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Mammographic density and breast cancer

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Mammographic density and breast cancer

  1. 1. Department of Surgical Oncology Centre for Oncology GRH,Royapettah
  2. 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. 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.
  4. 4. PROF.S.SUBBIAH et al.  4 major categories
  5. 5. PROF.S.SUBBIAH et al.
  6. 6. PROF.S.SUBBIAH et al. Two major problems Decreased detection sensitivity Greater risk for the development of breast cancer
  7. 7. PROF.S.SUBBIAH et al. 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. 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. 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
  10. 10. PROF.S.SUBBIAH et al. Percent density Incidence of breast cancer 5-24 1.79 25-49 2.11 50-74 2.92 > 75 4.64
  11. 11. PROF.S.SUBBIAH et al. 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. 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
  13. 13. PROF.S.SUBBIAH et al. Significant and inverse association
  14. 14. PROF.S.SUBBIAH et al. 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. 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. 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. 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
  18. 18. PROF.S.SUBBIAH et al. 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
  19. 19. PROF.S.SUBBIAH et al. Higher association of MD with ER- tumors including triple negative breast cancers compared to luminal A breast cancers
  20. 20. PROF.S.SUBBIAH et al. 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
  21. 21. PROF.S.SUBBIAH et al.  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. 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
  23. 23. PROF.S.SUBBIAH et al. 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
  24. 24. PROF.S.SUBBIAH et al. 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. 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
  26. 26. PROF.S.SUBBIAH et al.  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
  27. 27. PROF.S.SUBBIAH et al. CD36 is a transmembrane receptor that that is involved in adipocytes differentiation, angiogenesis, apoptosis, TGF – beta activation, cell extracellular matrix interactions and immune signaling
  28. 28. PROF.S.SUBBIAH et al.  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
  29. 29. PROF.S.SUBBIAH et al. 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. 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
  31. 31. PROF.S.SUBBIAH et al. 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
  32. 32. PROF.S.SUBBIAH et al. 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
  33. 33. PROF.S.SUBBIAH et al.  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
  34. 34. PROF.S.SUBBIAH et al.