This is the Health Show, a presentation of national productions.
Over the years, there have been two words that have summed up the most effective weapon
in the fight against cancer, early detection.
Now researchers are trying hard to make early detection quicker, easier and, well, earlier.
You're looking for the cancers that would have caused problems and are lethal in potential.
Today's Health Show will hear about advances in the early detection of cancer, and hear
from a clinical researcher about the feasibility of finding warning signs for cancer and blood.
We'll also focus on one of those tests that is generating a lot of controversy, the PSA
test for prostate cancer.
Dr. Nina Saks is away this week.
I'm Bob Barrett, and this is the Health Show.
In many cases, if you are showing symptoms of cancer, it could be too late to mount an
effective defense against the disease.
So for years, doctors and researchers have been searching for ways to screen people for
cancer before any signs of the disease begin to show.
Joe Bellinfee from the National Institutes of Health has more.
Some types of cancer can be found before they cause symptoms, checking for cancer or for
conditions that may lead to cancer, and people with no symptoms is called screening.
The goal of screening is to detect cancers that would be easier to treat, and particularly
to change the outcome.
Dr. Barry Kramer at the NIH says it's not enough to just detect cancer early.
They're looking for the cancers that would have cause problems and are lethal in potential,
hoping to pick them up at an earlier point in their development at a time when they can
be treated and the death from the cancer averted.
Screening is a tool that's used across many illnesses, but Dr. Kramer adds that there
are some particular challenges or differences when it comes to cancer screening.
In part, because not all the cancers that we detect are lethal, and yet under the microscope,
they look similar enough to the lethal cancers that they have to be treated.
Therefore in cancer screening says Dr. Kramer, there is an element of overdiagnosis.
There's also the concern of false positives.
That happens quite commonly with a variety of screening tests.
So the person without cancer actually has a positive test, and therefore they have to go
through the fear, the false alarm, and the anxiety of going through workups in the fear
that they may actually have cancer when they don't.
He also points out that screening tests can have some risks just from the test themselves.
But a key point Dr. Kramer emphasizes is that most screening tests are a closer call
than previously thought.
For too long, we have relegated messages about screening to sound bites, simply convincing
people that if you picked up a cancer when you didn't have any symptoms that was necessarily a good thing,
but we're learning more and more about the harms.
And it's a closer call than we often like to think.
He recommends that people carefully weigh and discuss the benefits and risks of cancer screening.
I think that the public should be aware of the trade-offs.
And if they're going to ask their doctor, they should come armed with a set of questions.
And that is what are the harms of the actual test?
What are the benefits of having the test?
How strong is the evidence?
What is the magnitude of the benefits?
For more information about cancer screening and to get details about measuring the effectiveness
of cancer screening tests and weighing the evidence from screening research studies,
visit cancer.gov.
Also, cancer screening and the science behind it is the topic of a recent special issue
of the NCI Cancer Bulletin, which is also available at cancer.gov.
This is Joe Bolinfi.
So the bottom line, early detection, good.
And that's been one of the primary objectives of many major cancer research initiatives.
Much of that research has gone into finding so-called biomarkers circulating in blood that
would indicate that cancer is forming in the body before any over-symptoms appear.
But is that really feasible?
There are just a few of these tests being used in clinical practice right now, and the
current controversy over the PSA test for prostate cancer is further caused for concern
over the reliability of these tests.
In the January 2013 issue of the journal Clinical Chemistry, Dr. Daniela Conforte wrote a
perspective article asking just that question.
Dr. Conforte is a graduate of the post-doctoral diploma program in clinical chemistry at
the University of Toronto, and is currently a clinical biochemist at Life Labs, a community
laboratory in Toronto.
Dr. Conforte, many of these blood-based cancer biomarkers are already commonly used in
clinical practice for risk surveillance and for monitoring therapy.
But effective blood-based biomarkers for early diagnosis of cancer, those are lacking.
Why are biomarkers for early detection of cancer so important?
Well, detecting any disease early, including cancer, is very important because it usually
means more opportunities for different interventions and therapies, with increased potential
for improving patient survival and quality of life.
For instance, there are many studies that have shown that early detection of breast cancer
in women over 50 years of age with annual mammogram screening programs improved survival
by about 20 to 25%.
Also patients with stage 1 ovarian cancer detected by transvaginal ultrasound have a five-year
survival rate of about 93%, compared to only 30% for patients with stage 3 to stage
4 disease at diagnosis.
The other examples of cancer screening procedures and biomarkers that have considerably improved
patient outcomes include pap tests and now molecular tests for cervical cancer, colonoscopy,
sygmy, doscopy, and fecal-cal blood tests for colon cancer, blood-human-chorionic gonadotropin
or HCG for testicular cancer and for gestational trophoblastic disease, and also blood alpha-phido
protein or ASP in those people who are at high risk of developing hepatic cellular carcinoma.
What criteria should a circulating biomarker for early detection of cancer fulfill?
As you mentioned in your introduction, Bob, only a few tumor biomarkers in clinical use
are suitable for population screening and or early diagnosis.
So a biomarker test for early detection of cancer should be sufficiently sensitive and
specific and here I refer to both diagnostic and analytical sensitivity and specificity.
Also it should be relatively inexpensive and safe to be applied to mass populations.
It should also be relatively non-invasive and provides sufficient lead time.
A lead time is the time interval from screen detected cancer to clinical diagnosis in
the absence of such screening.
In other words, it is the time between asymptomatic disease and metastasis.
The lead time for early cancer detection using a blood biomarker depends on the growth trajectory of a cancer.
An aggressive tumor will have a significantly shorter lead time than a slow progressing tumor.
Usually improved lead time means more effective interventions which leads to improved disease outcomes and improved survival.
Another important requirement for bringing a blood-based biomarker into routine clinical use
is developing a high throughput to use laboratory tests to reproducibly and accurately measure such biomarker.
In addition to these requirements, clinical benefits provided by tumor markers should clearly outweigh any potential harms.
Two examples are overdiagnosis and over treatment of indolent cancers that will not lead to symptoms or cause death.
Another potential harm is a lead time bias.
This refers to early diagnosis of a cancer that does not lead to improved survival.
One good example of a blood biomarker for early cancer detection whose benefits and harms are still
highly debated is prostate-specific antigen or PSA.
There's still not sufficient evidence to definitely answer the question of whether early detection of prostate cancer
always improves quality of life and or patient survival.
Well given this long list of requirements, how feasible is it to identify circulating biomarkers for early detection of cancer?
This is exactly the question that researchers Sharon Horry and Fengi of Gambar from Stanford University School of Medicine
tried to tackle in their article published in Journal Science Translational Medicine at the end of 2011.
The first objective of this study was to use mathematical modeling to quantify the time required for growing malignant tumor
to reach a sufficient size so that its blood biomarker levels can be detected by currently available blood tests.
Ovarian cancer and CA 125 biomarker were used to provide realistic baseline values for model simulation.
Ovarian cancer was chosen because it remains relatively asymptomatic until advanced
and there is a significant opportunity for improvement in early detection.
CA 125 is considered a gold standard biomarker test for surveillance of women with epithelial ovarian cancer.
It is not a screening test but the main advantage is that it has been sufficiently studied
with all the required model parameter values available from the literature.
The second objective of the study by Horry and Gambar was to use the model to identify biomarker related parameters
that most greatly affect early cancer detection and also quantify through simulations how much each
baseline parameter value has to change to achieve early tumor detection.
Tumor biomarker parameters that were tested in the model included
grade of tumor biomarker shedding into the blood, tumor marker clearance,
and the percentage of the tumor volume consisting of tumor cells.
They also modeled in analytical sensitivity of clinically available biomarker tests.
The authors chose a solid tumor with a diameter of 1 millimeter as the goal for early detection.
Briefly, the model was designed to predict changes in the blood biomarker levels as a function of time
and to relate them to the corresponding tumor burden, meaning tumor volume or tumor diameter.
Two growth models were used in the study.
The first model assumed exponentially growing tumor starting from its genesis.
The second and more physiologically plausible model assumed both
mono-exponential growth as well as tumor decay.
For each growth model, the authors tested two scenarios.
In one scenario, a biomarker was 100% tumor specific and in the other, a biomarker was
secreted by both tumor and normal cells.
Well, let's get to the last page of that.
Can you summarize the main findings of that study by Horian Gambier?
Well, the simulation-based analysis identified parameters that are useful in improving early
cancer detection. And those are tumor marker shedding rates, biomarker specificity,
and assay analytical sensitivity.
Importantly, the study also identified parameters that do not improve early detection.
And those are a fraction of biomarker reaching blood and the rate of its elimination from the
circulation. In addition, the model quantified how far the parameters I have just mentioned
must be perturbed to achieve early, in this case, sub-millimeter detection of cancer.
Though the estimated time until detection by current CA-125 test was found to be about 10.6
to 12.6 years, at which point, a variant tumor is about 4 centimeters in diameter,
and this agrees what is currently seen with transvaginal altarsine procedures.
According to the model, to detect a tumor within a diameter of 1 millimeter,
would require a biomarker that is almost 100% tumor specific and has a shedding rate of about
10,000 times higher than that of any known protein tumor biomarker.
Additionally, further improvements in the analytical sensitivity of current clinical assays
by 10,000 folds would also be required. This way, the tumor would be detected in 5.6 years,
which would provide us really with about 4 to 6 years of lead time advantage over current detection
methods. Collectively, as you can see, these results indicate that it may not be feasible to use
a single circulating biomarker for early detection of cancer.
Still to come, our conversation with Dr. Don Yellicon Forte continues with a look at the
limitations of the study by Horian Gambier. That's next on the health show.
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This is the health show. I'm Bob Barrett. Our guest today is Dr. Don Yellicon Forte, a graduate of
the postdoctoral diploma program in clinical chemistry at the University of Toronto,
and a clinical biochemist at Life Labs in Toronto. We're talking about the feasibility of using
circulating blood biomarkers for the early detection of cancer and honed in on a study by
Dr. Sharon Hori and Sanjeev Gambier from Stanford University School of Medicine. We heard about
that study's conclusion, so I asked Dr. Don Forte about the study's limitations.
Well direct extrapolation of the model predictions to the clinical use is hard to validate for
several reasons. One tumor age cannot be accurately measured at clinical diagnosis,
and two, there are no patient data correlating tumor size with blood biomarker levels,
either before and after cancer diagnosis, or for multiple time points throughout the natural
course of disease progression. So this relationship between tumor size and blood biomarker levels
that the model is based on is not really well understood. The model also may not be useful for
cancers whose parameters are not available from the literature, those cancers that haven't been
extensively researched like ovarian cancer. This means a lot of assumptions have to be made
in the modeling itself. The target of one millimeter for early detection that the author's
set may not be applicable or even a necessary in my opinion for every type of cancer.
The one millimeter target is more appropriate for early detection of an aggressive tumor
with a short doubling time than for a slow growing indolent tumor with a long doubling time.
So a small improvement in early detection will affect the lead time of indolent tumors much
more appreciably the death of aggressive tumors. I think that the goals of early cancer detection
still need to be debated among researchers and clinicians. So when selecting criteria for a
blood biomarker of interest, researchers have to consider the type of cancer and its aggressiveness.
How do you think the international research community can benefit from this in similar
mathematical models and their efforts to identify those biomarkers for early detection of cancer?
I think models like this can be used to address the potential and limitations of tumor biomarkers
and the early investigative stages. They can certainly help researchers to identify criteria
for prioritizing biomarkers, some may be more feasible to study than others. This can not only save
time but also help focus valuable resources that are so difficult to come by these days.
Furthermore, mathematical models like this one can be used to perform simulations quickly
across a wide range of biomarker-related parameters. Such simulations can also encompass the large
inter and intra individual biomarker variation, in other words biological variability that may exist
for some types of cancer and would make the model generalizable for any solid cancer that
secreeds a biomarker into circulation. With the current version of this model, only one or two
tumor-related parameters can be manipulated at a time. If future versions should include simulations
that are simultaneous of multiple parameters. My hope also is that models like this will be
really available to the researchers. Well finally, Dr. where do you think researchers should
aim their efforts in order to make blood-based biomarkers for early detection of cancer a reality?
I think the study by Hori in Gambert clearly shows that mathematical models can be important
tools in the evaluation of relevant parameters of blood biomarkers for early detection of cancer.
However, we have to understand that the models are as good as the assumptions they're based on
and is good as the baseline clinical parameters obtained from biological data which are used in
simulation studies. So what is needed in the future? For one, I think we need to expand our knowledge
of the natural process of cancer initiation and progression. We need to do more research to
better understand how tumor size relates to biomarker blood levels. For instance, what are
in vivo biomarker shedding rates? What are the effects of tumor microenvironment on those shedding
rates? What fraction of biomarker is reaching the blood and how do these parameters change with time?
These findings will clearly lead to development of multi-scale predictive mathematical models
that can more accurately select characteristics of biomarkers that are necessary to improve early
detection. Also, advertisements in the areas such as nanotechnology will help improve much needed
analytical sensitivity of tumor biomarker assays. We usually talk about protein biomarkers,
however, the research should also include non-protein blood biomarkers such as tumor-specific
microRNAs, epigenetic biomarkers, mitochondrial DNA markers, post-translational modification,
as well as anti-tumor immune response markers. As this study showed, it may not be feasible to rely on
single blood tests for early detection of cancer. A combination of a panel of circulating biomarkers
and diagnostic imaging procedures is more likely to do the job. Dr. Don Yellicon Forte is a
graduate of the post-doctoral diploma program and clinical chemistry at the University of Toronto,
and is currently a clinical biochemist at Life Labs, a community laboratory in Toronto.
Her perspective article, asking if early detection of cancer with circulating biomarkers is feasible,
appears in the January 2013 issue of the journal Clinical Chemistry.
Dr. Don Yellicon Forte mentioned the PSA test and the current controversy surrounding its
effectiveness is a screening tool for cancer. Well, according to a recent major report from the
prostate lung colorectal and ovarian cancer screening trial, a 17-year project of the National
Cancer Institute, six annual screenings for prostate cancer led to more diagnosis of the disease,
but no fewer prostate cancer deaths. The trial was designed to provide answers about the effectiveness
of prostate cancer screening. This particular report focused only on prostate cancer.
That's Dr. Christine Berg, the National Cancer Institute leader of the PLCO trial and senior author
of the study. And the straightforward analysis shows that at seven years of follow-up,
there was no decrease in death in the group that got actively screened compared to the group
that got screened by their local physicians. However, there were 500 more cancers found,
so we still saw 50 deaths in the actively screened group, 44 deaths in the less actively screened
group, but we had 2,800 cancers in the actively screened group and 2,300 cancers in the less
actively screened group. So detecting 500 more cancers did not prevent those other 50 deaths.
There were more than 76,000 men in the trial that was conducted at 10 centers around the United
States. Of the men in the trial, roughly 38,000 were randomly assigned screening, including annual
PSA tests. The others were randomly given usual care, but received no recommendations for or against
annual prostate cancer screening. Dr. Berg explains that the difference between the numbers of deaths in
the two groups was not statistically significant. Thus, there was no detectable mortality benefit for
screening versus usual care. And so, when a man who's deciding whether to be screened or not
needs to put this whole picture together, he needs to weigh his own individualized risk,
based on his age and family history and race. African-American men tend to be at a somewhat
higher risk, and he needs to look at his other health conditions, and he needs to talk with his
physician or his urologist. NCI does not have a recommendation about prostate cancer screening.
The US Preventative Services Task Force, whose recommendations are considered the gold standard
for clinical preventive services, recently concluded that there is insufficient evidence to assess
the balance of benefits and harms of prostate cancer screening in men younger than age 75,
and recommended against prostate cancer screening in men age 75 and older. But Dr. Berg emphasizes
that information from the PLCO trial will help. This is leading towards our holy grail of
individualized medicine. However, it comes with uncertainty in the process of us getting that
information. It's a very complex mixture before we can say, all right, you, you,
gentlemen sitting in my office today, this is what your chances are, you know, in the future.
And then it's still going to be a measure of risks and benefits and individual risk tolerance.
Dr. Berg adds that the National Cancer Institute wants to understand why some prostate cancers are lethal
even when found early by annual screening. And what approaches can be used to identify these
more aggressive cancers when they can be effectively treated.
That's all the time we have for this week's Health Show. If you'd like to listen again,
join us online at healthshow.org. You can explore the archive for any programs you might have missed
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And if you have any questions or comments about the programs, send them in. Our email address is
letters at healthshow.org. Dr. Nina Sacks will be back with us next week. I'm Bob Barrett.
Till then, stay healthy and be sure to join us next time for another edition of the Health Show.
Dr. Nina Sacks is a practicing member of the American College of Gastroenterology.
Bob Barrett is producer of the Health Show. Dr. Alan Shartock is executive producer.
The Health Show is a presentation of national productions, which is solely responsible for its
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