The document discusses the molecular pathology of breast carcinoma. It describes the cellular types in the mammary gland, identification of mammary stem cells, and the epithelial cell hierarchy model. It also covers molecular classification of breast cancer, luminal and basal-like phenotypes, mechanisms of E-cadherin inactivation in lobular carcinoma, breast cancer in hereditary diffuse gastric cancer patients, and morphological and immunohistochemical features of BRCA1 and BRCA2 breast carcinomas.

1. Patología molecular del carcinoma de mama José Palacios Servicio de Anatomía Patológica HHUU Virgen del Rocío, Sevilla Xàtiva, 12 de enero de 2009

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

4. CK5/6 CK14 CK17 P-CADHERIN p63 S100 CD10 CD44 VIMENTIN CAV1 OSTEONECTIN SMA CALPONIN H-CALDESMON CALPONIN p63 MYOEPITHELIAL MARKERS

6. Visvader and Lindeman, Cancer Res 2006 MODEL OF THE EPITHELIAL CELL HIERARCHY IN THE MOUSE MAMMARY GLAND.

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

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

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

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

23. BREAST CANCER AND THE BASAL-LIKE PHENOTYPE Palacios et al; Am J Pathol 1995 Tsuda et al; Am J Surg Pathol 2000

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

25. BASAL-LIKE PHENOTYPE ( ER/HER2-negative, CK5- and/or EGFR-positive) Rodríguez-Pinilla el al., Clin Cancer Res 2006

26. Medullary carcinoma

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

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

29. SOX2 EXPRESSION IN BREAST CANCER Rodríguez-Pinilla et al., Mod Pathol 2007 SOX2 Ki67 CK5/6 VIMENTIN SOX2 (-) SOX2 (+) P

31. HER2 EXPRESSION IN BREAST CANCER

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+

33. Laakso et al., Clin Cancer Res 2006 HER2 EXPRESSION IN BREAST CANCER

34. Oncogene 2005 Apocrine histology Non-basal ER-negative AR-positive HER2-positive (50%)

37. Natrajan et al, 2008

38. Natrajan et al, 2008

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

40. HER2/neu Y CARCINOMA INFLAMATORIO HER2 (+) CDI-NOS 15-20% CLA 30% CI 35-55%

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

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%

45. Histological type and grade BRCA BRCA2 Sporadic IDC 74% 71% 69% Medullary features 18% 3% 3% Grade 3 66% 41% 36%

46. Immunohistochemical markers BRCA1 BRCA2 Sporadic ER+ 20% 66% 65% PR+ 20% 49% 66% PR ER

47. Probability of carrying a BRCA1 mutation by age, ER status and grade (Lakhani et al, J Clin Oncol 2002)

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%

49. HER2 amplification BRCA1 BRCA2 Sporadic (n=14) (n=10) (n=54) HER2 (FISH) 0 0 22%

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

51. Sorlie et al. Proc Natl Acad Sci U S A. 2003 BASAL PHENOTYPE IN BRCA1 BREAST CARCINOMAS

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

54. Hereditary breast cancer GRADE ER PR BCL2 Ki67 p53 HER2 BRCA1 3 - - - ++ ++ - BRCA2 2/3 + + + + - - BRCA(-) 1/2 + + + - - +/- BRCA1/2: 30% BRCA (-): 70%

55. Dontu et al., 2004 BASAL PHENOTYPE BASAL AND LUMINAL MARKERS LUMINAL PHENOTYPE LUMINAL MARKERS ONLY

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-