low-grade serous carcinoma of the ovary or peritoneum
TRANSCRIPT
Low-Grade Serous Carcinoma of the Ovary or Peritoneum
David M. Gershenson, MD
The University of Texas MD Anderson Cancer Center
Disclosure
• No disclosures relevant to presentation
M.D. Anderson Grading System for
Ovarian Serous Carcinoma
• Low Grade:– Mild to moderate nuclear atypia
– Mitotic index of up to 12 mitoses/10 HPF (as
secondary feature)
• High Grade:– Marked nuclear atypia
– Mitotic index of > 12 mitoses/10 HPF (as
secondary feature)
Malpica et al
Am J Surg Pathol 2004
MAPK Pathway plays prominent
role in pathogenesis of LGSC
Molecular Biology of LGSC:The Emerging Story
Tumor Subtype BRAF Mutation KRAS Mutation
Serous Tumor LMP 20-40% 40%
LGSC 5% 20-40%
HGSC 0% 0-14%
KRAS G12V Mutation AssociatedWith Worse Prognosis
• KRAS G12V mutation is associated with significantly worse prognosis than KRAS G12D, WT, or variant
• In > 3000 colon cancer cases, of 12 different mutations in KRAS codons, only KRAS G12V was associated with poor OS
• Similar trend in lung cancer study
Tsang et al.J Pathol 2013
RPPA Analysis
Up-regulation of p-Akt
Down-regulation of p-ERK1/2
Down-regulation of Chk1
Combining AKTi (MK2206) is able to suppress the expression of pAKT up-regulated by MEKi (GSK)
Gene Expression Profiling(
Name p-Value
Role of BRCA1 in DNA Damage Response 1.7 E-13
Role of CHK Proteins in Cell Cycle Checkpoint Control 3.00E-08
Hereditary Breast Cancer Signaling 9.20E-08
Mitotic Roles of Polo-Like Kinase 1.47E-07
Cell Cycle Control of Chromosomal Replication 1.52E-07
MEKi down-regulates genes involved in BRCA1 DNA damage response and cell cycle checkpoint control
MEKi interacts with PARPi synergistically
IGF-1 Pathway in
Low-Grade Serous Carcinoma
• Significantly higher
IGF-1 expression in
LGSC vs SBT or
HGSC
• In response to IGF-
1, LGSC cell lines
showed more
intense upregulation
of pAkt than did
HGSC cell lines King et al.Gynecol Oncol 2011
High-Grade
Serous Carcinoma
Low-Grade
Serous Carcinoma
LGSC is Relatively Chemoresistant
Primary Treatment
112 stage II-IV LGSC pts: Primary surgery + chemo
Only 52% NED at completion of primary chemo
Only 5% negative second-look rate
median OS = 82 mos Gershenson et al. Obstet Gynecol 2006
25 advanced stage LGSC pts: Neoadjuvant chemo
Only 1/24 pts had objective response
88% had SD
50% had >50% decrease in CA 125 Schmeler et al. Gynecol Oncol 2007
Low-Grade Serous Tumor Registry
• 350 pts.– 57.3% clinically disease-free at completion of
primary therapy– Median PFS = 28.1 mo.– Median OS = 101.7 mo.
• 287 stage II-IV pts.– Primary surgery + platinum-based chemotherapy– On multivariate analysis, significant factors:
• Presence of tumor at completion of 1° therapy: HR = 1.96• PPC: HR = 0.59• Age > 36 yrs.: HR = 0.44-0.75
Relationship of LGSC to Breast Cancer
287 LGSC Patients Breast Cancer
• Several studies have revealed increased risk of recurrence and death in young (<35 y/o) luminal breast cancer patients
OS 73 vs 103 moP<0.001
Salvage Chemotherapy
• 52 pts received 98 evaluable salvage chemo
regimens
– Platinum-sensitive: 6% RR in 54 patient-
regimens
– Platinum-resistant: 2% RR in 44 patient-
regimens
• SD rate = 62%
– Duration: Median = 22.1 wks (Range, 8-79
wks)
• Median OS = 87.1 mo
• Median TTP = 6.8 mo (Range, 1-54.2 mo)
• 6-mo PFS = 58% Gershenson et al.Gynecol Oncol 2009
Hormonal Therapy = Targeted Therapy
Estrogen Receptor Agents
• Tamoxifen
• Aromatase Inhibitors– Anastrozole
– Letrozole
• GnRH AgonistTherapy– Leuprolide
– Goserelin
• Faslodex
Biomarker Profile of LGSC
• Compared to HGSC, LGSC has lower expression of p53, BCL2, WT1, HER-2/neu, c-KIT, Ki-67, MMP-9
• Compared to HGSC, LGSC has higher expression of ER, PR, ECAD
PR
ER
O-Neill et al.Am J Surg Pathol 2005
Wong et al.Int J Gynecol Pathol 2007
Hormonal Therapy forRecurrent LGSC
• 64 pts received 89 evaluable hormonal regimens
• Response rate = 9% (6 CR, 2 PR)
• Stable disease rate = 66%
– Platinum-sensitive = 83%
– Platinum-resistant = 54%
• Median TTP = 7.4 mos
• 6-mo. PFS = 61%
• ER/PR expression data available in 50 pts
• ER+/PR-: HR = 1.8 compared with ER+/PR+ (P = 0.056)
Gershenson et al.Gynecol Oncol 2012
TypeNo.
monthsPrimary
siteRegimen
(#)Platinum
Status
CA 125 atstart of regimen
CA 125 at end of
regimenER/PR
1 CR 117.6 PP Tamoxifen (4) Sensitive 64 27 Not done
2 CR 112.2 PP Anastrozole (2) Sensitive 99 25 Not done
3 CR 67.9 PP Letrozole (3) Sensitive 52 9 ER+/PR-
4 CR 52.2 PP Letrozole (4) Resistant 109 134 ER+/PR+
5 CR 11.9 Ovary Letrozole (3) Sensitive 12 37 ER+/PR+
6 CR 42.0 PP Letrozole (2) Sensitive 8 6.4 ER+/PR+
7 PR 22.0 Ovary Letrozole (2) Sensitive 13 18.1 ER+/PR+
8 PR 1.63 PP Letrozole (4) Sensitive 13 9.4 Not done
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; PP = primary peritoneal
Recurrent Low-Grade Serous Carcinoma: Responders to Hormonal Therapy
GOG 0239
• Open label Phase II study
• Eligible– Women with recurrent LGSC of ovary or peritoneum
– Measurable disease
• Biopsy proven
• Prospective pathologic evaluation • Treatment: Selumetinib 50 mg BID
• 1 cycle = 4 weeks
• 52 patients accrued between 17 Dec 2007 – 23 Nov 2009
GOG 239
Outcome
Best Response Current Status
No. Treatment Cycles Acute & Chronic AEs
Mutational Analysis
2/10/2009 6/2/2009
1.8 cm 0.9 cm
Tumor with KRAS mutation
responded to AZD6244
Significant association between pERK proteinexpression and clinical response
GOG 239
BACKGGOG 239ROUND
No correlation between pERK protein expression withBRAF or KRAS mutation status in FFPE specimens
R
GOG 281 Trial Schema
Arm A = Control ArmInvestigators Choice of following:
• Letrozole 2.5 mg po qd continuously• Tamoxifen 20 mg po bid continuously• Paclitaxel 80 mg/m2 IV over 1 hr on day
1 q. 7d, 3 wks on, 1 wk off• Pegylated Liposomal Doxorubicin 40 or
50 mg/m2 IV over 1 hr on day 1 q. 28d• Topotecan 4.0 mg/m2 over 30 min on
days 1, 8 and 15 of a 28 day cycleFor each arm, 1 cycle = 28 days
Arm B = Experimental ArmTrametinib 2 mg po daily
continuous treatmentFor each arm, 1 cycle = 28 days
Crossover to Trametinib
N = 250 patientsPrimary endpoint: PFSSecondary endpoints:• Adverse effects• Objective response• Overall survival• Molecular analyses• Quality of Life
AssessmentsClinical:• At screening day 1 of each
cycle• Following disease
progression, pts will be followed every 12 wk
CT Scans:Screening, then every 8 wkuntil disease progression
Progression
Off Study
ProspectivePathology Review
CT-GuidedFNA/Core Bx
GOG 281
PharmacokineticsProteomics
Plasma Cell-Free DNA Next Generation Sequencing
CT-Guided FNA/Core Bx
Randomized Phase III Trial
NCT01849874
Recurrent LGSC
Physician’s Choice:Paclitaxel
Liposomal DoxorubicinTopotecan
MEK162
Randomized Phase II Trial
NCT01936363
Recurrent LGSC
Pimasertib+
SAR245409
Pimasertib+
Placebo
Randomized Phase II Trial
RTM 1313
Newly Diagnosed Stage II-IV LGSC
Paclitaxel 175 mg/m2
Carboplatin AUC = 6Q. 21 d x 6 cycles
Trametinib 1.5 mg po dailyGSK 214170550 50 mg po daily
Q. 21 d x 6 cycles
Angiogenesis and Low-Grade Serous Carcinoma of the Ovary
• 17 pts treated with bevacizumab
– 10 with ovarian LGSC
– 3 with PPC LGSC
– 4 with SBT
• 15 with bev + chemo and 2 with bev alone
• RR = 40%
• SD = 33%
• 21 pts treated with bevacizumab
• 20 with bev + chemo and 1 with bev alone
• RR = 41%
• SD = 18%
Grisham et al.ASCO 2013
Schmeler et al.ASCO 2010
Key Pathways & Potential Targets:Low-Grade Serous Carcinoma
• MAP Kinase pathway (20-40% KRAS, 5% BRAF)– MEKi, BRAFi
• IGFR-1– AMG 479, BMS-536942, MK-0646
• Angiogenesis pathway– Bevacizumab, Aflibercept, AMG 386, etc.
• PI3K/AKT/mTOR pathway– Everolimus, Temsirolimus, and several others
Future Directions
• Continue to study hormonal therapy and relationship to hormone receptors
• Complete MEKi trials for recurrent LGSC
• Identify biomarkers that predict MEKi activity
• Identify MEKi-independent compensatory pathways
• Develop additional combination targeted agent trials