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Non-Epithelial Uterine Cancer (NEUC)

Robert L. Coleman, M.D.Professor, Vice Chair Clinical Research

University of Texas, M.D. Anderson Cancer Center

Mortality by Histology

2-3% of cases are sarcomas or carcinosarcomas with 50% mortality rate

Proportion of Cases

G1,G2 EC G3 EC USC Clear Cell

Proportion of Cancer Deaths

Parameter Type 1 Type 2Age 50s-60s 60s-70sObesity Common UncommonEstrogen Related Common UncommonEndometrium Hyperplastic AtrophicPrecursor EIN EGD, EICTransition Slow RapidType Endometrioid Serous, CCA or MixedMolecular deletions MSI, PTEN p53, 17p+1p,(her2-neu)Familial HNPCC BRCA?Depth of invasion Superficial DeepSpread LN, distal LN, peritonealConcurrent Ovarian Some UncommonPrognosis Good Poor

Pathogenesis of Uterine Cancer

Bokhman JV, Gynecol Oncol 15(1):10, 1983

Endometrial Cancer: TCGA

Dedes Nat Clin Oncol Rev 2011GainLoss

EndometrioidGrade 1 or 2

EndometrioidGrade 3 Serous

Andrew Cherniack, Broad

Challenges in Studying NEUC

• Few studies addressing the histology specifically– Included in phase III studies and stratified– Excluded from clinical trials (particularly early stage trials)

• Even when included…– Majority are clinically staged– Many combine outcomes for both Stage I and II– Multiple treatment regimens administered– Pre-operative vaginal radiation therapy– Limited follow-up– Unclear pathology criteria

OS in GOG Trials: Histology

McMeekin, Gynecol Oncol. 2007 Jul;106(1):16-22

Challenges in Studying NEUC

• Few studies addressing the histology specifically– Included in phase III studies and stratified– Excluded from clinical trials (particularly early stage trials)

• Even when included…– Majority are clinically staged– Many combine outcomes for both Stage I and II– Multiple treatment regimens administered– Pre-operative vaginal radiation therapy– Limited follow-up– Unclear pathology criteria

“Radical Surgery”(TAH-BSO)

CT RTor

RT CTChemo: Platinum-

based

RT(Ext ± Brachy)

NSGO EC-9501/EORTC-55991MaNGO (ILIADE-III)

• Primary Endpoint: PFS (ITT), TTP• NSGO

– N = 378– Stage I, II, IIIA (cytology), IIIC (pelvic)– All histology (including USC & CCA)

• MaNGO– N = 156– Stage IIA-IIIC– Only endometrioid

• Staging optional in both

Hogberg, Eur J Cancer (2010) 46:2422

NSGO EC-9501/EORTC-55991MaNGO (ILIADE-III)

Hogberg, Eur J Cancer (2010) 46:2422

OSPFS

NCCN Guidelines

Lymphadenectomy: USC

Early stage, Intermediate risk, Node negative

Node positive

Chan, Cancer (2006) 107:1823

Omentectomy in NEUC

• Frequently recommended given the intraperitoneal spread of even stage I disease limited to a polyp (>25%)

• Gehrig, et al., (2003)– 52 patients with omentectomy

• 34 – negative• 18 – positive

– 16 grossly positive– 2 microscopically positive (11%)

Stage is Prognostic in NEUC

Growdon, Int J Gynecol Oncol (2012)22:417

Stage I NEUC: Recurrence by Modality

Author N Observation N Pelvic RT

Huh 40 17% 12 16%

Elit 27 19% 4 25%

Grice 5 0% 6 33%

Kelley 21 29% 6 100%

Nguyen 5 0% 5 0%

Bristow 11 9% - -

Gallion 9 0% - -

Gehrig 6 33% - -

Stage I NEUC*: Recurrence by Modality

Study N Observation or RT Chemotherapy

Huh§ 70 31% (19/62) 0% (0/8)

Kelley 74 63% (20/32) 3% (1/29)

Havrilesky§ 81 30% (19/64) 24% (4/17)

TOTAL 215 37% (58/158) 9% (5/54)

* Completely Staged§ Omentectomy unspecified or no obtained in all patients

Early Stage NEUC: Chemotherapy

• Ten institutions• All patients were

comprehensively staged• Radiation was not used

– 1 recurrence in paclitaxel/carboplatin was vaginal and salvaged with XRT

• Recurrence (mean f/u: 41 mos)– 2 of 8 with non-taxane

regimen– 1 of 21 in taxane doublet

• Recurrence risk overall: 17%

Dietrich III, Gynecol Oncol (2005) 99:557

Stage IA Disease

Tumor at Hysterectomy

Chemotherapy ± XRT

XRT Observation

No residual 0/2 0/1 0/10

Polyp-Confined 0/7 0/3 1/9 (11%)

Other IA findings 2/28 (7%) 4/12 (33%) 2/27 (7%)

Del Carmen Gynecol Oncol (2012) ePub

NCCN Guidelines: Advanced Disease

Advanced Stage Disease

Author N FIGO Stage

Optimal Def % Optimal OS (mos) P

Rauh-Hain 79 IIIC/IV ≤ 1 cm 62% 36 vs 12 0.0001

Thomas 70 IIIC/IV ≤ 1 cm 60% 20 vs 12 0.02

Bristow 65 IVB ≤ 1 cm 55% 34 vs 11 0.0001

Lambrou 58 IIIC/IV ≤ 2 cm 72% 7 vs 2 0.0001

Chi 55 IV ≤ 2 cm 44% 31 vs 3 <0.01

Moller 52 IV ≤ 1 cm 53% 15 vs 8 <0.05

Bristow 31 IV ≤ 1 cm 52% 26 vs 10 <0.001

Advanced Stage Disease

• Data primarily from prospective adjuvant trials not exclusive for USC or CCA

Phase III Trials- Advanced Recurrent Disease

AC AP AT TAP TC

A GOG 48

GOG 107

AC GOG 139

AP GOG 163

GOG 177

TAP GOG 209

A=doxorubicin, AC= doxorubicin + cisplatin, TAP= paclitaxel + doxorubicin + cisplatin, TC= paclitaxel + carboplatin

Cont

rol A

rm

Experimental Arm

Endometrial Cancer: Chemotherapy

• Single agents vs Combos:– GOG 48: A vs. AC

• RR: 22% vs 33%• HROS: 0.83 (p = 0.048)• More toxicity

– GOG 107: A vs. AP (cisplatin)

• RR: 25% vs. 42% (P = 0.004)• PFS: 0.74 (P = 0.014)• OS: 9.0 vs 9.2 (NS)• More toxicity

• Combination comparisons: – GOG 163: AP vs. AT

• RR: 40% vs. 44% (NS)

– GOG 177: AP vs. TAP• RR: 34 vs. 57%• HRPFS: 0.60 P<0.001

• HROS: 0.75, P=0.038• More cardiac & neuro in TAP

GOG-209: Schema

Advanced, Recurrent Endometrial Cancer

Adriamycin 45 mg/m2 day 1Cisplatin 50 mg/m2 day 1Paclitaxel 160 mg/m2 24 hour day 2

G-CSF 5 mcg/kg days 3-12Q 21 days x 7

Carboplatin AUC 6 Paclitaxel 175 mg/m2 3 hr

Q 21 days x 7

Planned accrual: 900 patients/795 failures - 60 months (now 1312 includes non-measurable disease)Sample not inflated for LVEF-related crossover (0 pts)HR: 1.20 for Carboplatin/paclitaxel armOpened: 8/25/2003; Closed 4/20/2009

GOG-209: Demographics

Miller, LBA1, SGO 2012

GOG 209: Toxicity

Toxicity TAP TC PNeutropenia 52% 79% <0.01

Complicated Neutropenia 7% 6% NS

Thrombocytopenia (Gr 3/4) 23% 12% <0.01

Other Hematologic 30% 22% <0.01

Neurologic (G2+) 26% 19% <0.01

Vomiting 7% 4% <0.01

Diarrhea 6% 2% <0.01

Metabolic 14% 8% <0.01

Discontinued because of Toxicity 18% 12% 0.01

Completed 7 Planned 62% 69% 0.01

Miller, LBA1, SGO 2012

GOG: Outcomes

Outcome Measure TAP TC HRMedian PFS 14

mos14

mos1.03

Median OS 38 mos

32 mos

1.01

OS (90% CI, Non-inferiority) 1.16 P>0.1

Miller, LBA1, SGO 2012

Opened Jun 29, 2009Accrual Goal = 804

Study Chair D Matei

Surgical stage III or IVA endometrial carcinoma All Cell types Must have TAH and

BSO Pelvic node sampling and aortic node sampling optional

REGIMEN ICisplatin 50 mg/m2 IVDays 1 and 28plus Volume-directed RTfollowed by Carboplatin AUC 5*plus Paclitaxel 175 mg/m2q 21 days for 4 cycles

REGIMEN IICarboplatin AUC 6 plus Paclitaxel 175 mg/m2q 21 days for 6 cycles

Secondary endpoints TR and QOL

GOG-258: Replacement

RANDOMIZE

Novel Biologics in Endometrial Cancer

• PI3K pathway– PI3Ki’s– Rapalogs– MK2206 (Akt)– OSI-906 (IGF1-R)– Multiple combo’s

• Ras/raf Pathway– ZD6244 (MEK/Erk)

• EGFR– Cetuximab– ZD6474

• Other targets– Folate receptor (EC145)– PARP (BSI-201)

• Angiogenesis:– VEGF/R:

• Bevacizumab• Aflibercept• Sorafenib• Sunitinib• BIBF-1120• Pazopanib• On and on and on

– FGF/R:• Brivanib

– Endothelial• ACE-041 (Alk1)• TRC-105• AMG-386 (Ang/Tie)

Endometrial Cancer: GOG 229-series

STUDY AGENT N RR (%) PFS at 6 months (%)

229-C Gefitinib 26 3.8 15

229-D Lapatinib 30 3.3 10

229-E Bevacizumab 53 13.5 40

229-F Aflibercept 44 7% 41

229-G Bevacizumab-Temsirolimus 49 24.5% 47

229-H AZD6244 (MEKi) 50 6% 22

229-I Brivanib 53 19% 30

229-J Cediranib Second stage in progress

229-K BIBF-1120 First stage accrual

229-L AMG-386 First stage accrual

229-M OSI-906 (IGF1R) On hold for drug supply

MK-2206 (AKT) SU2C - Closed

GOG Randomized Ph II

GOG-86P

PI: Aghajanian

Bevacizumab

Bevacizumab

Temsirolimus

Maintenance Tx To Progression

Paclitaxel/CarboplatinBevacizumab

Paclitaxel/CarboplatinTemsirolimus

Ixabepilone/CarboplatinBevacizumab

No Prior ChemotherapyStage IVB (may be measurable)Recurrent (measurable mostly)N = 349 (closed)

New Targets: Dasatinib

• Phase 0/I pilot trial• Patients:

– Advanced/recurrent endometrial cancer

– No prior therapy for recurrent disease

– Biopsy amenable

• Endpoints:– EphA2 expression alteration in

post-treatment tissue bx– Toxicity, efficacy– Translational

• miR520d-3p expression• Downstream signaling (FAK,

paxillin, p130 cas)• EphB2, EphB4• CTC’s

Paclitaxel

Carboplatin

Tumor Biopsy

Dasatinib

weeks

-2 -1 0 1 2 3 4 5 6 7 8 9

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

Imaging X X

If not progressiveContinue treatment21 day cyclesImaging every 3 cyclesMaximum # of cycles: 6

PI: Coleman, RL

Thank You!