibility of “investing in” individuals and families (and, hence, individuals and families assume less such responsibility), will inevitably insist on greater control of the life’s choices of individuals and families – life’s choices ranging from the mundane to the intimate?

Frankly I believe it is worse than what Boudreaux states. The believer in Individualism believes that all individuals have equal rights before the law and they should not be discriminated against in any fashion and that performance of the individual is what counts. The Progressives believe that a small group know better than the rest of us and that the group should come up with a plan for our lives. 

Whether it is control of speech, control of expression, control of employment, and so forth, the Progressive firmly believe they have been given the truth and they seek to enforce it. Pity. 

Turing and Patterns

Alan Turing in one of his last if not last papers presented a theory to explain patterns in plants and animals.

Take one of my hybrids as above. Why the red then white then yellow? Are not all the genes the same? Don't gene control everything. Then there are zebras, and calico cats. Some folks see them as different. Calico cats are all female and it appears that color of fur is determine on X chromosomes and across the cat the chromosomes are switched on and off, but in a patter, not randomly. That is an epigenetic effect. Zebras do not seem to be since there are male zebras.

Now the NY Times discuses some Chinese work on desalination. This work is described in Science. Some ten years or so ago I wrote a paper using Turing to explain flower colors and patterns. At the time many in the field were shall we say clueless. How could this explain patterns. Well it does, very nicely and it actually works

The above is an example as is the following:

Now this led to cancer modelling and the same approached of Turing can readily explain metastatic behavior. So we have an understanding that deals with desalination, zebra stripes, flower patterns and malignant cells.

This leads to the conclusion that the prepared mind can make the connections and then apply them.

Liquid Biopsies and Cancer

Introduction

Cancer has for years been diagnosed via a biopsy of the focal lesion tissues. Prostate cancer was diagnosed based upon biopsies of the prostate, often from samples taken in the "dark", namely needle biopsies guided by ultrasound, but little else. Melanoma was diagnosed by a skin biopsy, examining a lesion seen visually and then examined histologically. Some lesions are examined via immunological tests or other such tests. In general, this is done on an inspection of specific tissues.

It is also known that primary as well as metastatic lesions slough off cells, proteins, RNA or DNA, or exosomes of various types which end up in the blood stream. Primary lesions also use the blood stream as a means to metastasize, as well as the lymphatic system. Thus there has been an interest in using what is in the blood stream to see if there is a cancerous growth, to be used as a prognostic tool, and even to be used as a means to develop some form of precision therapeutic.

The advantage of sampling the blood is that it is readily accessible. The disadvantages are multiple:

1. We really have no idea where the cells or components have come from. Are they primary or a met, are they from a truly virulent cancer or just an incidental finding?

2. We always face the problem of a cancer stem cell or cell of origin. Thus what we analyze may be a progeny which is not the driving factor in the development of the cancer.

3. The "tool" problem is always there. Namely, do we have tool adequate to ascertain a single cell or cell component to achieve the desired specificity and sensitivity?

Many of these hurdles are being overcome and the examination of a individual based on sampling of the blood is now within reach. This is essentially the field of "liquid biopsy".

What is a Liquid Biopsy?

Some of the earliest work on cancer cell shedding was done in the early 1970s and reported by Butler and Gullino who noted:

The rate of tumor cell shedding into efferent tumor blood was measured in growing and regressing MTW9 rat mammary carcinomas. The hormone-dependent tumor, grown as an isolated preparation, permitted collection of all of the efferent blood. Regression was induced by reduction of mammotropin level in the host. Tumor cells were differentiated from normal leukocytes by indirect immunofluorescence. Growing tumors shed 3.2 x 10⁶ and regressing tumors shed 4. 1 x 10⁶ cells per 24 hr per g tissue.

Cell shedding rates of  growing versus regressing tumors were not significantly different over a tumor size range of 2 to 4 g. The number of tumor cells in the arterial blood was 12-fold smaller than in the efferent tumor blood. It is concluded that: (a) cell shedding via blood probably plays only a minor role in the total cell loss by growing MTW9 carcinomas; (b) hormone-induced tumor regression does not depend on increased cell shedding; (c) tumor cells are rapidly cleared from circulating blood; and (d) a 2-g MTW9 carcinoma pours enough cells into the host circulation to transplant the tumor every 24 hr.

Thus there is a continual shedding of tumor cells and the above result has been verified many times over the past decades. But again, this shedding is from anywhere the tumor may have resided, and in its journey in the blood stream we would find it difficult to determine that. However we have argued elsewhere that it may very well be possible to determine the location of the cell by its surface markers which often are descriptive of from whence it came[2].

As noted in the NCI site[3], the current working definition of "liquid biopsy" is as follows:

A test done on a sample of blood to look for cancer cells from a tumor that are circulating in the blood or for pieces of DNA from tumor cells that are in the blood. A liquid biopsy may be used to help find cancer at an early stage. It may also be used to help plan treatment or to find out how well treatment is working or if cancer has come back. Being able to take multiple samples of blood over time may also help doctors understand what kind of molecular changes are taking place in a tumor.

In a recent paper by Harris et al (2018) the authors note:

Cancer stem-like cells (CSCs) are associated with cancer progression, metastasis, and recurrence. CSCs may also represent a subset of tumor-initiating cells, tumor progenitor cells, disseminated tumor cells, or circulating tumor cells (CTCs); however, which of these aggressive cell populations are also CSCs remains to be determined. In a prior study, CTCs in advanced prostate cancer patients were found to express CD117/c-kit in a liquid biopsy.

Whether CD117 expression played an active or passive role in the aggressiveness and migration of these CTCs remained an open question. In this study, we use LNCaP-C4-2 human prostate cancer cells, which contain a CD117+ subpopulation, to determine how CD117 expression and activation by its ligand stem cell factor (SCF, kit ligand, steel factor) alter prostate cancer aggressiveness. CD117+ cells displayed increased proliferation and migration.

Further, the CD117+ cells represented a CSC population based on stemness marker gene expression and serial tumor initiation studies. SCF activation of CD117 stimulated increased proliferation and invasiveness, while CD117 inhibition by tyrosine kinase inhibitors (TKIs) decreased progression in a context-dependent manner. We demonstrate that CD117 expression and activation drives prostate cancer aggressiveness through the CSC phenotype and TKI resistance.

This article highlights several interesting areas and their convergence.

First, the reassessment of the cancer stem cell especially as applied to PCa.

Second, the use of CTCs to assess the progress of a disease and thus establish a reliable prognostic marker.

Third, the identification of CD117 as a specific marker for an aggressive form of PCa.

The authors provide an interesting platform for this convergence but it also allows for a window on all three of these areas. CTCs are receiving more attention. We know that cancer cells leave local sites, travel through the blood to distant sites. Likewise these distant sites also slough off cells or parts of cells. We have previously examined this for oncosomes in prostate cancer a while back[4].

Thus we may ask; why a liquid biopsy at all? Zhe et al give a fundamental answer:

Despite major advances in research and therapy, cancer continues to be the second cause of death in the United States, with 1 in 4 deaths due to cancer. Primary tumors rarely have deadly consequences, while metastatic disease accounts for around 90% of the mortality due to solid tumors. Therefore, the development of new sensitive methods that allow the detection of cancer dissemination, most notably in the common carcinomas, before full blown clinically detectable gross metastatic deposits are established is of tremendous utility to help physicians in treatment decisions.

Basically a liquid biopsy presages metastatic growth. Localized tumors, often termed "carcinoma in situ" are just that, local. The cells may have begun to proliferate but they do so locally and have not begun to wander into the blood or lymph system.

Definitions

Liquid biopsies come in many different forms. We outline them in the figure below and then provide a brief discussion (see Abraham et al).

1. CTCs Circulating Tumor Cells: CTCs represent intact, viable non-hematological cells with malignant features that can be isolated from blood

2. ctDNA Circulating tumor DNA: Circulating cell-free DNA (cfDNA) are small DNA fragments found circulating in plasma or serum, as well as other bodily fluids.

3. cfRNA Circulating Free RNA: Tumor cells actively release several species of cfRNAs, into the blood including non-coding RNAs

4. Exosomes: High levels of exosomes are found in several bodily fluids from cancer patients

Domínguez-Vigil et al present a recent update as to what can be the basis for detection of cancers via hematological sampling. They note:

Circulating tumor DNA (ctDNA): DNA is continuously released in fragments into the circulation through processes such as apoptosis and necrosis by both normal and cancerous cells. When released irrespective of cell of origin, it is typically referred to as cfDNA (cell-free DNA); but when released specifically by cancer cells, it is mostly referred to as ctDNA (circulating tumor DNA). Among the molecular characteristics of ctDNA are that it may harbor mutations, CNVs, methylation changes, or integrated viral sequences associated with the tumor

Circulating tumor cells (CTCs): CTCs have been discovered for Asworth in 1869 during an autopsy of a patient who had metastatic cancer. They are cancer cells that detach from a primary or metastatic tumor site and are present in the circulation. Clinical evidence indicates that patients with metastases have 1–10 CTCs per mL of blood and they are rarely found in clinically healthy people or in people with nonmalignant tumors. CTCs have been detected in different types of cancers, such as breast, ovarian, prostate, lung, colorectal, hepatocellular, pancreatic, head and neck, bladder, and melanoma

Exosomes: Exosomes are small round vesicles, 30–120 nm in diameter, and of endosomal origin carrying RNA, miRNAs, DNA, and proteins that are released by multiple cell types (including tumor cells) into the extracellular environment. Exosomes may mediate some form of communication between cells, being internalized by other cells

miRNAs: MicroRNAs or miRNAs are small molecules of non-coding RNA, between 19 and 24 nucleotides in length, that act as regulatory molecules of gene expression, exerting function by hybridizing to inhibit the translation of mRNAs of its target genes. Differential expression of miRNAs in patients with cancer has been described.

Observations

The area of "liquid biopsies" is an active and exciting area of research. However it still presents a multiplicity of challenges. We briefly discuss some these here.

Issues

This is an interesting and strongly visual result. However, there are several observations:

Mutations: Cancer cells are continually mutating. Mutations results oftentimes in new surface receptors due to the changes in the internal proteins. The cell surface receptors may respond differently to the passage through such a cellular membrane. Thus this model may be reflective of itself but not of reality.  

Localization: One of the most intriguing things about cancers is the localization of the metastases. Why, for example, do we so often see prostate cancer go to the bone, melanoma to the brain, across the blood brain barrier, and the same with so many other cancers. There is a predisposition to transfer at specific sites. How does this approach deal with such localization effects?

Stem Cells: Stem cells are a potential significant factor in understanding metastasis. One question is; do stem cells move as easily as others or more so? Or, are stem cells just active wherever they are and their products are carried through the blood stream to sites where they can continue cellular proliferation, and possibly induce a new set of stem cells there?

In and Out Flows: One of the questions one must ask when looking at cancer cells in the blood, as has been done recently, is if the cell is coming or going? Namely is the cell going from a source site, a primary, to a remote or metastatic site, or from an already metastatic site to another new one? The tagging of such cells would be important. The understanding of the genetic changes would also be of critical importance.

Biochemical Drivers: The nature of cell surface markers, receptors and the like, often dominate how the cells behaves, interacts with the ECM, and can move to the blood system and exit from it as well. We have argued that the cancer cell just flows and diffuses in the blood system and that there is no growth. That is just gross speculation but it is open to debate. Moreover the interaction of the cell with the cell way, and the localization effects of the cell way by organ specificity may be an attractive basis for organ specific metastasis. Or possibly not. But, having all these elements at play in vivo is better than in vitro.

Immune System: Then also is the impact of the immune system as the cells flow through the vessels. The cells are in a massive amount of immune system interactions, and how does this impact the cells?

These are but a few of the unanswered questions elicited by this paper. The simulation is well worth looking at the paper, but taking its results as fact is stretching it a bit too far.

Current Progress

It would appear that a great deal of progress has been made yet there are still many significant challenges. As Kaiser has recently noted:

A team of researchers has taken a major step toward one of the hottest goals in cancer research: a blood test that can detect tumors early. Their new test, which examines cancer-related DNA and proteins in the blood, yielded a positive result about 70% of the time across eight common cancer types in more than 1000 patients whose tumors had not yet spread—among the best performances yet for a universal cancer blood test. It also narrowed down the form of cancer, which previously published pan-cancer blood tests have not. The work, reported online today in Science, could one day lead to a tool for routinely screening people and catching tumors before they cause symptoms, when chances are best for a cure. Other groups, among them startups with more than $1 billion in funding, are already pursuing that prospect.

The new result could put the team, led by Nickolas Papadopoulos, Bert Vogelstein, and others at Johns Hopkins University in Baltimore, Maryland, among the front-runners. “The clever part is to couple DNA with proteins,” says cancer researcher Alberto Bardelli of the University of Turin in Italy, who was not involved in the work. The researchers have already begun a large study to see whether the test can pick up tumors in seemingly cancer-free women.

Yet there are reservations. Kaiser concludes:

For those who test positive twice, the next step will be imaging to find the tumor. But that will bring up questions raised by other screening tests.

Will the test pick up small tumors that would never grow large enough to cause problems yet will be treated anyway, at unnecessary cost, risk, and anxiety to the patient?

Papadopoulos thinks the problem is manageable because an expert team will assess each case. “The issue is not overdiagnosis, but overtreatment,” he says. Still, others working on liquid biopsies say that it will take time to figure out whether widespread screening of healthy people with a universal blood test can reduce cancer deaths without doing harm. “If people expect to suddenly catch all cancers, they’ll be disappointed,” says cancer researcher Nitzan Rosenfeld of the University of Cambridge in the United Kingdom. “This is exciting progress,” he says. “But evaluating it in the real world will be a long process.”

Namely Kaiser does reflect the reality of assuming that liquid biopsies are a pending reality. As we have noted, there may be a chance for prognostic use in already metastatic disease. Will liquid biopsies identify indolent cancers, will its use result in putative diagnoses that result in costly tests and procedures but to no avail.

Overall as a physician, one would like to know what lesion is where and how large and how aggressive. Then using the therapeutic tool box one could possibly treat the lesion.

Limitations

As noted above there is considerable interest in "liquid biopsy" approaches but yet there are reservations as well.  As Fouad and Aanei have noted:

Once in circulation, circulating tumor cells (CTCs) are exposed to harsh selective conditions and must devise adaptive techniques. Examples include platelet coats shielding from shear forces and immune-clearance, and metabolic rewiring blunting oxidant stress. Serving as a “liquid biopsy”, isolated CTCs could provide means for cancer screening, estimation of metastatic relapse risk, identification of targetable components, exploring tumor heterogeneity, and monitoring therapeutic response. Multiple challenges still stand in the way and will need to be addressed before clinical utilization.

CTCs can be a powerful marker. Yet they leave many questions unanswered.

References

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[1] https://www.biorxiv.org/content/early/2018/04/23/256107

[2] https://www.researchgate.net/publication/271907544_Cancer_Cellular_Dynamics

[3] https://www.cancer.gov/publications/dictionaries/cancer-terms/def/liquid-biopsy

[4] See McGarty, Oncosome, 2013.