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. Ovarian Cancer 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

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. 1997
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

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

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

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
Primary outcome: death by ovarian cancer

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

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!
Population
Recommendation
Grade
Asymptomatic women
The USPSTF recommends against screening for ovarian cancer in asymptomatic women. D
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(?)
Liquid-based cervical p53 screening of exfoliated tubal epithelium

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

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 R0
Suboptimal > 1 cm
Median OS = 22 mo
0.50
0.25
0.00 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
Fagotti/MDACC Lscopic scoring (SGO-2016)
99 pts advanced ovarian cancer (34 excluded)
65 had laparoscopy
40 had score <8: 37 PDS % R0
25 had score 8+: NAC % 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)

51. Current state-of-the-science
Leaner randomized phase II trials run via consolidated
collaborative group (NRG Oncology)
NRG-GY007
Phase I dose-escalation study of ruxolitinib – followed by
randomized phase II component
Oral JAK1/2 inhibitor
Testing dose-dense carbo/paclitaxel
Testing maintenance therapy
Testing translational endpoints with longitudinal tissue
162 patient sample size

52. 2017 (Still) months of misdiagnosis until ovarian cancer suspected
Stage IV disease s/p bx and phase II NAC/immunotherapy trial
Interval minimally invasive (optimal) cytoreductive surgery
Investigational maintenance therapy in remission per protocol

54. 2037(?)
Histologic confirmation serous cancer
NextGen molecular profiling of tumors

55. 2037(?)
Histologic confirmation serous cancer
NextGen molecular profiling of tumors

56. 2037(?)
Histologic confirmation serous cancer
Laparotomy with primary debulking
NextGen molecular profiling of tumors
Minimally invasive surgery only

57. 2037(?)
Histologic confirmation serous cancer
Laparotomy with primary debulking
Platinum/paclitaxel and novel drug trials
NextGen molecular profiling of tumors
Minimally invasive surgery only
Patient triage based on specific predictors

58. 2037(?)
Histologic confirmation serous cancer
Laparotomy with primary debulking
Platinum/paclitaxel and novel drug trials
Achieve remission and wait for relapse
NextGen molecular profiling of tumors
Minimally invasive surgery only
Patient triage based on specific predictors
Maintenance therapy to prolong remission

59. 2037(?) Pelvic symptoms prompt diagnostic workup
Stage IIIC disease s/p bx and comprehensive molecular profile
Neoadjuvant oral combination of BRIP1/JAK2 inhibitor
Minimally invasive day-surgery with revision of therapy based on translational tumor response

60. 2037 and beyond

61. 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

62. Thank you