Instructor: Hello, and welcome to the second part
of our lecture on breast cancer epidemiology.
In this lecture,
we're going to turn to breast cancer prevention.
So to begin with, we see where we'll discuss tamoxifen.
So a key aspect of breast cancer
is that breast cancer specimens
or tissues that are collected
via biopsy or surgical procedures like mastectomy
are routinely subjected to laboratory analysis
of estrogen receptors and progesterone receptors.
Again, estrogen and progesterone being two key hormones
that may play a role in breast cancer risk or prevention.
Breast tumors, which are positive
for estrogen receptors may respond
to hormone therapy by the administration
of selective estrogen receptor modulators
or sSERMs like tamoxifen.
Tamoxifen is now being offered to women treated
for early stage breast cancer for protection
against the development of second primary cancer
in the contralateral breast or the other breast.
In the US,
the Food and Drug Administration has also approved tamoxifen
for use as a preventive agent in high-risk women.
And the use of tamoxifen really came from the results
of four randomized clinical trials that looked
at the possibility of breast cancer prevention.
Of these trials, one of them performed
in the US showed beneficial effects, and also,
there were two European trials
that did not find any effects.
In a fourth trial conducted in European centers,
tamoxifen reduced the incidence
of breast cancer by 32% compared to a placebo
but there was a significant excess
of deaths in the tamoxifen group.
So there's several adverse side effects
of tamoxifen as well, including endometrial cancer,
estrogen receptor negative breast cancer, colon cancer,
pulmonary embolism, and other thrombotic events.
The appearance of the breast
on a mammogram facilitates the partition
of tissues into different areas, looking at zones
that are primarily composed of adipose
or fat tissue and zones that are made mostly
of fibrous and glandular tissue.
In 1976, John Wolfe, a radiologist in Detroit, Michigan
was the first to describe differences
in breast cancer risk associated with variations
in the mammographic appearances of the breast.
And here we see
that one's breast cancer risk increases
when someone has a higher percentage of dense breast tissue.
Next, looking at NSAIDs or again,
these anti-inflammatory drugs,
we see that many epidemiologic studies
have noted a significant preventive effect
of non-steroidal anti-inflammatory drugs
or NSAIDs against breast cancer.
A meta-analysis of these investigations, which is depicted
on this slide, comparing all these many different studies,
suggests that the risk of breast cancer
is reduced by approximately 25%
with regular use of common over-the-counter NSAIDs,
like aspirin and ibuprofen.
Studies in molecular epidemiology
in animals suggest this effect is manifest primarily due
to blockade of Cyclooxygenase-2 or the COX-2 enzyme,
which is a rate-limiting inducible enzyme
of the inflammatory cascade.
As mentioned before, some of the key findings
about breast cancer risk
and breast cancer prevention were drawn
from the Women's Health Initiative Observational Cohort.
In this study, 80,741 women took part
without cancer at baseline.
These women were 50 to 79 years of age
and baseline data on NSAID use was collected.
When collecting four years of follow-up data
or nearly 300,000 person years,
1,392 cases of breast cancer were detected.
This showed that there was an annual breast cancer rate
of 481 per 105.
Conclusions from the study found
that NSAIDs reduced breast cancer risk by 28%
and ibuprofen or taking ibuprofen reduced the risk by 49%.
But at the same time, acetaminophen had no effect.
The key mechanism of action
was blocking the COX-2 inflammatory cascade.
So again, circling back
to prostaglandins and estrogens one last time,
we see the u pregulation of prostaglandins by induction
of the COX-2 gene, stimulates estrogen biosynthesis
by activation of the promoter II region of the CYP-19,
our aromatase gene,
and the key names of the CYP-19 gene
and the promoter II region are not as important
as remembering that prostaglandins
and estrogens play a key role
in the development of breast cancer.
And that COX-2 is an intermediate element of that cascade.
So as noted in the WHI study,
blocking that COX-2 mode of action has the potential
to lower one's risk for breast cancer.
And some of that is depicted here in this figure
that has a lot going on
and it's certainly not important to know all
of these different steps that may take part
in mammary carcinogenesis.
But this model is depicting some
of the relationships between key players
in the carcinogenesis of the mammary glands of the breast.
We see some key players, the epithelial tissues,
the adipose tissues, the role of chronic inflammation,
including cyclooxygenase 1 and 2.
We also see, as noted before,
that the CYP-19 gene leads to production of estrogen,
which will lead to mitogenesis and cell replication,
potentially leading to more mutations in cancer.
Finally, I just wanna remind everyone that a lot
of these findings were found
using the Hill's criteria of judgment.
So these criteria, as we'll recall,
are used to look at epidemiologic studies
and really weigh the strength of their conclusions.
So as you noted before, there may be times
when different studies find different things
or some studies find significant relationships
while others find no significant relationships.
It's important to use this criteria
for assessing the strength of any given study
and of the findings that that study might produce.