Mammographic density and breast cancer

1. Department of Surgical Oncology
Centre for Oncology
GRH,Royapettah

2. PROF.S.SUBBIAH et al.
Current molecular understanding of mammographic
density
Association with breast cancer risk
Demographics pertaining to mammographic density
Environmental factors that modulate mammographic
density
Availability of supplemental screening options for
women with dense breast

3. PROF.S.SUBBIAH et al.
It is based on proportion of stromal, epithelial and
adipose tissue
Mammographic density refers to percentage of dense
tissue of an entire brest
defined as fibroglandular mammary tissue consisting of
fibroblasts, epithelial cells, and connective tissue.

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 4 major categories

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Two major problems
Decreased detection sensitivity
Greater risk for the development of breast cancer

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Sensitivity of mammogram depends on density of
breast
Women with dense breast more likely to experience
both false positives and false negatives
Highly dense breast tissue interfere with early detection
goal of screening mammography and thereby make the
mammogram results inconclusive.

8. PROF.S.SUBBIAH et al.
In a study by Kolb et al. it is found that sensitivity of
mammogram declined to 48% in extremely dense
breasts

9. PROF.S.SUBBIAH et al.
Mammographic breast density – an
independent risk for breast cancer
Wolfe was the 1st researcher to observe this association
A large meta analysis conducted by McCormack and
collegues compared percent density and breast cancer
incidence

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Percent density Incidence of breast cancer
5-24 1.79
25-49 2.11
50-74 2.92
> 75 4.64

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In a study comparing mammographic density among
monozygotic and dizygotic twins, the correlation
coefficient between MD was about twice as high in
monozygotic twins

12. PROF.S.SUBBIAH et al.
But this is still unknown whether this heritable effect
is influenced by non heritable environmental factors,
as well as factors related to individuals behaviour

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Significant and inverse association

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Greatest mammographic density was seen in Asian
women ( significantly higher in the Chinese ethnicity)
Lowest mammographic density was seen in African
American women
Diet and environmental exposure also have significant
influence on the risk of developing breast cancer in
various ethnic groups

15. PROF.S.SUBBIAH et al.
Western diet pattern ( high fat and proteins)
Alcohol intake – more than 7 servings per week, have
17% higher mammographic density compared to non
drinkers

16. PROF.S.SUBBIAH et al.
Estrogen and progesterone combined HRT known to
increase MD ( estrogen therapy alone does not
significantly increase MD)
In a study 18 months of tamoxifen usage decrease
breast density by 7.3% when compared to placebo. But
decrease in MD in tamoxifen group is short term

17. PROF.S.SUBBIAH et al.
In a randomized breast cancer prevention trail women
on tamoxifen had 10% reduction in the MD and 63%
reduction in the breast cancer risk
Resluts concluded 18 months regimen of tamoxifen can
reduce MD and also breast cancer risk

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There is a positive association between MD and ER-
HER2- breast cancers in woman younger than 55yrs
High MD is strongly associated with larger tumors,
positive lymphnode and ER- tumors in women younger
than 55 yrs of age

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Higher association of MD with ER- tumors including
triple negative breast cancers compared to luminal A
breast cancers

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Collagen type-1 is one of the major component of the
stormal extracellular matrix network that influence
tissue density
 Collagen re-organization and cross linking act as a
scaffold aiding cancer cells to migrate and invade
surrounding tissue and thus associated with
metastasis and poor prognosis in best cancer
patients

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 Small leucine rich proteoglycans also make up large portion of
extracellular matrix and high levels of proteoglycans increase
tissue density and carcinogenesis
 Lumican is an important protein that plays a role in the tissue
repair and embryonic development, there is an increased
expression of Lumican in high density compared to low density
tissue
 High expression of lumican can induce initiation and progression
of breast cancer by increasing angiogenesis, cell growth,
migration and invasion


22. PROF.S.SUBBIAH et al.
Higher levels of lumican are associated with high tumor
grade, lower expression of ER receptor in cancer cell
Decorin follows the same expression pattern as Lumican,
With higher expression in high density versus low density
tissue
the role that high expression of lumican and decorin play in
high density breast tissue are unclear and need further
exploration

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currently Decorin and Lumican are under study stage where
they're an attractive target for modulating mammographic
density
 Better understanding of molecular interplay between small
leucine rich proteoglycans in major oncogenic signaling
pathways in dense versus non dense tissue may lead to the
ability to alter tissue density effectively and reduce breast
cancer incidence

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A correlation between breast tissue density with Ki-67
reported a decrease in CD 44 and a TGF beta target and an
increase in COX-2 in the storm of high versus low breast
density tissue
 TGF – beta repression elevate the expression of COX - 2
and Ki - 67 in women with high versus low density breast
tissue providing some evidence of why women with high
density breast tissue are at risk of developing breast cancer

25. PROF.S.SUBBIAH et al.
 COX - 2 over expression is associated with invasive breast
cancer and ductal carcinoma insitu but its association with
dense tissue has not been fully investigated

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 Since highly dense stroma tissue can trigger proliferation in
the breast epithelium in women with high mammographic
density there must be a cross talk between stroma cells (
fibroblast ) and epithelial cells in dense microenvironment
Indeed high density associated fibroblast express
significantly decreased levels of CD 36 compare to low
density associated fibroblast

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CD36 is a transmembrane receptor that that is
involved in adipocytes differentiation, angiogenesis,
apoptosis, TGF – beta activation, cell extracellular
matrix interactions and immune signaling

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 Down regulation of CD 36 observed in both
high density associated fibroblast of disease
free women and carcinoma associated
fibroblast which can be an early event in the
tumor formation

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Dense breast tissue also has greater expression of DNA
damage response gene (DDR) and shorter telomere length
compared to low density breast tissue
DDR gene Is associated with an increase in the activin-a
expression and reduction in expression of PPAR Gama a
transcription factor regulating CD 36

30. PROF.S.SUBBIAH et al.
27% of breast cancer missed in women with dense
breasts due to lesion obscuration
 multi-modal screenings offer the best chance of
enhancing breast cancer screening effectiveness
 MRI, ultrasonography, digital breast tomosynthesis
can all be great supplemental tools

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Compared to mammography ultrasound has high
sensitivity to detect breast cancer regardless of
breast tissue density however the specificity is low
which results in high false positive rates
Ultrasonography in adjunction to mammography
significantly increased the number of breast cancer
detected in women with mammographic density
compared to mammography alone

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Combined screening methods detected 27% additional
cancers but lack of specificity still remains a limitation of this
adjunctive screening
Digital breast tomosynthesis which is three dimensional xray
imaging technology
 Digital breast tomosynthesis limits the possibility for missing
tumors because of the overlap of breast tissue seen in the
2D images of traditional screening mammogram

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 With digital breast Tomosynthesis there is a significantly lower false
positive cancers reported then digital mammography alone but digital
breast tomosynthesis uses twice as much radiation as conventional
mammography thus adoption is limited
 Another disadvantage is that interpretation of DBT xray images is
dependent on radiologist expertise, so highly variable
 there remains a pressing need for development of additional non
invasive tests that can be used in conjunction with mammography

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