1. Ovarian Clear Cell Carcinomas - from the eyes of biological markers Speaker: Cheng MH Modulator: Twu NF Date: Jan 15, 2007

2. Ovarian Cancer The U.S. (2001) The 5th most common women’s cancer 13,000 deaths (5%) Taiwan (2002) The 10th most common women’s cancer (729 women, 9.92% of gynecological cancers) 308 women deaths (0.90%) The 10th most common women’s death cause

3. Ovarian Clear Cell Carcinoma Incidence in ovarian cancers The U.S.: 5-10% Taiwan: 9.74% VGH-TPE: 9.6% (103/1071) (including missing data) 2.8% (24/828)

4. Ovarian Clear Cell Carcinoma Characteristics of OCCC Early initial stage, lower surgical substage (Ic, IIc) Less ascites, smaller tumor volume Lower pre-operative CA125 Poorer response to platinum-based chemotherapy Poorer survival duration and survival rates Arising from endometriosis? (Cancer 2000;88:2584-9) (J Surg Oncol. 2006;93(5):379-86)

5. Case Presentation A case of ovarian clear cell carcinoma Mrs. C, 46-year-old lady, gravida 3, para 2 Bilateral cystectomy for endometriomas 10 years ago Initial presentation of abdominal pain for 2 weeks Initial stage IV due to supraclavicular lymphadenopathy Suboptimal surgery followed by serial chemotherapy (taxol, carboplatin, cisplatin, lipodox, topotecan, gemcitabine, Irresa) Disease progression complicated with embolism

6. Analysis of Biological Markers Her-2/neu(+) tau(+)c-myc(+)Topo1(borderline)Topo2a>10% ERCC1(-)P53(-)Faint TS

7. Ovarian Clear Cell Carcinoma Searching from PubMed P53: 43 PTEN: 11 Her-2/neu: 7 ERCC1: 1 Tau: 0 Topo1: 0 Topo2A: 0 TS:0

8. ERCC1 Nucleotide excision repair (NER) Repair of damage to DNA Rate-limiting step: excision of damage from DNA strand 16 proteins for repairosome ERCC1, XPB, …. Chemoresistance to platinum (Cytotechnology 1998;27:187-201) (Cancer Treat Rev. 1998;24:331-344)

9. ERCC1 Heterodimers with XPB Incision into 5’ of the site of damage Positive relationship between ERCC1 mRNA and active DNA repair process ERCC1 mRNA levels correlates with resistance to platinum-based exposures in ovarian cancers (Biochem. Pharmacol. 2000;60:1305-1313) (Anticancer Res. 2000;20:645-652)

10. ERCC1 and OCCC 126 advanced (stage III & stage IV) ovarian ca RT-PCR (Clinical Cancer Research 2003;9:5299-5305) **** **

11. PTEN PTEN/MMAC1/TEP1 Chromosome 10q23.3 Tumor suppressor gene A dual-specificity lipid phosphatase (Science 1997;275:1943-7)

13. PTEN

14. PTEN and OCCC 81 ovarian tumors PCR and LOH analysis (Cancer Research. 1998;58:2095-2097)

15. PTEN and OCCC 40 ovarian clear cell carcinoma Immunohistochemistry (IHC) ( Gynecologic Oncology 2006;101:71-75) **** **

16. P53 Chromosome 17p13.105 53-kD Tumor suppressor gene Regulate transcription of growth-regulatory gene

17. P53 and OCCC P53-positivity 2.6% (1/38) (Gynecol Oncol 2001;80:189-93)

18. P53 and OCCC P53-positivity 0% (0/13) (Cancer 1999;85:669-77)

19. P53 and OCCC P53-positivity 7.4% (2/27), stage I-II (Int J Oncology 2005;26:177-183) 0% (0/16), stage II-IV (Int J Gynecol Cancer 2003;13:776-784)

20. P53 and OCCC P53-positivity 64 ovarian ca (37 OCCC, 27 EC) PCR-SSCP and IHC No mutations or overexpression Not a determinant of survival (Gynecologic Oncology 2003;88:318-325)

21. Her-2/neu Her-2/neu, c-erb-2 Chromosome 17q21 185-kDa A component of growth factor receptors EGFR (Her-1), Her-2, Her-3, Her-4 For cell differentiation and proliferation A transmembrane receptor with tyrosine kinase activity 25-30% overexpression in breast cancers (Semin Oncol 1999;26:51-59)

22. Her-2/neu

23. Her-2/neu and OCCC 15 ovarian clear cell carcinoma Stage Ia: 20%, Stage Ic: 40%, Stage IIb: 6.7%, Stage IIIb: 6.7%, Stage IIIc: 20%, Stage IV: 6.7% HercepTest (IHC) (Int J Gynecol Cancer 2003;13,28-31)

24. Her-2/neu and OCCC (Int J Gynecol Cancer 2003;13,28-31) 6.7 %

25. Her-2/neu and OCCC 90 ovarian clear cell carcinoma IHC (Gynecologic Oncology 2004;94:735-739)

26. Her-2/neu and OCCC Overexpression of Her-2/neu not related to stage (Gynecologic Oncology 2004;94:735-739)

27. Her-2/neu and OCCC Stage I: Her-2/neu(+) not associated with survival P=0.3616

28. Her-2/neu and OCCC Stage III: Her-2/neu(+) not associated with survival P=0.9873

29. Her-2/neu and OCCC Her-2/neu(+) not associated with lymph nodes metastasis

30. Her-2/neu and OCCC 79 early stage (stage I and stage II) IHC and FISH (Gynecologic Oncology 2004;95:570-575)

31. Ovarian Clear Cell Carcinoma “Unclear” from the eye of the biological markers Rare data Methodological difference Variability in IHC Antigen fixation Length of storage Significance of staining system Interobserver’s difference in the scoring system Biological markers ≠ Complex regulatory mechanism ……

32. Thank You for Your Attension