High Grade Serous Ovarian Cancer

High Grade Serous Ovarian Cancer (as per latest international guidelines)

1. Iqra Yasin High Grade Serous Ovarian Cancer Fellow Gynecologic Oncology SKMCH & RC, Lahore

2. Outline Epidemiology Classification Genetics Origin Pathology Risk / Protective factors Clinical presentation Dissemination Screening Diagnosis Staging Treatment Follow up Prognosis Recurrent disease Summary References

3. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries CA: A Cancer Journal for Clinicians, Volume: 71, Issue: 3, Pages: 209-249, First published: 04 February 2021, DOI: (10.3322/caac.21660)

4. Epidemiology Ovarian cancer Worldwide 8 th most common female cancer (225,500 cases/year) 8 th leading cause of cancer-related mortality (140,200 cases/year) Most lethal gynecological malignancy USA (SEER) 11.6 cases / 100,000 women per year (incidence) 5 year survival: 47.4 %

5. Epidemiology Average lifetime risk: 1.3 % Risk of mortality: 1 % At time of diagnosis 80 % advanced stage 20 % early stage

6. Epidemiology

7. Epidemiology

8. Classification

9. Classification (Epithelial Ovarian Cancer) Serous cancer Low grade (< 5 %) High grade (70 – 80 %) (HGSOC) Endometroid (15 %) Clear cell (5 %) Mucinous (3 %) Transitional Undifferentiated

10. Classification (clinicopathological and genetics basis)

11. Genetics Universal p53 expression The Cancer Genomic Atlas (TCGA) BRCA 1  12.5 % (Germline 9 %, Somatic 3.5 %) BRCA 2  11.5 % (Germline 8 %, Somatic 3.5 %) Small number of somatic mutation involving CSMD3 (6 %) , NF1 (4 %), CDK12 (4 %) Gene copy number variation Amplification (CCNE1, MYC, MECOM)

12. Origin The precise cell and tissue of origin of HGSOC Controversial Theories 1. Unifying traditional theory of Ovarian Surface Epithelium (OSE) Monolayered modified mesothelium with uncommitted morphology and differentiation Fathalla theory of incessant ovulation No. of ovulatory cycles ∞ risk of acquiring HGSOC

13. Origin

14. Origin Theories 2. Tubal origin of serous cancer Piek et al proposed dysplastic lesion and occult HGSC in fallopian tube in patient with BRCA 1/2 mutants Subsequent studies confirms presence of STIC (Serous Tubal Intraepithelial Cancer) using SEEFIM (sectioning and extensively examining the fimbriated end) protocol Molecular studies: confirms identical p53 mutation and CCNE1 amplification in STIC (Precursor lesion) and HGSC

15. Origin

16. Origin Theories 3. Early implantation of FTSEC (Fallopian Tube Secretory Epithelial Cells) in OSE (= endosalpingiosis ) Incorporation of FTSEC in Cortical inclusion cyst (CIC) Metaplasia under influence of ovarian hormones Neoplasia due to pro inflammatory / pro-oxidative environment of ovary

17. Pathology

18. Pathology

19. Risk factor Geographical distribution High incidence (Northern and eastern Europe) Intermediate (West Europe, Australia, America) Low (Asia, Africa) Age Median age of diagnosis: 63 (55 – 64) years Median age of death: 71 (65 – 74) years

20. Risk factor Genetics Germline BRCA 1 (3.6 %), BRCA 2 (3.3 %) mutation Germline + sporadic BRCA 1 / 2 (10-20 % cases) 44 % risk at age of 70 year Homolog recombination pathway gene mutation BRIP1 (5.8 % lifetime risk), RAD1C (5.2 % lifetime risk) RAD1D (12 % lifetime risk)

21. Risk factor Genetics Family history (3 - 4 fold increase risk) Lynch Syndrome (HNPCC) DNA mismatch repair gene MLH1, MSH2, MSH6, PMS2 Single nucleotide polymorphism (SNPs)

22. Risk factor Ethnicity Non-Hispanic Caucasian > Hispanic, Asian, African American Reproductive / Hormonal Early menarche Late menopause Nulliparity Ovulatory cycles

23. Protective factor Pregnancy Breast feeding Tubal ligation Salpingoophorectomy (BRCA 1 / 2 mutant ) Combination OCP Wild type p53 Functionally normal homolog recombination DNA repair pathway

24. Clinical Presentation

25. Clinical Presentation History Variable and nonspecific symptoms Abdomen/pelvis examination Abdominal or pelvic masses bilateral, solid-cystic, firm, fix, irregular surface, nodularity of pouch of Douglas

26. Dissemination Direct dissemination Exfoliation of tumor cells in peritoneal cavity ( Transcoelomic ) Lymphatics Hematogenous (rare)

27. Screening No effective screening strategy for early detection of ovarian cancers PLCO Screening trail (CA 125, TVS) Promising result in early detection Failure to improve patient outcomes (survival) Genetic testing may be helpful Family history Prophylactic oophorectomy (BRCA 1 / 2; 80-90 % reduction)

28. Diagnosis Tumor marker CA-125 50 % early stage, 80 % late Diagnostic and prognostic Imaging US/CT/MRI/PET-CT Laparoscopy (staging/diagnostic)

29. Diagnosis Tumor marker CA-125 50 % early stage, 80 % late Diagnostic and prognostic Imaging US/CT/MRI/PET-CT Laparoscopy (staging/diagnostic)

30. Staging

31. Staging

32. Staging

33. Staging

34. Treatment Early stage EOC (FIGO I and II) Surgical staging Midline/laparoscopy (selected cases) Peritoneal washings Systemic exploration of all abdominal surfaces and viscera in a clockwise fashion Any suspicious area / adhesion on peritoneum should be biopsied

35. Treatment Early stage EOC (FIGO I and II) Surgical staging Random blind peritoneal biopsies (if normal peritoneal surface) Right and left paracolic recesses Right and left pelvic side walls Right hemidiaphragm Urinary bladder recession Cul-de-sac

36. Treatment Early stage EOC (FIGO I and II) Surgical staging Hysterectomy + BSO Omentectomy Retroperitoneal space dissected and explored to evaluate pelvic LNs. Para aortic area should be explored

37. Treatment Advanced EOC (FIGO III and IV) Mainstay = Debulking/cytoreductive surgery + chemotherapy Types of debulking surgery Immediate primary Delayed primary (interval) Secondary

38. Treatment Factors impacting probability and extent of surgery Patient related factors Age Performance status Comorbidities Non acceptance of blood transfusion and stoma formation

39. Treatment Factors impacting probability and extent of surgery Disease related factors Involvement of SMA Diffuse deep infiltration of proximal small bowel mesentery Diffuse carcinomatosis infiltration of small bowel Multiple liver parenchymal pulmonary metastases Brain metastases Tumor infiltration of hepatoduodenal ligament/celiac trunk Extensive lymphadenopathy extending into chest

40. Treatment Advanced EOC (FIGO III and IV) Aim of cytoreduction Removal of primary and all metastatic tumor No visible (R1) tumor after surgery Rationale of cytoreduction Physiologic benefit of tumor mass excision Enhanced immunologic response Improve tumor perfusion and growth fraction and better response to chemotherapy

41. Treatment Advanced EOC (FIGO III and IV) Standard procedures in cytoreduction Hysterectomy + Oophorectomy Pelvic , para-aortic LND ESMO (LION Trial) recommends PLND if LN bulky/suspicious Routine LND not recommended

42. Treatment Advanced EOC (FIGO III and IV) Standard procedures in cytoreduction Omentectomy Bowel resection (if involved) Non standard procedures in cytoreduction

43. Treatment

44. Quantitative Prognostic Indicators Prior Surgical Score (PSS) Peritoneal Cancer Index (PCI) Complete Cytoreduction (CCR) Score

45. Quantitative Prognostic Indicators Prior Surgical Score (PSS) PSS 0: No previous abdominopelvic (AP) surgery PSS 1: 1 AP region dissected PSS 2: 2-5 AP regions dissected PSS 3: ≥ 6 AP regions dissected Low PSS associated with good median survival

46. Quantitative Prognostic Indicators PCI score Median Survival 5 year survival rate < 10 80 months 65 % > 10 38 months 29 %

47. Quantitative Prognostic Indicators Complete Cytoreduction (CCR) Score Median survival Adequate / Optimal CC-0 to CC-2 (1 cm) 55 months Suboptimal CC-3 8 months

48. Treatment

49. Treatment

50. Treatment

51. Treatment

52. Treatment Bevacizumab Humanized monoclonal anti- VEGR antibody ICON-7 and GOG218 trials Recommended as 1 st line therapy of advanced stage EOC to be used along side chemotherapy and continued for 15 months as maintenance therapy.

53. Treatment Intraperitoneal chemotherapy Delivers higher amount of chemotherapy intraperitoneally as compare to IV route NCCN recommends it as potential option for stage II or III EOC after optimal debulking surgery Based on improved survival outcome reported in GOG172 RCT.

54. Treatment HIPEC (Hyperthermic Intraperitoneal Chemotherapy) OVIHIPEC-1: Significant improved OS/PFS Korean Trail: No improved OS/PFS Not recommended as 1 st line treatment option. Need further Phase III RCT

55. Treatment

56. Follow-up / Surveillance

57. Prognosis

58. Recurrent disease Platinum sensitive If ovarian cancer recur ≥ 6 months of platinum based therapy Platinum resistant If ovarian cancer recur < 6 months of platinum based therapy.

59. Recurrent disease

60. Recurrent disease

61. Recurrent disease PARPI (Poly(ADP-Ribose) Polymerase Inhibitors) Olaparib, Niraparib, Rucaparib, veliparib Dramatic change in outcome of stage III-IV HGSOC in BRCA mutant and Homologous recombinant deficient (HRD) tumor 20 % HGSOC: Somatic / germline mutation in BRCA 1 and 2 genes. 50 % HGSOC: HRD deficient

62. Recurrent disease

63. Recurrent disease

64. Summary Inspite of Uncommon incidence, OC still represents a silent public health concern due to dismal long term survival outcome. HGSOC is most common and by far the deadliest. Unspecific symptoms and few early warning signs , rarely diagnosed at an early stage. Few recurrent driver mutations in p53, genomic instability and gene number alterations. Mainstay of treatment is debulking surgery and platinum-based chemotherapy Despite excellent response to platinum-based chemotherapy, recurrence occurs and that response to PARP inhibitors and bevazicumab .

65. References Textbook of Gynecological Oncology (European Society of Gynecological Oncology) Berek & Hacker ‘s Gynecologic Oncology (6 th edition) NCCN guidelines (version 1.2021) Lisio MA, Fu L, Goyeneche A, Gao ZH, Telleria C. High-Grade Serous Ovarian Cancer: Basic Sciences, Clinical and therapeutic standpoints. Int J Mol Sci. 2019 Feb 22;20(4):952. PMID: 30813239. DOI :10.3390/ijms20040952. Mahmood RD, Morgan RD, Edmondson RJ, Clamp AR, Jayson GC. First-Line Management of Advanced High-Grade Serous Ovarian Cancer. Curr Oncol Rep. 2020 Jun 4;22(6):64. PMID: 32494876. DOI: 10.1007/s11912-020-00933-8. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries . CA Cancer J Clin. 2021 May;71(3):209-249. PMID: 33538338DOI: 10.3322/caac.21660. Epub 2021 Feb 4.

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