A discussion about low grade serous ovarian cancer with Dr. Amanda Nickles Fader, Director of Kelly Gynecologic Oncology Service, Johns Hopkins Hospital. This type of ovarian cancer behaves differently and is treated differently than other ovarian cancers. Join the conversation to learn more and ask an expert your questions.

1. Updates in Low-Grade Serous
Ovarian Carcinoma
Amanda Fader, MD
Johns Hopkins Hospital

2. Disclosures
Case-based learning: The JH patient cases
discussed in these slides are presented with
permission.
--Amanda Nickles Fader, MD

3. Objectives
• To review the molecular biology and clinical
behavior of low-grade serous carcinoma
(LGSC)
• To appraise the evidence supporting best
surgical, chemotherapy, and hormonal
practices for these tumors through case
studies

4. Case 1
• 61-year-old female with 1 month of abdominal
distention, constipation, narrower stools
• CT of the chest, abdomen and pelvis
performed and revealed 10x15 cm abdominal
mass, bilateral ovarian masses, multiple
peritoneal and splenic implants
• Tumor marker CA-125: 270

5. Case 1
• Surgery: Exploratory laparotomy/total
hysterectomy/bilateral ovarian and fallopian
tube removal/removal of rectosigmoid
colon/omentectomy/splenectomy/tumor
debulking to ”no gross residual”
• Uncomplicated recovery
• What are next steps in management?

6. National Comprehensive Cancer
Network Ovarian Cancer Guidelines:
Every Woman Gets the Same
Treatment

7. Less Lumping, More Splitting?
• Epithelial ovarian cancer (EOC) is not one,
but several, distinct entities
• Yet in last decade, most women with EOC
have been treated identically
• Advances in the understanding of
heterogeneity of ovarian malignancies
– Refining pathologic diagnostic criteria
– Molecular biology and genetics
Jemal, Cancer Stats. 2014

8. Two-Tiered Pathology Criteria
Variable LGSC
(Grade 1)
HGSC
(Grade 2/3)
Nuclear atypia Uniform round to
oval with little
variation
+++
Marked variation
Mitotic Index <12 mitosis per 10
hpf
>12 mitoses per
10 hpf
Chromatin and
variation in size of
nucleus
Little Marked (nuclear
size ratio ≥3)
Mutation KRAS ++
BRAF +
ER/PR +++
PAX2 +
P53 +++
Precursor Serous borderline
tumor
Tubal
intraepithelial
neoplasia
LGSC
HGSC
Malpica et al, Am J Path, 2007 ; Kurman et al, Am J Path, 2007

9. Epidemiology
• Women w/ LGSC diagnosed at a younger age
and have a longer overall survival than those
with HGSC
– Pooled retrospective data on 5-year survival
– 40-56% for advanced LGSC versus 9-34% for
HGSC
• However, those with LGSC have lower
response rates to conventional chemo so
can be more challenging to treat
Gershenson et al, Gynecol Oncol, 2012
Fader et al, Obstet Gynecol, 2013

10. Absence of Data and Variability in
Management
• There is no upfront trial data in LGSC
• Survey of SGO members
– 194 GYN ONCs 2/3 at a university based setting and
treated a high volume of OC
– Treatment preferences for primary disease varied by
debulking status.
– 48% use hormone antagonism as consolidation after
primary treatment
Siemon, Gershenson, Slomovitz,
Schlumbrecht ; Int J Gyn Cancer, 2019

11. LGSC: Factors Impacting Survival
What are the most important factors
related to excellent outcomes in the
primary setting?
• Surgery
• Targeted, tailored approach to
treatment

12. Surgery is Perhaps the One of the
Most Important Aspect of Treatment

13. Analysis of
GOG Trial 182
• An ancillary analysis of women with stage
III-IV epithelial ovarian cancer
– Treated with primary cytoreductive surgery
– T/C compared with triplet or sequential doublet
regimens
• 189 had Grade 1 disease (surrogate for
LGSC)
• On multivariate analysis, only residual
disease status after primary debulking was
significantly associated (p=.006) withFader et al, Obstet Gynecol, 2013

14. Ancillary Analysis of GOG 182
Fader et al, Obstet Gynecol, 2013
Patients with microscopic residual had a significantly longer median
progression-free (33.2 months) and overall survival (96.9 months) compared
with those with residual 0.1-1.0 cm (14.7 months and 44.5 months,
respectively) and more than 1.0 cm of residual disease (14.1 months and
42.0 months, respectively; progression-free and overall survival, P<.001).

15. LGSC is Often Chemoresistant
• AGO (German) mega-database: four RCTs of >5000
pts, women w/ LGSC were less likely to respond to
chemo than those w/ HGSC
– 23.1% RR in LGSC suboptimal debulked cohort compared to
90.1% response rate in the HGSC control cohort (p<0.001)
• National Cancer Database study of 755 women with
Stage IIIC-IV LGSC
– Median OS not significantly different among 140 pts who
received chemo after primary CRS (OS = 88 months)
compared to 140 pts did not receive chemotherapy (OS =
95.9 months; P=0.7).
Grabowski et al, Gynecol Oncol 2016
Gockley et al, Obstet Gynecol, 2016

16. Hormonal Receptors
• LGSC 2x more likely to robustly express
estrogen and progesterone receptors than
HGSC
Fader et al, Gyne Onc, 2017; Malpica 2007

17. The MD Anderson Experience
– 203 pts w/ stage II-IV LGSC received
primary CRS and paclitaxel/carbo
– 70 pts also received hormonal therapy
maintenance (HTM)
– HTM=aromatase inhibitors (letrozole,
anastrazole, tamoxifen etc)
– All w/ ER/PR tumoral expression
• Median PFS for those w/ HTM was 64.9 mos
compared to 26.4 mos for those receiving
chemo alone (P<.001)
• 88.1 mos for subgroup w/ NGRD post-surgery
of women who received HMT vs. 30 mos
(P<.001) Gershenson, JCO, 2017

18. Johns Hopkins and Cleveland Clinic
Experience
• Since 2011, have treated women with
advanced LGSC after primary cytoreductive
surgery with hormonal therapy alone
– Aromatase inhibition (letrozole)
– Continue indefinitely until disease progression or
toxicity
• To date, more than 50 women treated with
this regimen
• Initial report:
– 27 initial patients, 89% with Stage III disease,
optimal debulking in 85%
Fader AN, Gynecol Oncol, 2017

19. 3 Year PFS and OS
3-year OS 93.1%
3-year PFS 79.0%
Fader et al, Gynecol Oncol, July 2017
Median PFS and OS have not been reached.

20. In 2017, guidelines allow for advanced stage
low grade serous carcinoma to be treated
with chemotherapy f/b hormonal therapy vs.
hormonal monotherapy (letrozole,
anastrozole, tamoxifen or leuprolide
acetate): Category 2B recommendation

21. NRG-019 Trial: National Cancer
Institute Trial

22. Case #2
• 38-year-old with large liver, spleen,
bowel, and metastases just below the
skin; bilateral large ovarian masses
• CA-125: 155; biopsy: LGSC

23. Case #2
• Received carboplatin/paclitaxel x 2 cycles
neoadjuvantly (i.e., chemo before surgery)
• Developed N/V and inability to tolerate PO
and interval CT scan demonstrated disease
progression and high grade small bowel
obstruction

24. Case #2: Patient with Stage IV LGSC
Treated with Neoadjuvant Chemo
Progression and SBO after 2 cycles of
chemotherapy
Pre-chemo

25. Neoadjuvant Chemotherapy
• Relative chemoresistance also observed in a
review of women who received neoadjuvant
chemotherapy for advanced stage LGSC
• 25 patients, median age 45 years
• Only 4% response rate
• Half of evaluable patients had a greater than
50% reduction in serum CA 125 levels after
chemo--only one patient had by imaging
assessment

26. Case #2
• The patient did not tolerate conservative
management for small bowel obstruction
• Debulking surgery with hysterectomy and
removal of bilateral ovaries/total colectomy
(colon removal)/omentectomy/splenectomy/
liver implant removal/resection of abdominal
wall implants
• Residual disease: optimal <1 cm residual
nodules in the liver that could not be

27. Case #2
• Tumor
– ER +90%
– PR +40%
• Letrozole 2.5 mg po initiated
• CT @ 6 months w/ regression of all liver mets
• Asymptomatic w/ no observable liver mets x
12 months
• Progression free survival (remission) 34
months, overall survival thus far 75 months

28. Estrogen Therapies and ESR1
Mutations
• Activating mutations in the estrogen receptor
(mutESR1) contribute to resistance to endocrine
therapy, especially aromatase inhibitors (AIs).
• Can help guide therapeutic choices with hormone
therapy
• Only 1-2% of GYN cancers will have activating ESR1
mutations
• Clinical benefit seen with selective ER-targeted
therapies. (ie, fulvestrant, exemestane etc)
Gaillard et al, Gynecol Oncol, 2019

29. Case #3
• 65 year old diagnosed with Stage IIIC LGSC
who received optimal debulking surgery
• Received carboplatin/taxol x6 and letrozole
maintenance
• 4 years progression-free survival, now with
CT scan demonstrating 2 cm pelvic/rectal
mass and 1.8x3.2 cm spleen mass

30. Surgical vs. Medical
Management…or Both?
• Secondary tumor
debulking/splenectomy/pelvic mass
resection/tumor resection with ileo-
ascending colon resection and anastomosis
to NGR
• Tumor: ER: 30%, PR: 50%
• GOG Trial 213—no improvement in OS with
2nd CRS Coleman et al, ASCO, 2018

31. Surgery: Mainstay at Recurrence?
• Retrospective MD Anderson study of 41 pts
• Median PFS for patients with no gross
residual disease after CRS was 60.3 months
vs 10.7 months for patients with gross
residual disease (p = 0.008)
• Median OS from the time of SCRS for
patients with no gross residual disease was
93.6 months compared to 45.8 months (p =
0.04)
Crane et al, Gynecol Oncol, 2015

32. Treatment Options at Recurrence
Clinical/Molecular
Features
Low Grade Serous
(LGS)
High Grade Serous
(HGS)
Median Age at
Diagnosis
40-50’s years 50-60’s years
Response Rate to
Neoadjuvant
Chemotherapy
4-23%3 80-90%
Historical
Response Rates to
Chemotherapy in
the Recurrent
Setting
Platinum Sensitive:
5%5
Platinum Resistant:
2%5
Platinum
Sensitive:57%7
Platinum Resistant:
12%6
Molecular
Genetics1
Mutant: BRAF, RAS
Wild type: p53
Mutant: p53, BRCA,
HRD
Wild type: BRAF,
RAS
1:Grisham, RN. Oncology
2016; 7:650-2. J Natl
Cancer Inst 2014;106(4):1-
8; 2:Bodurka et al. Cancer
2012;118:3087-94;
3:Schmeler et al. Gynecol
Oncol 2008;108:510-4;
4:Grabowski et al, 2016.
5:Gershenson et al. Gynecol
Oncol 2009; 114(1):48-52.
6:Pujade-Lauraine et al. J
Clin Oncol 2014;
32(13):1302-8. 7:
Aghajanina et al. J Clin
Oncol 2012; 30(17): 2039-
45.

33. Treatment Considerations
• Consider NGS mutational profile
– ESR1 hot spot mutations
• Tamoxifen, AI, fulvestrant, exemestane
• Avastin
• Chemo and targeted agent combinations (ie,
doxil/avastin, weekly taxol/avastin etc)
– Overall response rate (CR+PR) to bevacizumab-
containing regimens was 47.5%. Clinical benefit
(CR+PR+SD) was seen in 77.5% of patients
• Consider MEK inhibitor (trametinib)
Dalton et al, Gynecol Oncol, 2017

34. MILO/ENGOT-ov11:
Phase-3 Study of Binimetinib versus
Physician’s Choice Chemotherapy in Recurrent
or Persistent Low-grade Serous Carcinomas of
the Ovary, Fallopian Tube, or Primary
Peritoneum
• Primary:
– To compare progression-free survival (PFS) of binimetinib
vs. physician’s choice of selected chemotherapies
(liposomal doxorubicin, paclitaxel and topotecan)
• Secondary:
– Obtain additional estimates of the efficacy (including
overall survival [OS]) of binimetinib vs. physician’s choice
of selected chemotherapies
– Safety and tolerability

35. Study Design
• Study initiation: June 2013
• Interim analysis cutoff date:
January 2016 (N=303)*
• Updated analysis cutoff date:
January 2019 (N=341)
*Study enrollment discontinued after
this planned interim PFS analysis
crossed the predefined futility
boundary (observed hazard ratio of
1.21).
**Crossover allowed following PD on
PCC
Stratification:
Platinum-Free Interval (≤ 182 days vs > 182 days )
# of Prior Systemic Chemo Regimens (1 or 2 vs. >2)
Randomization 2:1
Physicians’ Choice of
Chemotherapy (N=113)**
Pegylated
Liposomal
Doxorubic
in
(40mg/m2 IV, day 1
of 28 day cycle)
Paclitax
el
(80mg/m2 IV on
days 1,8,15 of
28 day cycle)
Topoteca
n
1.25 mg/m2 IV on
Days 1-5 of 21 day
cycle)
Binimetinib
(N=228)
(45mg PO BID)
Patients with Recurrent/Persistent LGS Carcinoma of the Ovary,
Fallopian Tube or Primary Peritoneum
≥1 prior platinum based regimen but ≤ 3 prior lines of chemo
Unlimited prior hormonal therapies (ENGOT Model C)

36. Progression-free Survival Data: No
Significant Difference in Treatment
Arms

37. PFS in KRAS-mutated vs
nonmutated patients on binimetinib
Median PFS for Binimetinib treated
patients: KRAS Mutant: 17.7 months (12,
NA)
KRAS WT: 10.8 months (5.5, 16.7); P=
0.006

38. GOG 281: A Randomized Phase II/III Study to Assess the
Efficacy of Trametinib in Patients with
Recurrent or Progressive Low-Grade Serous
Ovarian or Peritoneal Cancer
Eligibility Criteria
Digital path review
Measurable disease by
RECIST 1.1
At least 1 prior
platinum regimen
Unlimited no. prior
therapies
No prior MEKi, BRAFi
Cannot have received
all 5 SOC
Recurrent LGSOC
Prospective
R
Trametinib 2
mg
daily
continuously
until
progression
Standard of Care
1.Letrozole 2.5 mg daily
2.PLD 40-50 mg IV Q. 28d
3.Weekly Paclitaxel 80
mg/m2 3/4 weeks
4.Tamoxifen 20 mg bid
daily
5.Topotecan 4.0 mg/m2
on days 1, 8, 15 Q. 28d
Trametinib 2 mg
daily continuously
until progression
Crossover
Allowed

39. GOG 281: PFS
130 36 3 0
130 61 18 3 0
0 12 24 36 48
Months at Risk
0.00
0.25
0.50
0.75
1.00
ProportionAliveandProgressionFree
SOC
Trametinib
130 36 3 0
130 61 18 3 0
0 12 24 36 48
Months at Risk
0.00
0.25
0.50
0.75
1.00
ProportionAliveandProgressionFree
SOC
Trametinib
Trametinib
SOC
Randomized RX
+ Censored
Trametini
b
Control
(SOC)
Median
(Months)
95% CI
13.0
(9.9 –
15.0)
7.2
(5.6 -
9.9)
Hazard
Ratio
95% CI
0.48
(0.36 –
0.64)
One-sided
p-value
< 0.0001
OS increased by 8 mos, just
missed achieving statistical
significance (P = .054).
More than 4x as many patients
achieved ORRs with MEK
inhibitor than control arm

40. Summary
• Rare, low-grade serous carcinoma should be treated
distinctly from other ovarian cancer subtypes
• Do not overtreat; instead, target receptors/mutations
– Minimize ineffective cytotoxics
– Maximize targeted therapies, endocrine agents & strategic
combinations
• Please consider enrolling on clinical trials
• Encouraging centers to open trials and be rare tumor
superheroes!

41. Thank you!
• SHARE
• Our patients
• Kelly Gynecologic
Oncology Service
afader1@jhmi.edu