Ovarian Cancer: The Last 20 Years – The Next 20 Years

1. Ovarian Cancer: The Last 20 Years – The Next 20 Years John O. Schorge, MD August 12, 2017

2. Disclosures I have no disclosures to make

3. Ovarian Cancer uptodate.com

4. 22,000 diagnoses each year 15,000 deaths in the USA Two-thirds diagnosed with advanced disease 80-90% relapse rate Each patient has a very personal story Ovarian Cancer

5. Learning Objectives • To understand progress made in the past 20 years of ovarian cancer management • To appreciate the state-of-the-science today • To speculate on what ovarian cancer prevention & treatment will look like 20 years in the future

6. Ovarian Cancer

7. Ovarian Cancer

8. 1997

9. 1997 Your speaker begins his fellowship in gynecologic oncology

10. 1997 • Fatigue and abd pain: 10 months of misdiagnosis • Stage IV disease with Xlap/suboptimal debulking • Platinum-based therapy with <1 year in remission • Bowel perf and death within 6 months of relapse

11. Oral contraceptives (OCs) reduce risk of ovarian cancer by inducing quiescent surface epithelium Bilateral salpingo-oophorectomy (BSO) at time of hysterectomy in women >40 years Prophylactic BSO in high-risk patients as identified by pedigree of familial clustering Federal grant support of prospective large screening studies designed to foster early detection 1997

12. OCs have prevented some 200,000 cases of ovarian cancer worldwide over the past 50 years, but mechanism unclear Current state-of-the-science Lancet Jan 2008; NCI Cancer Bulletin 2010

13. Integrated model of ‘ovarian carcinogenesis’ Current state-of-the-science

14. Current state-of-the-science Growing Acceptance of Removing Fallopian Tubes But Keeping Ovaries to Lower Ovarian Cancer Risk

15. Current state-of-the-science • First large-scale population-based cohort study • 250,000+ women • Bilateral salpingectomy: 50% decrease in risk of ‘ovarian cancer’ • Support the hypothesis that a substantial fraction arise in the tube

16. Current state-of-the-science

17. Current state-of-the-science • OCs have prevented some 200,000 cases of ovarian cancer worldwide over the past 50 years, but mechanism unclear • Opportunistic bilateral salpingectomy (BS) at time of hysterectomy to reduce risk of ovarian cancer

18. Current state-of-the-science “Any individual with ovarian cancer warrants further genetic risk evaluation”

19. Current state-of-the-science • BRCA1 • BRCA2

20. Current state-of-the-science • BRCA1 • BRCA2 • BRIP1 • RAD51C • PALB2 • CHEK2 • Others…

21. Current state-of-the-science • OCs have prevented some 200,000 cases of ovarian cancer worldwide over the past 50 years, but mechanism unclear • Opportunistic bilateral salpingectomy (BS) at time of hysterectomy to reduce risk of ovarian cancer • Prophylactic BSO in high-risk patients as identified by genetic testing

22. Current state-of-the-science • RCT at 13 sites England, Wales, N Ireland • Women aged 50-74 • 1:1:2 of CA125/ROCA (MMS), USS or no screening • Enrolled 200,000+ between 2001-2005 • Primary outcome: death by ovarian cancer

23. Regular CA125 Test Risk of Ovarian Cancer Algorithm based on longitudinal CA125 values (ROCA) Intermediate low < ROCA < high Elevated ROCA > high Normal ROCA < low Repeat CA125 Interval determined by ROCA TVS + CA125 Current state-of-the-science

24. Current state-of-the-science

25. Current state-of-the-science

26. Current state-of-the-science • Despite enormous effort, there is no proof that routine screening in either the high-risk or general populations with markers, sonograms, or pelvic examinations decreases mortality. • Further evaluation is needed to determine whether any novel biomarkers, or panels of markers, have utility in early detection. Gynecol Oncol 2010

27. Current state-of-the-science Balance of Benefits and Harms: Annual screening with TVS and CA125 in women does NOT decrease ovarian cancer mortality. Instead, it can lead to important harms, including major surgical interventions in women who do not have cancer. Therefore, the harms of screening for ovarian cancer outweigh the benefits. Sept 10, 2012

28. Current state-of-the-science

29. Current state-of-the-science UPDATE! This recommendation does not apply to women who are known carriers of genetic mutations that increase their risk for ovarian cancer (e.g., BRCA1 or BRCA2 gene mutations). July 24, 2017

30. Current state-of-the-science • OCs have prevented some 200,000 cases of ovarian cancer worldwide over the past 50 years, but mechanism unclear • Opportunistic bilateral salpingectomy (BS) at time of hysterectomy to reduce risk of ovarian cancer • Prophylactic BSO in high-risk patients as identified by genetic testing • Prospective large trials have largely failed to meaningfully impact ovarian cancer mortality rates

31. 2017 • Ashkenazi Jewish with family hx & BRCA1 mutation carrier • Enrolls in CA125/TVS screening trial • Elects to have prophylactic laparoscopic BSO age 37 • Occult stage IC fallopian tube cancer identified

33. Liquid-based cervical p53 screening of exfoliated tubal epithelium 2037(?)

34. Natural Orifice Transluminal Endoscopic prophylactic BS 2037(?)

35. 2037(?) • Genetic testing in childhood identifies BRCA1 mutation • Annual liquid-based cervical p53 screening (positive) • NOTES bilateral salpingectomy at age 33 • STIC lesion detected that does not require further treatment

36. 2037 and beyond

37. Ovarian Cancer

38. 1997

39. 1997 Your speaker begins his fellowship in gynecologic oncology

40. 1997 • Ann Dunham developed stomach pains abroad 1994 • Months of misdiagnosis until ovarian cancer suspected • Stage IV disease s/p suboptimal debulk with prolonged course • Platinum-based treatment with early relapse and death age 52

41. 1997 • Advanced ovarian cancer patients 1st undergo vertical laparotomy with debulking surgery • Postoperatively, IV carboplatin and paclitaxel chemotherapy x 6 cycles • NCI collaborative group trials of large phase III chemotherapy trials ongoing • Relapsed disease managed with a provider-specific sequence of 3 or 4 cytotoxic chemo drugs

42. Current state-of-the-science Sept 2010

43. Current state-of-the-science

44. Current state-of-the-science MGH primary debulking OVCA: Jan 2000 – Dec 2009 1.00 No Residual Disease Median OS = 69 mo P < 0.001 Optimal ≤ 1 cm Median OS = 38 mo 0.75 Suboptimal > 1 cm Median OS = 22 mo R0 0.50 0.25 0.00 0 5 10 15 Years

45. Current state-of-the-science

46. Current state-of-the-science Laparoscopic scoring to predict resectability (to R0)

47. Current state-of-the-science

48. Fagotti/MDACC Lscopic scoring (SGO-2016) Current state-of-the-science • 99 pts advanced ovarian cancer (34 excluded) • 65 had laparoscopy • 40 had score <8: 37 PDS 86% R0 • 25 had score 8+: NAC 78% R0

49. Current state-of-the-science • Intraperitoneal chemotherapy • 16-month survival advantage • Rare NCI clinical announcement • Time-table to study completion Jan 2006

50. Current state-of-the-science Leaner randomized phase II trials run via consolidated collaborative group (NRG Oncology)