Download LESSON 5.2 WORKBOOK What do cancer screens really tell

LESSON 5.2 WORKBOOK
What do cancer screens really tell
us?
DEFINITIONS OF TERMS
Mortality rate – The rate at
which people die from a specific
cancer.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 5.2
Treating cancer successfully requires that we are able to detect it early. As more
diagnostic techniques are developed it becomes important to understand how
reliable they are – how many cancers will they miss and how many times will they
indicate that cancer is present when it is not? This lesson discusses the concepts
of sensitivity and specificity and shows how screens can lead to ‘overdiagnosis’ and
why overdiagnosis poses a problem, using recent findings with breast and prostate
cancers as an example.
Evaluating cancer screens: specificity and sensitivity
As we have discussed in previous lessons, an abiding problem with cancer treatment is that symptoms
may appear well after the primary cancer has metastasized. When this happens it is almost inevitable
that the cancer has become more difficult, even too difficult to treat. It is clear that reliable screens to help
us identify those benign tumors that are going to become malignant and malignant tumors before they
metastasize are key. In the last lesson we began to examine the screening programs that are available
to identify tumors at these early stages. But in order to evaluate how useful a screening program may be
we need to have more information than how it works. We need to know whether it is effective in detecting
tumors at the important stages before metastasis and whether it targets tumors for treatment that would
never have been problematic. These kinds of evaluation pose another problem – the difference between
population statistics and individual behavior. When a program is evaluated on the basis of its effectiveness
for the population as a whole it gives no information to an individual as to how they themselves might fare.
Sometimes an individual may fare in the same way as most of the population. Other times they may act
like outliers and have an experience very different from the population as a whole. This is another challenge that we need to deal with when assessing which screens and treatments are most effective.
Notes:
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LESSON READINGS
DEFINITIONS OF TERMS
Specificity – how accurate a
screen is in identifying abnormal
cells.
False negatives – Those cells
(or people) that are abnormal,
but are falsely identified as being
normal.
Sensitivity – how likely a screen
is identify abnormal cells.
False positives – Those cells
(or people) that are normal, but
are falsely identified as being
abnormal.
Let’s assume we are
evaluating two screens
that have been designed,
like the Pap smear, to
detect pre-cancerous and
malignant cells. Let’s say
one screen detects the
abnormal cells by dying
a protein in the cells red,
while the second screen
detects abnormal cells by
their shape. We evaluate
the screens using two
criteria.
1. According to Figure 1, how many
people are false positives detected
by Screen 2?
aa. 20%.
bb. 30%.
cc. 70%.
dd. 80%.
Figure 1: Two sample screens for a population. A highly
specific screen (Screen 1) will only identify diseased individuals,
but may miss people who are diseased that do not test positive
for the screen. A highly sensitive screen (Screen 2) will identify
everyone with the disease, but may falsely identify some people
as having disease that actually don’t.
The specificity of a
screen tells us how
accurate the screen
is in identifying abnormal cells. The red screen would be good at identifying cells that are red, but will
miss cells that are abnormal - if they aren’t strongly red for example. These cells will be called ‘false
negatives’; that is, they are abnormal, but the screen hasn’t detected them.
On the other hand the sensitivity of a screen tells us how likely the screen is to identify abnormal cells. A
cell shape screen will identify cells that are clearly abnormal well, but it may be more likely to define cells
as abnormal that are really normal. These cells will be called “false positives”.
Figure 1 compares how two different screens on a population of people some of whom are normal
(green smiley faces) and some of whom are sick (orange sad faces).
■■ Screen 1 is in purple. Out of the 10 people in the population it has correctly identified 20% as sick
and correctly identified all the normal people. However it has missed 20% of the population. These
false negatives are sick but think they’re normal.
■■ Screen 2 is in red. Out of the 10 people in the population it has detected everyone who is sick, but it
has also identified 30% of the normal population as sick These false positives are really normal.
Wo r k b o o k
Lesson 5.2
MC Questions:
In reality all screens struggle to achieve the right balance between false negatives and positives – but
what is right?
2. True or False: The best screens will
have no false positives and no false
negatives
aa. True.
bb. False.
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154
LESSON READINGS
Screening outcomes: the problem of overdiagnosis
DEFINITIONS OF TERMS
Non-progressing cancers –
cancers that have evolved such
that they can no longer grow or
spread to other tissues. These
cancers will not cause disease.
Overdiagnosis of cancer –
diagnosis of cancer that will never
be life-threatening.
Wo r k b o o k
Lesson 5.2
One important take-home message
from this module is that cancer is the
end-point of an evolutionary process
that starts with a normal cell becoming able to hyperproliferate and ends
with metastases. But there is no
single path from benign to malignant
and metastatic. Figure 1 illustrates
four distinct ways the disease could
progress from an initial screen
(indicated by the ‘abnormal cell’ in the
bottom left. In the 1st model ‘very fast’
the cancers progresses very quickly.
Figure 2: Model for progression of abnormal
(cancer) cells. Fast growing tumors will be likely to
Individuals will likely display sympcause disease and death from cancers, while patients
toms very quickly after the cancer
with slow growing tumors and non-progressing
has been detected and are likely to
tumors will likely die from unrelated causes before
die if they are not treated. Clearly they
they will die from cancer.
would suffer greatly if they were a
false negative on the screen, as would
individuals in the 2nd model ‘fast’. On the other hand, in the 3rd model ‘slow’ and the 4th model ‘nonprogressing’ the cancer is growing so slowly that they will more likely to die from unrelated causes (like
age) than they will from the cancer itself. This group would not suffer physically at all if their cancer was
never identified. Not only that they will also be spared considerable non-productive anxiety over the years.
The $64,000 question an informed patient would want answered is: ‘Before I get tested how can you tell
which model my cancer would fall under if it was detected?’. It should be very clear from this module that
we are still nowhere near having an answer to that critical question. Because of this the strategy that has
been used is to screen and treat all cancers as though they fall into the worst case scenario – that is if a
screen detects evidence of a benign tumor, treat it as if it will become malignant, if it detects evidence of
a malignant tumor treat it as if it will metastasize. This strategy would be appropriate for Models 1 and 2,
but not for Models 3 and 4. The problem it causes has been termed overdiagnosis. Overdiagnosis then
results in overtreatment. We can easily understand why overtreatment is problematic simply by knowing
that the three major cancer treatments we have available, namely surgery, radiation, and chemotherapy
are commonly referred to as “slash, burn, and poison”. Because cancer treatments themselves are so
painful and traumatic, the decisions to treat when it is not required should not be taken lightly..
MC Questions:
3. True or False: All cancers will
progress to metastasis.
aa. True.
bb. False.
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LESSON READINGS
Cancer overdiagnosis and
overtreatment
Breast Cancer
DEFINITIONS OF TERMS
US Preventative Services
Task Force (USPSTF) – a
governmental agency responsible for determining guidelines
for screening programs for the
population.
Prostate-specific antigen – a
protein that is produced by prostate cancer cells that is secreted
into the blood. This protein has
been used as a diagnostic test for
prostate cancer.
Wo r k b o o k
Lesson 5.2
Mammograms have been used as routine
screens for detection of breast tumors since the
1980s. Programs to raise awareness of breast
cancer have promoted the notion that ‘early
detection is the key to a cure for breast cancer’.
And the best method for early detection was
a yearly mammogram for every woman over
the age of 40. Recently, the US Preventative
Services Task Force (USPSTF), a governmental agency charged with determining the
guidelines for screening programs throughout
the country, changed these recommendations.
Now mammograms are only recommended for
women over the age of 50 and then only every
1-2 years, not necessarily annually.
Figure 3: Since mammograms were
introduced as routine screens in the 70s,
there has been a rise in detected cancer,
but this rise has not increased in a rise of
late stage cancers. We are identifying many
more cancers, but these may never become
problematic.
These changes left many people perplexed. What had happened? Was early detection no longer the
key to cure? In fact the USPSTF report provided good evidence that the original mammogram screening
program had detected many more early stage breast tumors and cancers (which is why the blue line in
Figure 1 rises). However this increased detection hadn’t improved the rate at which late stage cancers
were diagnosed (the brown line in Figure 1 stays flat). Why not? The problem comes in connecting
detection with cure. The USPSTF realized that most of the early stage tumors the mammogram
screening program was detecting would never become the late stage aggressive metastatic cancers
that cause severe disease (if they did the brown line in Figure 1 would fall). So, the screens were actually
overdiagnosing cancer, by identifying women under age 50 who had malignant tumors in the Model 3 and
Model 4 category. Many of those women were often also overtreated with extensive surgeries leading to
extreme anxiety.
MC Questions:
4. Overdiagnosis is a problem because:
(Circle all correct.)
aa. Screens will falsely identify
people with cancer who don’t
have disease.
bb. People don’t need to know if
they have cancer.
cc. Cancer treatment is so painful
and traumatic.
dd. Some cancers will not ever
metastasize and cause severe
symptoms.
5. Why did the USPSTF change
recommendations for
mammograms? (Circle all correct.)
aa. They were trying to reduce
overdiagnosis of breast cancer.
bb. Mammograms are unaffordable
under most health care plans.
cc. The identification of late stage
cancer was not being reduced
by mammogram screenings.
dd. Early stage cancers were not
being identified early enough.
6. True or False: Screening
recommendations for the population
are always under review.
aa. True.
bb. False.
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LESSON READINGS
Prostate Cancer
DEFINITIONS OF TERMS
Double mastectomy – surgical
removal of both breasts.
Prostate cancer is extremely common – it has been estimated that 80% of men over the age of 80 have a
prostate cancer diagnosis. The ‘early detection, early cure’ principle pushed for development of a routine
screen. The prostate gland supplies the fluid for semen, and produces a protein called prostate-specific
antigen (PSA), which promotes sperm movement. The prostate normally secretes low levels of PSA
into the blood. Whenever the prostate is damaged, the secreted PSA levels in the blood rise. This is
particularly true when prostate cells are hyperproliferating. Because of this, men over the age of 50 were
recommended to have regular screens for blood PSA levels. If levels were high they were recommended
for either surgery or radiation. Both of these treatment options are highly unpleasant. Because of the
location of the prostate close to the urinary tract and genitals surgery commonly left men incontinent or
impotent or both. Recently these recommendations have also changed and the USPSTF now no longer
recommends PSA screens at all. Why? Two main reasons: First, prostate glands increase secretion of
PSA whenever they are damaged, not just during cancer and many men, particularly aging men have
high levels of PSA for other reasons such as because the prostate is inflamed. Second even though
prostate cancer might be present and correlated with high PSA levels, this does not necessarily mean that
a cancer will progress. In fact most prostate cancers fall solidly in Model 4 – they never progress to severe
disease. The recommended approach now is ‘watchful waiting’. The physician will regularly monitor a
prostate tumor and only perform surgery or radiation treatment when there is evidence it is growing.
Genetic Screens
Cancer research has pinpointed mutations in several genes that are hallmarks for cancer. Individuals
having these mutations may be predisposed to developing cancer since their cells are already ‘on the
way’ to becoming able to hyperproliferate. In particular certain combinations of mutations have clearly
been associated with increased incidence (mutations to both BRCA 1 and 2 for example predispose
to both breast and ovarian cancer). Angelina Jolie inherited both BRCA mutations and chose to have
prophylactic surgery - she underwent a double mastectomy thereby reducing her risk of developing
breast cancer by over 90%. However single mutations may never progress to cancer formation, and
hence prophylactic surgery in this case is likely to be overtreatment.
Wo r k b o o k
Lesson 5.2
As we’ve described in this module, it takes many steps for a tumor to become a cancer, and we are
not able to predict what path any once cell will take. While some people might favor life-altering cancer
treatment under any conditions, others might alter their treatment plan if they understand when receiving
a diagnosis of cancer does not necessarily meant developing a life-threatening disease. Individual health
choices may vary from what the USPSTF recommends, but it is important that these choices are made
through informed decisions.
MC Questions:
7. Which of the following is a
reason that PSA screens are not
recommended for prostate cancer?
(Circle all correct.)
aa. The PSA test is not very accurate
in identifying PSA levels.
bb. Prostate cancer is a slowgrowing disease.
cc. Many people have high blood
PSA levels normally.
dd. PSA is secreted non-specifically.
8. True or false: A genetic screen of
your DNA sequence will reduce your
risk of cancer overdiagnosis.
aa. True.
bb. False.
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STUDENT RESPONSES
Explain how specificity and sensitivity are a trade-off in cancer screens. Also, what instances would you want a highly specific
cancer screen? When would you want a highly sensitive cancer screen? (Hint – think about severity of disease vs. severity of
treatment.)
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Remember to identify your
sources
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Wo r k b o o k
Lesson 5.2
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TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 5.2
DEFINITION
Double mastectomy
Surgical removal of both breasts.
False negatives
Those cells (or people) that are abnormal, but are falsely identified as being normal.
False positive
Those cells (or people) that are normal, but are falsely identified as being abnormal.
Non-progressing cancers
Cancers that have evolved such that they can no longer grow or spread to other tissues. These cancers will
not cause disease.
Overdiagnosis of cancer
Diagnosis of cancer that will never be life-threatening.
Prostate-specific antigen
A protein that is produced by prostate cancer cells that is secreted into the blood. This protein has been
used as a diagnostic test for prostate cancer.
Sensitivity
How likely a screen is identify abnormal cells.
Specificity
How accurate a screen is in identifying abnormal cells (or people).
US Preventative Services
Task Force (USPSTF)
A governmental agency responsible for determining guidelines for screening programs for the population.
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