George Miklos on Cancer Cures

GEORGE MIKLOS

1
CANCER CURES AND BLOCKBUSTER DRUGS:
WHO CAN HANDLE THE TRUTH?
George L Gabor Miklos PhD and Phillip John Baird MD PhD
Statement
George L Gabor Miklos and Phillip John Baird are Director and CEO, respectively, of Secure Genetics and
Integrated Diagnostic Pathology. The former is a molecular genetics-based data evaluation company, the latter a
clinical diagnostic pathology company. Neither is affiliated with, nor receives any monetary compensation, gifts or
other payments in lieu, from pharmaceutical companies, government funding bodies or private institutions in the
cancer or drug development areas. 2
THE FRONT LINES OF CANCER
The patients
The costs of anticancer drugs
Patient time and incentives
Pharmaceutical sales
The media
Governmental institutions
DO NOT LISTEN TO WHAT THEY SAY — GO SEE.
Patients rarely die from a primary tumor
Facts and figures from the American Cancer Society
Facts and figures from the National Cancer Institute
Different cancers respond differently to chemotherapy and radiation
Blockbuster drugs
THE CHICAGO DRUG SHOW
The 2007 progress report
THE CANCER CELLS THAT LEAVE HOME HAVE EXTRA DNA CAPABILITIES
Normal cells
Cancer cells
The danger lies in the diversity within a cancer cell population
The cancer cells that leave home have increased informational diversity
Most cells in a primary tumor never leave
DRUG RESISTANCE AND THE RETURN OF CANCER
Normal cells are inflexible in a crisis
Cancer cells have additional flexibility in a crisis
How different is drug resistance in each person?
Handling the truth
NEW FRONTIER OR YET ANOTHER UNFULFILLED PROMISE?
Personalized treatment for the individual patient
DNA profiling
Single letter mutations
Drug combinations
The reality of massively disrupted DNA contents
THE EARLIEST STAGES OF CANCER
Once four DNA copies are attained, all hell breaks loose
The mutationists
The BRCA1 and BRCA2 breast cancer genes
CANCERGATE
Finding all the mutations in all cancers
The fatal flaw
Cancer genes
The Delusionists and the Spin Doctors
The clinical deliverables: patients are still waiting…and waiting…and waiting
THE HOPE
FAILURE IS NOT A CRIME. FAILURE TO LEARN FROM FAILURE IS.
REFERENCES 3
In the movie A Few Good Men, there is a heated exchange between the military characters portrayed by
Tom Cruise and Jack Nicholson, an exchange which is relevant to the War on Cancer.
Jessep: You want answers?
Kaffee: I want the truth!
Jessep: You can’t handle the truth!
The distinction between answers and truth is perfectly illustrated in the cancer arena where competing
interests form a volatile mix. The patients want cures, the media want stories, the researchers want grants,
politicians want votes, the doctors want to save lives and the pharmaceutical companies want to sell drugs.
The War on Cancer has become a global industry where fact and fiction have become indistinguishable
and where the truth often goes missing. Some truths are airbrushed out, leaving doctors to deal with the fears and
financial predicament of their patients. What do the front lines in cancer treatment and management really look
like?

To better appreciate them, we attempt to provide the latest facts. The medical ones can be checked at the
National Cancer Institute, (http://seer.cancer.gov), the American Cancer Society, (www.cancer.org), the Armed
Forces Institute of Pathology, (www.afip.org) and in the referenced scientific articles. The business figures are from
The Wall Street Journal, BusinessWeek, Forbes, CNNMoney and pharmaceutical companies.
THE FRONT LINES OF CANCER
The patients
Dina Rabinovitch, author of Take off your party dress; when life’s too busy for breast cancer, reveals the
day to day traumas of a breast cancer patient with an advanced form of the disease
1
. The cancer has spread to
other organs and her third different drug treatment is underway. It began with chemotherapy and intravenous
doses of the blockbuster drug Herceptin
2
and when the cancer returned, Omnitarg was prescribed. Now the
regimen is; five pills per day of the latest miracle drug Tykerb, plus eight daily tablets of the chemotherapeutic
agent Xeloda every two weeks out of three, plus two morphine tablets and a diclofenac every morning and
evening.
She states bluntly; My cancer keeps recurring. Nobody can tell me why. I did the genetic screening and I
don’t, apparently, carry the faulty genes. So angry and increasingly so cynical about these doctors in whom I have
to put complete trust.
The costs of anticancer drugs
In 2007, the costs per patient for major anticancer drugs were summarized in the Journal of the National
Cancer Institute
3
. If used for a full year, the two blockbusters, Herceptin for breast cancer and Avastin for lung
cancer, would cost $36,000 and $106,000, respectively. For colorectal cancer, Erbitux and Vectibix would cost
$120,000 and $96,000, respectively, while for breast cancer Tykerb would amount to $35,000. Cancer drugs
represent 40% of all Medicare drug expenditures.
These skyrocketing costs place doctors in the position of having to advise their patients about whether the
clinical benefits are worth the financial burden. Nearly a third of them report discomfort in telling patients about
costs and another 20% do not consider it to be their role. Many physicians say they are not health policy persons
and just want to do the best job for the patient
3
.
Physicians are trained to save lives and have little time to evaluate the effectiveness of a blockbuster drug
or genetic test. Furthermore, cancer genetics has moved so rapidly that most doctors do not have the specialist
molecular and statistical knowledge to make informed decisions about molecular tests, the clinical claims of which
are usually overstated and often have little validity
4-8
. 4
Patient time and incentives
The director of the American Society of Clinical Oncology, Dr Peter Eisenberg states that the system does
not value a doctor’s time with patients
9
. The system also provides incentives to prescribe drugs with the highest
profit margins and many doctors follow the money, after all, oncology is a business
10
. Dr Richard Deyo of the
University of Washington points out that; there are plenty of patients for whom there’s little hope, who are
terminally ill, whom chemotherapy is not going to help, who get chemotherapy
11
. What choice do oncologists
have? By ending treatment the doctor would be acknowledging that hope is gone. Treatments therefore go ahead.
Pharmaceutical sales

In 2006, the breast anticancer drug Herceptin and the colorectal anticancer drug Avastin generated $2.6
and $1.7 billion in sales, while Erbitux generated $1.1 billion in the colorectal market. Worldwide, anticancer drug
sales are expected to rise nearly 20% per year through 2010 to reach between $60 and $70 billion
12
. All large
pharmaceutical companies strive to produce new anticancer drugs. GlaxoSmithKline, for example, predicts it will
launch five new anticancer drugs in the next three years
13
.
The media
The public’s desperation for cancer cures distorts its perceptions of breakthroughs and miracle drugs. With
headlines such as Breakthrough liver cancer treatment found
14
and the spectacular but completely incorrect, US
scientists have cracked the entire genetic code of breast and colon cancers, offering new treatment hope
15
, it is
a wonder that oncology wards are not completely deserted. Unfortunately they are working at full capacity.
Breakthroughs have become totally devalued and are accepted uncritically by the public, charitable organizations,
politicians and the media.
The fascination with cancer cures is illustrated by the media’s attention to celebrities. In the 1970s it was
Betty Ford and Happy Rockefeller with breast cancer. In the 1990s, it was General Norman Schwarzkopf and Time
magazine Man of the Year Andy Grove, both with prostate cancer. Currently it’s Elizabeth Edwards whose breast
cancer has spread to the bone marrow and White House Press Secretary Tony Snow, whose colorectal cancer
has spread to the liver. Snow’s message is that …a lot of conditions… are now curable or people are racing toward
cures
16
. Celebrities serve as pillars of hope, but their comprehension of cancer cures conflicts with clinical reality.
Cancers that have spread are quite unlike diabetes and heart conditions where people live for decades by taking
fairly harmless drugs
17
.

Governmental institutions
Far away from the frontlines of the War on Cancer, the directors of various institutions vigorously defend
the progress in curing cancer. No matter how implausible, almost anything is said to attract more funding. The
previous director of the National Cancer Institute, Andrew von Eschenbach, outlined an extraordinary goal;
eliminating death and suffering from cancer by 2015
18
. This statement was so misleading that senior scientists
were aghast at such overt distortions of scientific reality
19
. It is also a very dangerous statement as it provides
false hope to patients. Some cancer sufferers, believing it to be true that death and suffering from cancer will be
eliminated by 2015, could delay seeking treatment in the hope that a pill will soon be available to cure their cancer.
When it’s all said and done, where are all the promised cancer cures since Richard Nixon signed the
National Cancer Act into law on the 23rd of December 1971?
In terms of the fiery exchange that began this essay, do we wish to face the truth, or not? The choice is an
intensely personal one. If readers prefer not to know the facts, they should read no further. 5
DO NOT LISTEN TO WHAT THEY SAY — GO SEE.
Chinese proverb

Patients rarely die from a primary tumor

Problems arise when a cancer spreads (metastasizes) to another part of the body and destroys a vital
organ
20-23
. In breast cancer, it is not the lump that is the killer, it is the cells that leave that lump and spread to the
brain and bones, for example, eventually replacing a vital organ with tumor tissue. Ninety percent of the deaths
from cancer are due to the spread of these maverick cells that develop the capacity to leave home and embark on
a journey throughout the body. If a primary tumor is diagnosed before any of its cells have left and the tumor is
surgically removed, the patient is completely cured. This is the only cure that exists; removal of a primary tumor
before any of its cells have moved to other parts of the body.
Facts and figures from the American Cancer Society
An estimated 560,000 US citizens will die from cancer in 2007 (www.cancer.org). The five largest
categories of deaths will be; lung cancer, (160,000), colorectal (53,000), breast (41,000), pancreas (33,000) and
prostate (27,000). Most cancers will occur in individuals 55 years or older. Deaths from childhood cancers,
between the ages of 0 and 14, are relatively rare, estimated to be 1,500.
Facts and figures from the National Cancer Institute
The latest figures from the NCI’s publicly accessible databases reveal the relative 5 year survival of
patients with various metastatic cancers over the 30 year period, 1973 to 2004 (http://seer.cancer.gov/csr).
survival with metastatic breast cancer improved from 19 to 23 percent.
survival with metastatic colorectal cancer improved from 6 to 9 percent.
survival with metastatic prostate cancer improved from 28 to 34 percent.
survival with metastatic lung cancer improved from 1 to 2 percent.
The improvements in survival are less than 0.2 percent per year, a miniscule change. Dr Jane Weeks, an
oncologist at the Dana-Farber Cancer Center provides clinical candour; A surprisingly high proportion of patients
with metastatic solid tumors don’t realize that there is no chance for cure. I’ve wondered how many patients in
exactly that situation have been shocked to learn otherwise from the coverage about Elizabeth Edwards
17
.
The truth is that all metastatic cancers are incurable despite the enormous sums of money poured into
research and drug development, as well as the large amounts of chemotherapy, radiation and new drugs that have
been poured into patients
24,25
.
Some patients do respond to blockbuster drugs. Increased survival times, however, are of the order of
months, not years. Side effects are common and the quality of life is dreadful. Approximately ten percent of breast
cancer patients who receive Herceptin, for example, develop cardiac toxicity, while another thirty percent develop
metastases to the brain
26
.
Different cancers respond differently to chemotherapy and radiation
There are hundreds of different types of cancer that have been carefully classified by pathologists
(www.afip.org). Each differs in its aggressiveness to spread and its resistance to drugs.
A common misconception is that if one type of cancer can be cured, so can all others. The case of Lance
Armstrong, who was cured of testicular cancer, is believed to be generalizable to other cancers. However, cancer
is a variety of types. Thus testicular cancer encompasses seminoma, embryonal carcinoma, teratoma and
choriocarcinoma. Seminomas are generally slow growing, whereas non-seminomas tend to spread more quickly.
Grade 1 seminomas are sensitive to both chemotherapy and radiation therapy and if detected early enough and
treated, over ninety percent of patients are alive after 5 years and hence are considered to be cured
27
. 6
In contrast, other cancers, such as colorectal cancer, pancreatic cancer and melanomas of the skin are
intrinsically resistant to radiation and chemotherapy. Less than five percent of patients with pancreatic cancer are
alive after five years.
Blockbuster drugs
The effectiveness of anticancer drugs is measured in two major ways. The most accurate is Median
Overall Survival, the time by which half the patients have died from disease. The other is Progression-Free
Survival, which essentially measures how long after drug treatment the cancer begins to grow again. This is a
subjective measurement since it involves estimating tumor size by scans. Given these two methods, how do the
various drugs perform?
THE CHICAGO DRUG SHOW
The annual meeting of the American Society for Clinical Oncology is the premier forum in which upcoming
cancer treatments are presented. It is the cancer equivalent of the Detroit Auto show. New drugs are exhibited by
all the pharmaceutical firms and media and stock market analysts report on the upcoming drug pipeline. This
year’s meeting was attended by 30,000 oncologists, researchers and drug and biotechnology company
representatives. What progress emerged on cancer cures?
The 2007 progress report
Nexavar. Onyx Pharmaceuticals and Bayer HealthCare Pharmaceuticals reported on a new use for their
drug Nexavar. In combination with chemotherapy, Nexavar boosted median overall survival of liver cancer patients
by 2.8 months. This improvement was described in Forbes as a breakthrough liver cancer treatment
14
and by Dr
Llovet of the Mount Sinai School of Medicine in New York city as; a new reference standard for systemic therapy of
liver cancer patients after thirty years of research and more than 100 randomized controlled trials performed
14
.
Surely after thirty years, innumerable clinical trials, billions of dollars invested and an increased median survival
time of 2.8 months, the use of the word breakthrough is absurd.
Axitinib. Pfizer reported that their drug Axitinib plus chemotherapy for advanced pancreatic cancer boosted
median overall survival by 1.3 months compared to chemotherapy alone. When used for metastatic breast cancer,
Axitinib plus chemotherapy boosted progression-free survival by 1.2 months compared to chemotherapy alone.
However, along with this extra 5 weeks of life, there were common adverse events such as nausea, fatigue,
proteinuria, stomatitis/mucositis, hypertension, diarrhea and neutropenia. Further risks are documented in Pfizers
Annual Report Forms, 10-K, 10-Q and 8-K.
Erbitux. ImClone Systems and Bristol-Myers Squibb provided data on Erbitux for head and neck cancer,
the results being highlighted in BusinessWeek. Erbitux plus a chemotherapeutic regimen boosted median overall
survival for head and neck cancer patients by 2.7 months compared to chemotherapy alone.
Avastin. The Wall Street Journal reported on data released by Genentech on the drug Avastin
28
. Avastin
plus interferon boosted progression-free survival for kidney cancer by 4.8 months compared to interferon alone. In
addition, Avastin plus a chemotherapeutic regimen for advanced forms of lung cancer boosted median
progression-free survival by 6 weeks compared to chemotherapy alone.
Herceptin. The New York Times reported on concerns with the allocation of patients to receive Herceptin,
which is held to be the paragon of personalized medicine in breast cancer
29
.
Women with breast cancer are classified into two groups on the basis of molecular tests involving a gene
called HER2. The groups are termed HER2-positive and HER2-negative. Only HER2-positive patients usually
receive Herceptin, as the drug is thought to have little benefit for the HER2-negative group. However, it was
reported that some women experienced a benefit irrespective of their HER2 status, indicating that Herceptin may
be being incorrectly targeted to these two groups
29
. 7
These findings left some doctors incredulous and confused as to what treatments to now apply to their
breast cancer patients. Here we are, 10 years into it and we don’t know how to test for it, said Dr Marc Citron an
oncologist from Lake Success, New York
29
.
The main message to emerge from this prestigious forum is that specific drugs in combination with
chemotherapeutic regimens do extend median survival for a period varying from weeks to months. However, these
figures apply to a population of patients, not to an individual. One patient may survive for years, whereas another is
gone after a few weeks. Currently there is no accurate way by which a doctor can predict an outcome for a
particular patient.
THE CANCER CELLS THAT LEAVE HOME HAVE EXTRA DNA CAPABILITIES
The cells that leave the primary tumor have different DNA characteristics to those that remain. It is their
altered properties that enable these emigrants to leave in the first place and for their descendants to infiltrate and
destroy vital organs
20,21,22,30,31
.
Normal cells

All normal cells have two copies of their DNA, one set from the mother and one set from the father. There
are thus two DNA code books (instructions-for-cell-survival) in every normal cell. If one book is damaged, there is
always a good copy from which to make repairs in an emergency. Normal cells carefully follow the instructions
encoded in their DNA and execute them in a particular order and at specified times. Normal cells are tightly
constrained by their two-book genetic operating manuals.
Cancer cells

By contrast, cancer cells that have left the primary tumor and are in transit or have arrived at their final
destinations, have massively disrupted DNA contents. Their instructions-for-cell-survival books have been copied
and they have more than two of them, but with profound differences. Enormous errors have occurred during the
copying process so their books now contain some extra chapters, sentences and paragraphs, while some other
chapters, paragraphs and sentences have been completely deleted. Furthermore, differing amounts of text have
been shifted from one place to another and at the most basic level, single letters have been changed. These
single letter changes are commonly referred to as mutations
6,32
.
The extent of these massive alterations in DNA is aptly described by Dr Garth Anderson, of the Roswell
Park Cancer Institute in Buffalo, NY; in most adult solid tumors the genome is shot to hell by the time the tumor is
found…and…a mutation will not be in every cell in the tumor
33
.
The danger lies in the diversity within a cancer cell population
The mistake-prone process of DNA copying, cutting and pasting that goes on in cancer cells produces
remarkable outcomes. Cancer cells no longer have to obey instructions. They have been liberated from the
rigidity of conventional two-book genetic operating manuals. The ongoing process of massive alterations in DNA
provides a cancer cell population with novel instructions on how to cope with various emergencies. Thus when
chemotherapeutic drugs are encountered, some cancer cells in the population have different ways of dealing with
drugs. No matter what defenses the body may deploy, some cancer cells in a population always have a new
combination of instructions ready to face a crisis.
The cancer cells that leave home have increased informational diversity
The cancer cells that leave a primary tumor are often first found in the nearest lymph node draining the
tumor and later in more distant places such as the bone marrow. A comparison of the DNA contents of individual
cancer cells from the lymph nodes and bone marrow of the same patient to those of individual cells in the primary
tumor reveals that cancer cells at these different locations have accumulated their own specific changes in their
DNA contents
22
. 8
The cancer cells that leave the primary tumor represent a diverse population upon which selection will act.
Some cancer cells are destroyed by the immune system, others reach the lymph nodes and progress no further,
whereas still others reach an organ but are held in check by the local resident cell population and cannot
proliferate. Finally, some cancer cells survive all these hazards, grow at their new sites and ultimately destroy a
vital organ. In a nutshell, this is metastatic cancer.
Most cells in a primary tumor never leave
Only a small number of the cells in a primary tumor ever develop the DNA alterations to emigrate
21,34,35
. If
all cells had the capacity to leave, no primary tumor would be left
21
. When the cells of a primary tumor are tested
both clinically and experimentally for their ability to form a new tumor, only approximately 1 in 50,000 cells has the
capacity to do so
34-38
. Only cells that have sufficiently altered genetic operating systems or stem cell-like
properties
39-41
break free of the local constraints and depart. Normal cells always remain in their local
neighborhood.
DRUG RESISTANCE AND THE RETURN OF CANCER
Normal cells are inflexible in a crisis
When normal cells are subjected to chemotherapeutic drugs, the cells have a limited capacity to either
inactivate the drug or to expel it using various pumps that are found at the cell surface
42,43
. Some cells respond
better than others, since they have more efficient versions of these pumps and/or more efficient drug inactivating
systems. As the level of the drug increases, however, the inactivation and pump systems are overwhelmed and
normal cells die from drug toxicity. They lack operational flexibility, even in times of crisis, because they can only
implement the fixed instructions in their two-book operating manuals.
Cancer cells have additional flexibility in a crisis

By contrast, when cancer cells encounter a chemotherapeutic drug, the diversity within the cell population
is so great that some cells always have a novel combination of instructions courtesy of their massively disrupted
DNA contents. Some cells survive and grow back even in the face of different drug combinations. Thus the return
of cancer is understandable when viewed from the perspective of cancer cell populations, the members of which
have diverse and flexible operating systems. These attributes have yet to be recognized by most cancer
researchers who are generally unfamiliar with classical manipulations of large chunks of DNA and the
consequences of the additive effects of genes that are slightly sensitive to abnormal dosage
44
.
The flexibility inherent within a massively disrupted DNA cell population was clearly demonstrated by the
experimental removal of the main drug pumps from cells
45-48
. With their frontline multidrug defences completely
missing, such cells were nevertheless rapidly able to become drug resistant because of their massively disrupted
DNA contents.

How different is drug resistance in each person?

Every human being (except for identical twins) is unique at the DNA level. Hence each cancer cell
population follows a unique trajectory as the cells leave the primary tumor. Each woman with breast cancer will not
only differ in terms of drug resistance, but also in her intrinsic ability to control the growth of any particular cancer.
For example, breast cancers in African-American women are more aggressive and less responsive to treatment
than breast tumors in Caucasian women
49
. Some women will have cancers that return quickly, others more
slowly. The majority of women who respond to Herceptin will develop drug resistance within a year
50
, but others
take longer. Some cancers will even remain dormant for years.
Handling the truth
The earlier statements of Dina Rabinovitch, My cancer keeps recurring. Nobody can tell me why, are now
less mysterious when viewed in the context of the differences in flexibility between normal and cancer cells. 9
Most cancers rapidly become drug resistant because each population of cancer cells is different in terms of
its massively altered DNA contents. Each cancer reacts to drugs in its own way leading to the selection of those
cells with novel genetic operating systems that resist drug effects. It is the ability of any cancer population to
continuously adapt that makes it so dangerous.
NEW FRONTIER OR YET ANOTHER UNFULFILLED PROMISE?
Personalized treatment for the individual patient
Examining a person’s DNA profile has been popularized by forensic medicine and is now being applied to
cancer patients. Dr Victor Velculescu of John Hopkins University explains personalized cancer treatment
51
.
A cancer patient comes into a clinic and has her tumor analyzed. Then she is treated based on a spectrum
of her mutations with a cocktail of drugs. It doesn’t mean a new drug for each person, just a different combination
of drugs.
The above seems like a dream come true and is being heavily promoted as the new frontier in cancer, with
billions of taxpayers dollars due to be spent in this new area
52-55
. Pharmaceutical companies have recognized the
potential of increased sales and are designing new drugs to target cancer-based gene products in order to obtain
the biggest slice of this upcoming $60-$70 billion market.
DNA profiling
Current DNA profiling technology of single letter DNA mutations is straightforward, but how relevant is a
drug combination prescribed on the basis of profiling a primary tumor to shutting down metastatic growths?
Single letter mutations
When fully sampled, a primary breast tumor will harbor millions of mutations
6,32,56
. In addition, each
breast and colorectal patient analyzed to date
6
has been found to have a unique combination of mutations
15
. This
huge number of mutations, plus the unique combination of them in an individual, poses enormous challenges in
demonstrating the clinical relevance of mutations. Clinical relevance cannot be sufficiently emphasized.
Since only about 1 in 50,000 of the cells in a primary tumor has the potential to become metastatic
34-38
,
which of the millions of mutations are in the dangerous cells that leave? It is not possible to determine this
without first isolating these maverick cells from the bulk of the solid tumor. Since this is not done, DNA profiling
reflects the sum total of all the mutations in the primary tumor. Any clinically relevant mutations remain diluted by
millions of clinically irrelevant mutations. A DNA profile from a primary tumor consists almost entirely of noise.
Drug combinations
Future personalized drug combinations will require clinical trials and separate FDA approval. There are
currently only five FDA-approved combination regimens for one of the most intensely trialled major cancers,
colorectal cancer
57
, but the number of possibilities for new drug targets generated by the millions of mutations in a
primary tumor is astronomical. The mere thought of developing new drugs each specific to one of the millions of
potential new targets, given the current ten year time frame for the development and testing of each new drug, is
delusory.
Drug combinations can be dangerous. As Dr Steven Hirschfeld of the FDA points out; These are all myths
having to do with anticancer drugs…that they’re very targeted, when in fact all these drugs have multiple targets.
That they’re nontoxic, when in fact the latest ones have their own set of side effects. And that they’re cures, when
they are not
58
. There are no anticancer drugs that are specific for a single target; all bind to several
59,60
.
The data show that each cancer cell population is unique, each anticancer drug is nonspecific and each
patient differs with respect to drug resistance. Personalized cancer medicine in its currently practiced form of
determining the extensive DNA profile of a primary tumor via single letter changes and then prescribing drug 10
combinations is simply another promotional exercise
52,53,61-65
. The glib statement that, it doesn’t mean a new
drug for each person, just a different combination of drugs
51
, is completely out of touch with the reality of clinical,
pharmaceutical and FDA implementations.
The reality of massively disrupted DNA contents
Current personalized cancer medicine focuses on single letter mutations rather than the massively
disrupted DNA component of cancer. Half a century of genetics, however, shows that the effects of massive
changes involving many genes dwarf the effects of single letter mutations. Analyses of additions and deletions of
DNA in experimentally manipulable organisms reveal that varying the dosage of large chunks of DNA has far more
important biological effects on the flexibility of genetic operating systems than the small scale mutational changes
that can be induced in normal cells
44
.
So how have we reached this preoccupation with personalized DNA profiling of mutations when our
answer lies not in the bulk of the tumor, but in the tiny population of maverick cells with their massively disrupted
DNA contents? The answers lie in the fashions that dictate cancer research.
THE EARLIEST STAGES OF CANCER
To understand how cancer begins, it is useful to examine readily accessible tissues for the earliest stages.
One such place is the cervix where billions of PAP smears and other gynecological examinations have been
conducted. Here the first microscopically recognizable changes reveal that some cells have four copies of their
DNA instead of two
66-68
. Why is this finding so important?
Once four DNA copies are attained, all hell breaks loose
The two-copy to four-copy event is rare but can occur spontaneously in any normal cell population. Two
normal cells may fuse, or a normal cell may replicate its DNA but then not divide. Such events can also be caused
by viral infection
69
.
Once attained, a four-copy DNA state is 1000-fold more unstable than a two copy state
70-72
. These cells
with their doubled-up DNA begin to jettison the excess DNA or to silence their genes by mutation or chemical
modifications. Systems fail, errors increase enormously and deletions, additions, rearrangements and mutations
devastate the DNA.
Thus every-day cell biological processes, once started, wreak havoc. A population of cells is generated
with massively disrupted DNA contents leading to modifications in metabolism and further accumulation of
changes including single letter mutations
65,73-76
. The flexibility of this population far exceeds anything that can be
achieved by mutations alone in a two-copy DNA system. It is this flexibility which drives the spread of cancer and
subsequent drug resistance.
The mutationists
The theory of the mutational basis of cancer in humans is predicated on the progressive accumulation of
mutations in “cancer” genes in two-copy DNA systems. This interpretation received a boost when three specific
genes were experimentally introduced into a cell line and those human cells formed tumors when transplanted into
mice
77,78
. Mutations then became the drivers of cancer and the massively altered DNA contents of the metastatic
cells in patients, (which are crucial to drug resistance), were quietly ignored.
The results from this artificial three gene system, however, turned to dust. Reexamination of the original
cells not only revealed them to have massively altered DNA contents, but other investigators could not repeat
these findings using exactly the same three genes
79,80,81,82,83
.
These inconvenient truths, however, were ignored and investigators began a frenzied search for mutated
“cancer” genes in every tumor source. Having found mutations, however, few investigators attempted to determine
their clinical significance. It is axiomatic that if a mutation in a gene causes cancer, then reintroducing a good copy 11
of that gene into a cancerous cell should restore the cell to normalcy. When this simple test was conducted,
however, the cells did not revert to normalcy
80
. The basic premise of causality failed the most elementary test.
Worse follows. Recent population-based data on two famous breast “cancer” genes calls into question the
clinical significance of the extensively studied mutations in these genes, for which many women are tested
84
.
The BRCA1 and BRCA2 breast cancer genes
Most women are aware of these two genes and dread that they may carry mutations within them. After
decades of detailed examination of mutations in these genes, however, definitive clinical data now reveal that
breast cancer specific rates of death among women who are carriers of BRCA1 or BRCA2 mutations, are no
different to those of women without these mutations
84
. Clinical data have thus rendered irrelevant a decade or
more of mutation-based research data.
Despite all the clinical and experimental data to the contrary, leading cancer figures regard the mutational
basis of cancer as some sort of Final Truth which is not to be questioned; only the details need to be filled out.
Cancer researchers ferociously defend any genes on which they work as being absolutely crucial to some aspect
of cancer, no matter how tenuous, distant or vaguely relevant, the clinical connection may be. This is hardly
surprising; finding “cancer” genes is now a prerequisite for fundraising and for Big Science enterprises.
CANCERGATE
Finding all the mutations in all cancers
The director of the National Institutes of Health, Elias Zerhouni, approved major funding for a pilot project
to find all the mutations in certain cancers. As reported in the New York Times in 2005, this search would be
expanded into a $12 billion megaproject if it were to show signs of success
85
. In June of 2007, however, it was
revealed that fifty percent of the particular brain samples to be used for this study are unusable. This is due to the
discovery of large amounts of dead (necrotic) tissue in the samples
86
. Any competent pathologist would have
pointed out this problem before the start of the project, since large amounts of necrotic tissue are a well-known
hallmark of this particular brain cancer, termed glioblastoma multiforme. For the megaproject proponents to
somehow stumble upon this basic realization, after more than two years, is nothing short of a scandal. In
scrambling to limit the fallout from this deficiency in planning, the NCI is now allocating more funds to determine
the best practices to use in tissue sample preservation
86
.

The fatal flaw
There is an even bigger problem with the mutational basis of the megaproject. Most of the hundreds of so
called “cancer” genes that have already been prioritized to date have been designated as such on the basis of
statistical attributes, not on their clinical significance
6
. Reanalysis of these much-touted data on newly found
“cancer” genes
6
has now shown that; few if any of these genes are in fact significant
7
. There is no proper
statistical basis for their elevation to “cancer” gene status.
Cancer genes
The public is lead to believe by prominent cancer researchers and the media that every important “cancer”
gene is in the process of being tracked down by applications of new sophisticated technologies. The promise is
that once all “cancer” genes have been cataloged, it will be clear where the drug targets will be found. However,
the criterion being used for a “cancer” gene is simply that it carries a mutation in some tumors. Thus a particular
gene which was found to be mutated in only 1 out of 61 lung cancer patients is still considered to be a “cancer”
gene
61
. Another gene, mutated in 74 out of 199 colorectal cancers, 1 out of 24 lung cancers, none out of 11
pancreatic cancers and none out of 12 brain cancers, is nevertheless classified as a “cancer” gene
61
. The
“cancer” gene proponents seem unable to comprehend that such weak correlations are not indicative of causation.
12
More recently, analysis of over 500 genes considered to be potentially critical in causing cancer, were
tested for the presence of mutations in each of them in over 200 different tumors.
Nearly 40% of the histologically documented tumor samples from patients had no mutations
whatsoever in these supposedly important “cancer” genes
32
.
The party line on such data is straightforward. As long as a particular gene is mutated in some cancers, it
is considered to be a “cancer” gene, even though the data fail to satisfy even the minimum scientific standards for
causality
61
. When the standards have fallen this low, then we are no longer in the realm of world class research
but in the realm of voodoo genes and scientific spin. It is nothing short of a disgrace.
The Delusionists and the Spin Doctors
There is now an overwhelming amount of clinical and drug resistance data pointing to the ill-conceived
nature of the mutational megaproject and for the lack of a causative role of hundreds of “cancer” genes. The spin
doctors are nevertheless busy, arguing that if you turn over every rock, there is a lot more to be found
87
. Indeed
there is. However, the reality is that most of what is found has no clinical relevance whatsoever. What we are
witnessing is third rate science. It is indicative of stale and unimaginative leadership
54,87-91
.
The mutational Delusionists doggedly continue to examine the minutiae of the wounded (the millions of
mutations in primary tumors), hoping to learn what is going wrong
6,32,51,54,87-94
. They fail to face the one
important issue in the War on Cancer, are mutations the main enemy? As the clinical data on BRCA1 and BRCA2
have revealed so clearly, mutations are not the main drivers of cancer. The focus needs to be on clinically relevant
entities that bear on the survival of the patient, namely the massively altered DNA contents in metastatic cells that
play a pivotal role in drug resistance and survival.
The clinical deliverables: patients are still waiting…and waiting…and waiting
The above findings expose the contrasts among the absolute necessity for careful examination of tumor
tissues, the statistical pitfalls inherent in data analyses and the importance of generating data that relate to the
survival of the patient. Unless First Class standards are soon reinstated, there will be no clinical deliverables. As
pointed out recently in Newsweek by Sharon Begley, This is no way to cure cancer
95
.
The realism is that there is currently no magic bullet that targets a specific solid cancer for reasons that
should now be apparent
47,48
. It is massive DNA alterations that drive cancer
31,45-48,52,53,61,65,73-76,80
. Thus if
drugs are currently still the only immediate source of therapies, then they need to be applied in innovative ways to
metastatic growths
96,97
.
It is paradoxical that American medical technology is outstanding, that American doctors are better paid
than anywhere else in the world and yet vacuous cancer enterprises of marginal clinical value are so strongly
supported by American institutions.
The National Cancer Institute has an annual $5 billion budget and a unique track record. It has consistently
delivered one product year after year; unfulfilled promises of cancer cures (they’re still just around the corner). Are
patients and doctors still unable to see that the current approach, namely; more money, more technology and more
stratospheric hype, is not leading to cures?
THE HOPE
Cervical cancer demonstrates the generic way ahead, with its exemplary diagnosis and treatment involving
regular PAP smears and liquid based cytology. Of the projected 560,000 cancer deaths in the US in 2007, only
about 4000 will be due to cervical cancer. In parts of Asia, however, cervical cancer is the biggest killer of women
because diagnosis is either not performed or left too late.

Increased investment is needed in imaging and screening technologies for early detection such as
nanotechnologies that are able to detect whether cancer cells have left the primary tumor and accumulated in 13
lymph nodes
98
. It is time for early diagnosis and prevention to take precedence over research aimed at shutting
down cancers after they have spread
99
. Cancer agencies, well meaning charitable organizations and foundations
need to stop being automatic teller machines for basic science
100
.
One immediate preventative measure is staring everyone in the face. More people in the US will die from
lung cancer in 2007 (approximately 160,000), than all the deaths from colorectal, breast, pancreas and prostate
cancer combined. Tobacco usage is also a risk factor for the development of many other cancers. Stop its usage
and the incidence of lung and other cancers will be greatly reduced.
FAILURE IS NOT A CRIME. FAILURE TO LEARN FROM FAILURE IS.
Walter Wriston, former chairman of CitiCorp
It is time to heed Walter Wriston’s warning. The failure of various institutions to learn from failure is a
tragedy for cancer patients. If the current mindset is not replaced, the next 30 years will be a carbon copy of the
last. The losers will be members of our families, our neighbors and our friends.
This is the third article in a series. All three will be available on line at www.securegenetics.com
The first is;
Miklos, G.L.G. & Baird, P.J. The Latest Surge in the War on Cancer; Tour de Force or Tour de Farce,
Barnesworld, March 5 2007. http://barnesworld.blogs.com/barnes_world/2007/03/george_l_gabor_.html
The second is;
Miklos, G.L.G. & Baird, P.J. Curing Cancer; Running on Vapor,
Genetic Engineering and biotechnology News, (GEN), 2007, May 1, 27, (9), 6-10.
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Copyright © George L Gabor Miklos and Phillip John Baird

One Response to George Miklos on Cancer Cures

  1. Brian O'Donnell says:

    George, even to a lay person such as I, this is a revelation. Brian O’Donnell

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