1. ENDOMETRIAL CARCINOMA UPDATES Dr Marco Matos Gold Coast Cancer Care, Gold Coast University Hospital and Pacific Private Oncology Group

2. USA. Uterine cancer: new cases and dates ● 1990330004000 ● 2000361006500 ● 2010434707950 ● Ovarian cancer 21880 new cases and 13850 deaths ● Cervical cancer: 12200 new cases and 4210 deaths

3. ● In Australia endometrial cancer affects 1 in 69 women before the age of 75. ● In 2010, 2100 women were diagnosed. 6 /day ● 370 expected deaths a year ● The incidence is increasing

4. [TITLE] Obesity significantly increases the risk of developing cancers including endometrial cancer

5. [TITLE] In 2020, more than 70% of the population of Australia will be overweight

6. [TITLE] Non endometrioid (serous, clear cell carcinoma) cancers disproportional contribute to deaths in comparison with endometrioid histology

7. [TITLE]

8. Carcinogenesis model of type I endometrial cancer: PTEN, MSI and K- ras alterations playing an earlier important role. P53 mutations a late event

9. [TITLE] Carcinogenesis model of type II endometrial cancer: P53 mutation an early event

10. Molecular alterations differ in Type 1 vs type 2 endometrial cancers ● Endometrioid adenocarcinoma (Type 1 ) – PTEN loss of function (up to 60%) – PI3KCA mutation (30%) – K ras mutation (10- 20%) – FGFR2 mutations (12- 16%) – Microsatelalite instability (20 – 45%) – Nuclear accumulation of b- cadherin (18 – 47%) ● Papillary Serous (Type 2) – P53 mutations (90%)

12. [TITLE]

14. MANAGEMENT

15. Survival improves in the hands of a trained Gynae-oncologist

16. Hormonal therapy of endometrial cancer AgentTumour grade NumberRR % Medroxyprogesterone 800 mg/d Podratz 1985 123123 14 17 27 40 15 2 Tamoxifen 40 mg/d alternating with medroxyprogesterone 200mg/d Whitney 2003 123123 15 17 27 33 Medroxyprogesterone 160 mg/d x 3 weeks then Tamoxifen 40 mg /d x 3 weeks Fiorica 2003 123123 16 17 22 38 24 22

17. Response rates and survival to single agent chemotherapy AGENTPrior treatment NumberRR%Prob PFS (>6 mo) OS months Etoposide2500.088.7 PaclitaxelNo48250.218.9 Caelyx4390.238.2 Topotecan2870.259 Oxaliplatin52130,2710.9 Docetaxel77% prior Rx 2780.116.4 Pemetrexed2740.289.4 Ixabepilone94% prior Rx 50120.208.7

18. Biological agents: response rate and PFS Agent NRR % Prob (PFS> 6 mo) Clinical Benefit Ratio (CR + PR +SD) Duration of stability (median months) TKI and VEGF inhibitors Gefitinib293.80.15 Lapatinib303.30.10 Bevacizumab5213.50.40 MTOR inhibitors Temsirolimus1825826.7 Temsirolimus277513.8 Deferolimus45733<4 Everolimus350434.5

20. LET’S LOOK AT THE DATA:

22. GOG 30 Adryamicin in advanced / recurrent endometrial cancer ● Adryamicin 60 mg/m2 ● N = 43 ● CR= 26 % + PR= 12% = 37% ● Better survival for responders, p<.05 ● Active agent

23. GOG 34 Phase III, surgery + radiotherapy +- Doxorubicin in stage IC, II and IIIA EC ● Doxo 60 mg/m2 q 3 /52 up to 500 mg ● No G 3 – 4 cardio toxicity ● Survival 60 vs 66%, p= NS ● “Unable to determine effect” ● Morrow et al Gyn Onc 36: 166, 1990

24. GOG 99 Surgery +- adjuvant radiotherapy

26. GOG 107 phase III trial, doxorubicin +- cisplatin in stage III/ IV EC ● Doxo 60 +- CDDP 50 mg/m2 q 3/52 ● N= 281 ● G3-4 leucopenia (62 vs 40%), anaemia (22 vs 4%), N/V (13 vs 4%) ● Dox; CR 8%+ PR 17%= 25%, PFS 3.9 mo, OS 9 mo ● Dox + CDDP; CR 19% + PR 23% = 42%, PFS 5.7 mo, OS 9.2 mo ● Adding cisplatin improves RR and PFS but not OS at the cost of more toxicity

27. GOG 122 Adjuvant Radiotherapy vs AP

28. ● Adverse events were more common with AP ● At 24 mo: p<0.01: – DFS: WART 46 vs AP 59%, OS: WART 59% vs AP 70%

29. GOG 177 RR: 57 VS 34%, PFS 8.3 vs 5.3, mOS 15.3 vs 12.3mo all in favour of TAP but at increased neurotoxicity

30. GOG 184

32. OTHER UPDATES

33. [TITLE]