Low-grade serous ovarian cancer

Question 1

LGSOC accounts for ___% of serous cancers of the ovary

Answer 1

10%

Question 2

What is the relapse rate for LGSOC?

Answer 2

>70%

Question 3

Are germline mutations associated with LGSOC?

Answer 3

No

Question 4

How does LGSOC arise? Does it impact prognosis?

Answer 4

• Arises either de novo or following serous borderline tumor
• It does NOT impact prognosis (same survival curses)

Question 5

Compared to HGSOC, what are the clinical characteristics of LGSOC?

Answer 5

• Characterized by younger age at diagnosis, relative chemoresistance, responsiveness to endocrine therapy, and prolonged OS compared to HGSOC
• Like HGSOC, most patients present with advanced stage disease, and > 70% relapse

Question 6

What pathway plays a prominent role in pathogenesis of LGSOC?

Answer 6

MAPK pathway

Question 7

What are the histologic differences between LGSOC vs HGSOC?

Answer 7

LGSOC

• Mild to moderate nuclear atypia
• Mitotic index of up to 12 mitoses/10 HPF (as secondary feature)

HGSOC

• Marked nuclear atypia
• Mitotic index of > 12 mitoses/10 HPF (as secondary feature)

Binary classification of serous tumors (MDA)

Question 8

2014 WHO classification

• Typical serous borderline tumor = ___________________
• Micropapillary/cribriform serous borderline tumor = ______________
• Invasive peritoneal implants = ______________

Answer 8

• Typical serous borderline tumor = atypical proliferative tumor (APT)
• Micropapillary/cribriform serous borderline tumor = non-invasive low-grade serous carcinoma
• Invasive peritoneal implants = low-grade serous carcinoma

Question 9

Characterize the mutational profile of BRAF, KRAS, and NRAS mutation prevalence in LGSOC

Answer 9

See figure

Question 10

What is the impact of mutations on prognosis for LGSOC?

Answer 10

LGSOC with KRAS or BRAF mutations had better OS compared to those without

• 106.7 vs 66.8 months (Gershenson)

Patients with somatic MAPK pathway mutations had better OS compared to those without

• 161.7 vs 89.5 months

Question 11

What are keypathways and potential targets in treatment of LGSOC?

Answer 11

MAP Kinase pathway

• KRAS mutation (20-40%)
  
  • KRAS inhibitor
• BRAF mutation (5-10%)
  
  • BRAF inhibitor
• NRAS mutation (up to 26%)

Estrogen receptor (90%+)

• Aromatase inhibitors, etc

Angiogensis pathway

• Bevacizumab

Question 12

What is the impact of R0 after cytoreductive surgery for LGSOC?

Answer 12

• Improves PFS and OS
• Ancillary data analysis of Gynecologic Oncology Group protocol 182, a phase III study of women with stage III–IV epithelial ovarian carcinoma treated with carboplatin and paclitaxel compared with triplet or sequential doublet regimens. Women with grade 1 serous carcinoma (a surrogate for low-grade serous disease) were included in the analysis.

Question 13

What are the response rates to chemotherapy?

• First-line setting?
• Neoadjuvant setting?
• Recurrent setting?

Answer 13

• First-line Adjuvant: > 40% pts have persistent disease at completion
  
  • From AGO data: for suboptimal debulked patients, chemotherapy has a 23% response rate (n = 39)
• Neoadjuvant: Only 4% ORR in first reported study; 11% ORR in update
• Recurrent: Only < 5% ORR in first reported study

Question 14

What’s the ORR to bevacizumab?

Answer 14

• CR 0 - 7.5%
• PR 40%
• SD 33%

Question 15

• LGSC is similar to which cancer?
• Women under ______ years old have worse survival
• LGSC responds to which type of anti-estrogen therapy? ORR?
• What is the role of hormonal maintenance therapy following TRS +platinum-based chemo?

Answer 15

• At least 80% of LGSC are ER+ and is similar to breast cancer
• Women < 35 yrs have significantly worse survival
• LGSC responds to anti-estrogen hormonal therapy (AI, tamoxifen, leuprolide, fulvestrant, etc.) in the recurrent setting (ORR = 9%)
• Following primary surgery and platinum/taxane chemotherapy, hormonal maintenance therapy is associated with superior PFS and OS compared to observation
  
  • Gershenson et al. JCO 2017 Apr 1;35(10):1103-1111: Retrospective data comparing 133 OBS vs 70 HMT: mPFS 64.9 vs 26.4 months (diff seen both in disease-free or persistent disease)
• Following primary surgery, hormonal monotherapy appears promising

Question 16

What is GOG 239?

Answer 16

• Phase II study of selumetinib (MEKi) in women with recurrent LGSC (n = 52)
• ORR = 15%
• Clinical benefit rate = 80%
• No correlation of outcome with KRAS/ BRAF mutations (but there are patients with KRAS mutations who respond)

Question 17

What was MILO/ENGOT-ov11? Findings?

Answer 17

• Study design (see figure)
• Prelim results
  
  • Although the MEK Inhibitor in Low-Grade Serous Ovarian Cancer Study did not meet its primary end point, binimetinib showed activity in LGSOC across the efficacy end points evaluated. A higher response to chemotherapy than expected was observed and KRAS mutation might predict response to binimetinib

Question 18

What is the NRG-GOG 0281 trial? Findings?

Answer 18

• A Randomized Phase II/III Study to Assess the Efficacy of Trametinib in Patients with Recurrent or Progressive Low-Grade Serous (n = 260)
  Ovarian or Peritoneal Cancer
• Prelim results
  • Compared to physician’s choice standard of care (SOC), trametinib was associated with improved:
    
    • mPFS: 13.0 vs 7.2 mo [HR = 0.48] (p < 0.0001)
    • ORR: 26.2% vs 6.2% [OR = 5.4] (p < 0.0001)
    • DOR: 13.6 vs 5.9 mo
    • OS: 37.0 vs 29.2 mo [HR = 0.75] (p = 0.054)
    • TRAE: Principal > Grade 3 AE for trametinib vs SOC were hematologic (13.4% vs 9.4%), GI (27.6% vs 29%), skin (15% vs 3.9%), and vascular toxicities (18.9 vs 8.6%)
    • Authors conclude that trametinib represents new standard of care treatment option for women with recurrent low-grade serous carcinoma

Question 19

Summary slide for treatment of LGSOC

Answer 19