Low-grade serous carcinoma of the ovary or peritoneum
Transcript of Low-grade serous carcinoma of the ovary or peritoneum
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Low-Grade Serous Carcinoma of the Ovary or Peritoneum
David M. Gershenson, MD
The University of Texas MD Anderson Cancer Center
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Disclosure
• No disclosures relevant to presentation
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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
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MAPK Pathway plays prominent
role in pathogenesis of LGSC
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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%
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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
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RPPA Analysis
Up-regulation of p-Akt
Down-regulation of p-ERK1/2
Down-regulation of Chk1
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Combining AKTi (MK2206) is able to suppress the expression of pAKT up-regulated by MEKi (GSK)
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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
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MEKi interacts with PARPi synergistically
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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
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High-Grade
Serous Carcinoma
Low-Grade
Serous Carcinoma
LGSC is Relatively Chemoresistant
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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
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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
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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
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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
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Hormonal Therapy = Targeted Therapy
Estrogen Receptor Agents
• Tamoxifen
• Aromatase Inhibitors– Anastrozole
– Letrozole
• GnRH AgonistTherapy– Leuprolide
– Goserelin
• Faslodex
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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
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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
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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
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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
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GOG 239
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Outcome
Best Response Current Status
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No. Treatment Cycles Acute & Chronic AEs
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Mutational Analysis
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2/10/2009 6/2/2009
1.8 cm 0.9 cm
Tumor with KRAS mutation
responded to AZD6244
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Significant association between pERK proteinexpression and clinical response
GOG 239
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BACKGGOG 239ROUND
No correlation between pERK protein expression withBRAF or KRAS mutation status in FFPE specimens
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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
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GOG 281
PharmacokineticsProteomics
Plasma Cell-Free DNA Next Generation Sequencing
CT-Guided FNA/Core Bx
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Randomized Phase III Trial
NCT01849874
Recurrent LGSC
Physician’s Choice:Paclitaxel
Liposomal DoxorubicinTopotecan
MEK162
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Randomized Phase II Trial
NCT01936363
Recurrent LGSC
Pimasertib+
SAR245409
Pimasertib+
Placebo
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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
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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
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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
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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