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Patología Molecular Del Cáncer De Mama

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Patología Molecular Del Cáncer De Mama

  1. 1. Patología molecular del carcinoma de mama José Palacios Servicio de Anatomía Patológica HHUU Virgen del Rocío, Sevilla Xàtiva, 12 de enero de 2009
  2. 3. CK8, 18, 19 Cadherina-E CK5/6, 14, 17 P-Cadherin Actin vimentin Luminal epithelial Myoepithelial (Basal) CELLULAR TYPES IN MAMMARY GLAND Basal epithelialmarkers Mesenchymal markers
  3. 4. CK5/6 CK14 CK17 P-CADHERIN p63 S100 CD10 CD44 VIMENTIN CAV1 OSTEONECTIN SMA CALPONIN H-CALDESMON CALPONIN p63 MYOEPITHELIAL MARKERS
  4. 5. <ul><li>Limiting dilution transplantations studies </li></ul><ul><li>Retroviral-tagged mammary implants </li></ul><ul><li>Prospective isolation of putative stem cells using cell surface markers </li></ul>IDENTIFICATION OF MAMMARY STEM CELLS Multipotent epithelial cells (“stem cells”) with the ability to generate the entire functional mammary epithelium
  5. 6. Visvader and Lindeman, Cancer Res 2006 MODEL OF THE EPITHELIAL CELL HIERARCHY IN THE MOUSE MAMMARY GLAND.
  6. 8. AEP/ADH/ LG-DCI S ALH/LCIS +8q +17q -17p P53 HER2 MYC - 16q + 11q CCND1 E-CD (-) BREAST CANCER PROGRESION MODEL Invasive Lobular Carcinoma Low Grade (invasive ductal G1, tubular, cribiforme...) High grade (invasive ductal G3, apocrine, medullary metaplastic...) HG- CDIS Breast epithelium TDLU CCC
  7. 10. Perou et al., Nature 2000 <ul><li>c Luminal, ER+ (A and B) </li></ul><ul><li>ERBB2 </li></ul><ul><li>Basal </li></ul><ul><li>Normal </li></ul>MOLECULAR CLASSIFICATION OF BREAST CANCER
  8. 11. <ul><ul><li>Sorlie et al; PNAS 2003 </li></ul></ul>
  9. 12. LUMINAL (ER+) PHENOTYPES Invasive ductal carcinoma (grade 1-2/3) Invasive lobular carcinoma Tubular carcinoma Invasive cribiforme carcinoma Mucinous carcinoma LUMINAL A/B PHENOTYPES GRADE 1-2/3 ER LEVELS PROLIFERATION MARKERS HER2 EXPRESSION
  10. 13. <ul><li>Invasive breast carcinoma composed by non-cohesive cells individually dispersed or arranged in single-file linear pattern in a fibrous stroma. </li></ul>LOBULAR BREAST CANCER <ul><li>INCREASING INCIDENCE (HRT?) </li></ul><ul><li>HIGHER AGE AT DIAGNOSIS </li></ul><ul><li>HIGHER SIZE AT DIAGNOSIS </li></ul><ul><li>DIFFUSE GROWTH PATERN </li></ul><ul><li>LOWER SENSITIVITY OF MAMMOGRAPHY TO DETECT ILC </li></ul><ul><li>HIGHER RATE OF FAILURE AFTER BCT? </li></ul><ul><li>METASTATIC PATTERN </li></ul>
  11. 14. Lobular carcinomas completely lack E-cadherin expression Lobular carcinoma in situ Infiltrating lobular carcinoma Invasive Ductal carcinoma Absence of E-cadherin >80% Reduced E-cadherin: 50% Gamallo et al; Am J Pathol 1993
  12. 15. C-terminal <ul><li>CDH1 is a tumor and invasion suppressor gene </li></ul>16q22.1 The E-cadherin/catenin adhesion complex Protein Mw Gene location E-cadherin 120 kDa 16q22.1  -catenin 102 kDa 5q31  -catenin 92 kDa 3p21  -catenin 83 kDa 17q21 p120ctn 120 kDa 11q11  -catenin CBD JMD E-CADHERIN actin p120  -catenin
  13. 16. E-CADHERIN INACTIVATION IS THE HALLMARK OF LN E-CD E-CD Sarrió et al; Int J Cancer 2004 N IS IF D16S398 Wt N T IF IS
  14. 17. Mechanisms of CDH1 inactivation in lobular tumors <ul><li>CDH1 LOH (60-80%) </li></ul><ul><li>CDH1 promoter hypermethylation (40-60%) </li></ul>D16S265 CDH1 D16S496 D16S398 D16S3057 D16S752 16q22.1 T N D16S496 -126 -21 +81 +144 +1 M U M U M U M U M U M U M U M U 14 15 16 17 24 25 38 H 2 O CDH1
  15. 18. 1712 G > C <ul><li>CDH1 mutations (20-40%). </li></ul>60-70% produced truncated proteins. Mechanisms of CDH1 inactivation in lobular tumors Sarrió et al, Int J Cancer 2003 6 6 Wt Exon 13 Wt 5 5 Exon 10 Wt 19 19 Exon 2 Wt 52 52 Exon 11 C N SIG PRE Ca 2+ binding domain TM CP
  16. 19. <ul><li>HDGC is caused by germline mutation of CDH1 . </li></ul><ul><li>The lifetime risk of developing gastric cancer by age 80 is 65%-80%. </li></ul><ul><li>Female CDH1 mutation carriers are at increased risk for developing lobular breast cancer. </li></ul><ul><li>Penetrance studies have shown that female CDH1 germline mutation carriers have an additional risk of breast cancer, particularly lobular breast cancer, in about 39% of patients. </li></ul>
  17. 20. <ul><li>Some families have been misclassified as breast cancer families due to clustering of breast cancer cases. </li></ul><ul><li>This suggests that families with negative test results for BRCA1/2 in whom the proband has lobular breast cancer should be reevaluated for HDGC and screened for CDH1 mutations. </li></ul>BREAST CANCER IN HDGC PATIENTS
  18. 22. Perou et al., Nature 2000 <ul><li>c Luminal, ER+ (A and B) </li></ul><ul><li>ERBB2 </li></ul><ul><li>Basal </li></ul><ul><li>Normal </li></ul>MOLECULAR CLASSIFICATION OF BREAST CANCER
  19. 23. BREAST CANCER AND THE BASAL-LIKE PHENOTYPE Palacios et al; Am J Pathol 1995 Tsuda et al; Am J Surg Pathol 2000
  20. 24. ER/HER2-negative, CK5- and/or EGFR-positive Nielsen et al., Clin Cancer Res 2004 BASAL-LIKE PHENOTYPE VIMENTIN, P-CADHERIN, EGFR, CK5/6, FASCIN p63, CD10, OSTEONECTIN, SMA, CALPONIN, H-CALDESMON
  21. 25. BASAL-LIKE PHENOTYPE ( ER/HER2-negative, CK5- and/or EGFR-positive) Rodríguez-Pinilla el al., Clin Cancer Res 2006
  22. 26. Medullary carcinoma
  23. 27. Differences between invasive breast carcinomas with medullary features (IBCMF) and grade 3 invasive ductal carcinoma of no special type (IDCG3). Rodríguez-Pinilla el al., Am J Surg Pathol 2007 <0.001 7/37 (18.9%) 30/37 (81.1%) 22/35 (62.9%) 13/35 (37.1%) Basal-like phenotype Positive Negative 0.001 3/38 (7.9%) 35/38 (92.1%) 14/35 (40.0%) 21/35 (60.0%) P-Cadherin Positive Negative 0.007 26/38 (68.4%) 12/38 (31.6%) 13/35 (37.1%) 22/35 (62.9%) Ck19 Positive Negative 0.553 9/37 (24.3%) 28/37 (75.7%) 9/35 (25.7%) 26/35 (74.3%) EGFR Positive Negative <0.001 7/39 (17.9%) 32/39 (82.1%) 21/35 (60.0%) 14/35 (40.0%) Ck5/6 Positive Negative 0.002 9/38 (23.7%) 29/38 (76.3%) 0/35 (0.0%) 35/35 (100.0%) HER2 Positive Negative <0.001 24/39 (61.5%) 15/39 (38.5%) 2/35 (5.7%) 33/35 (94.3%) ER Positive Negative P IDCG3 IBCMF
  24. 28. MORPHOLOGICAL AND IMMUNOHISTOCHEMICAL HETEROGENEITY OF BREAST CARCINOMAS WITH BASAL-LIKE PHENOTYPE VIMENTIN, P-CADHERIN, EGFR, CK5/6, FASCIN p63, CD10, OSTEONECTIN, SMA, CALPONIN, H-CALDESMON Medullary carcinoma Metaplastic carcinoma Poorly differentiated carcinoma with central acellular zones
  25. 29. SOX2 EXPRESSION IN BREAST CANCER Rodríguez-Pinilla et al., Mod Pathol 2007 SOX2 Ki67 CK5/6 VIMENTIN SOX2 (-) SOX2 (+) P
  26. 30. Perou et al., Nature 2000 <ul><li>c Luminal, ER+ (A and B) </li></ul><ul><li>ERBB2 </li></ul><ul><li>Basal </li></ul><ul><li>Normal </li></ul>MOLECULAR CLASSIFICATION OF BREAST CANCER
  27. 31. HER2 EXPRESSION IN BREAST CANCER
  28. 32. BASAL+ HER2+ BASAL/HER2- RE (-) 95% 60% 20% RP (-) 93% 58% 37% GRADO 3 98% 55% 32% CK5 57% 10% 6% CK8 50% 98% 95% P53 (>30%) 55% 42% 16% Ki67 (>15%) 72% 46% 32% EGFR (+) 35% 10% 5% DIFERENCIAS ENTRE TUMORES CON FENOTIPO BASAL+ Y HER2+
  29. 33. Laakso et al., Clin Cancer Res 2006 HER2 EXPRESSION IN BREAST CANCER
  30. 34. Oncogene 2005 Apocrine histology Non-basal ER-negative AR-positive HER2-positive (50%)
  31. 37. Natrajan et al, 2008
  32. 38. Natrajan et al, 2008
  33. 39. n HER2 (+) Anderson (2003) 20 16 (80%) Fu (2001) 14 14 (100%) Schelfhout (2000 ) 30 26 (85%) Meissner (1990) 23 23 (100%) ENFERMEDAD DE PAGET y HER2/neu
  34. 40. HER2/neu Y CARCINOMA INFLAMATORIO HER2 (+) CDI-NOS 15-20% CLA 30% CI 35-55%
  35. 43. DSS in non-treated patients Basal-like tumors (n=12) Non Basal-like tumors (n=95) Log Rank P=0.001 Survival Time (Months) % Survival DSS in CMF-treated Survival Time (Months) Log Rank P=0.633 % Survival Basal-like tumors (n=13) Non Basal-like tumors (n=85) ER/HER2-negative, CK5- and/or EGFR-positive BASAL-LIKE PHENOTYPE AND CMF RESPONSE IN BREAST CANCER Rodríguez-Pinilla el al., Clin Cancer Res 2006
  36. 44. Breast cancer Ovarian cancer Male BC BRCA1 65% 40% - BRCA2 45% 11% 8% BCLC M eeting. Madrid, Jun e 2003 Hereditary breast cancer BRCA1/2: 30% BRCA (-): 70%
  37. 45. Histological type and grade BRCA BRCA2 Sporadic IDC 74% 71% 69% Medullary features 18% 3% 3% Grade 3 66% 41% 36%
  38. 46. Immunohistochemical markers BRCA1 BRCA2 Sporadic ER+ 20% 66% 65% PR+ 20% 49% 66% PR ER
  39. 47. Probability of carrying a BRCA1 mutation by age, ER status and grade (Lakhani et al, J Clin Oncol 2002)
  40. 48. Immunohistochemical markers BRCA1 BRCA2 Sporadic Ki67 high 56% 21% 22% Cyclin D1 30% 56% 79% Cyclin E 47% 35% 27% P53+ 45% 27% 12% HER2+ 0-7% 0-6% 18%
  41. 49. HER2 amplification BRCA1 BRCA2 Sporadic (n=14) (n=10) (n=54) HER2 (FISH) 0 0 22%
  42. 50. Morpholgical and immunohistochemical features of BRCA1 and BRCA 2 breast carcinomas GRADE ER PR BCL2 Ki67 p53 HER2 BRCA1 3 - - - ++ ++ - BRCA2 2/3 + + + + - - Ki67 p53 BCL2 PR ER
  43. 51. Sorlie et al. Proc Natl Acad Sci U S A. 2003 BASAL PHENOTYPE IN BRCA1 BREAST CARCINOMAS
  44. 52. BRCA1 BRCA2 Sporadic Cytokeratin 5/6 46% 9% 8.5% Vimentin 80% 15% 23% Fascin 84% 17% 25% Laminin 75% 7% 39% Caveolin 1 22% 0 4.2% BASAL CELL MARKERS Palacios et al, J Nat Cancer Inst 2004 Rodríguez-Pinilla et al, Clin Cancer Res 206; Breat Cancer Res and Treat 2006; J Clin Pathol 2007 Cytokeratin 5/6
  45. 54. Hereditary breast cancer GRADE ER PR BCL2 Ki67 p53 HER2 BRCA1 3 - - - ++ ++ - BRCA2 2/3 + + + + - - BRCA(-) 1/2 + + + - - +/- BRCA1/2: 30% BRCA (-): 70%
  46. 55. Dontu et al., 2004 BASAL PHENOTYPE BASAL AND LUMINAL MARKERS LUMINAL PHENOTYPE LUMINAL MARKERS ONLY
  47. 56. HER2 PIK3CA RAS -16q CDH1 IDC-G1/2 MUCINOUS CRIBIFORME TUBULAR LOBULAR METAPLASTIC MEDULLARY IDC-G3 IDC-G2/3 APOCRINE BRCA1 EGFR P53 MYC SMA VIMENTIN C-KIT EGFR P-CADHERIN CK5/6 CK8/18/19 HER2 AR CK8/18/19 ER PR GATA3 CK8/18/19 BASAL BASOLUMINAL HER2 APOCRINE LUMINAL B LUMINAL A LP ER- LP ER+ Luminal cells Luminal Progenitors Common Progenitor Stem Cell ER- ER-

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