KOREAN GYNECOLOGIC ONCOLOGY SOCIETY

KOREAN GYNECOLOGIC ONCOLOGY GROUP

UTERINE SEROUS CARCINOMA: EVOLUTION OF THE YALE MANAGEMENT APPROACH

Peter E. Schwartz, MD

Yale University School of Medicine

UTERINE PAPILLARY SEROUS CARCINOMA (UPSC): A HIGHLY MALIGNANT FORM OF ENDOMETRIAL

ADENOCARCINOMA

SALIENT MORPHOLOGIC FEATURES:

Cytology – Marked nuclear pleomorphism Architecture – Complex papillary architecture Associations – Psamomma bodies (30%)

– Clear cell component Spread pattern – Vascular invasion prominent

Hendrickson M, et al. Am J Surg Pathol 1982; 6:93

UTERINE PAPILLARY SEROUS CARCINOMA (UPSC): A HIGHLY MALIGNANT FORM OF ENDOMETRIAL

ADENOCARCINOMA

SALIENT MORPHOLOGIC FEATURES (cont.)

The extent of myometrial invasion and lymphatic permeation was often underestimated by gross examination of the surgical specimens Uteri were often small and atrophic The extent of adnexal and cervical involvement was often grossly unapparent

Hendrickson M, et al. Am J Surg Pathol 1982; 6:93

COMPARISON OF CLINICAL FEATURES OF UPSC AND NON-PAPILLARY CARCINOMAS

Clinical Feature

UPSC, Stage I (n=26)

Non-papillary Stage I (n=230)

Mean age (yrs.) 66.1 59.1

Postmenopausal 100% 88%

Hx estrogen 21% 53%

Nulliparous 25% 31%

Abnormal PAP at Presentation

23% 5%

Bleeding 100% 93%

Hendrickson, M, et al. Am J Surg Pathol 1982; 6:93

UTERINE PAPILLARY SEROUS CARCINOMA (UPSC): A HIGHLY MALIGNANT FORM OF ENDOMETRIAL

ADENOCARCINOMA

RELAPSES

PATIENTS WITH UPSC ACCOUNTED FOR 50% OF THE RELAPSES IN THE TOTAL GROUP OF STAGE I ENDOMETRIAL CARCINOMAS TREATED AT STANFORD UNIVERSITY HOSPITAL (1959-1975)

Hendrickson M, et al. Am J Surg Pathol 1982; 6:93

EFFECT OF MYOMETRIAL INVASION ON RELAPSE-FREE SURVIVAL OF STAGE I UPSC PATIENTS (N=26)

100

80

60

40

0 2 8 16 18 20 TIME (years)

Perc

ent R

elap

se F

ree

Surv

ival

20

Henderson M et al. Am J Surg Pathol 1982; 6:93

14 12 10 4 6

No Myometrial Invasion

Superficial Invasion

Deep Invasion

UTERINE SEROUS CARCINOMA (YNHH 1974-1984)

Stage Clinical Surgical *

I 19 9

II 9 6

III 1 4

IV 8 13

Total 37 32

*5 patients did not undergo surgery Chambers JT, et al. Obstet Gynecol 1987; 69:109

UTERINE SEROUS CARCINOMA (YNHH 1974-1984)

Surgical Stage

No. Pts.

Estimated Survival 3-Year 5-Year

I 9 ▬ 32.9%

II 6 ▬ 80.0%

III-IV 17* 11% 0%

*11 received platinum-based chemotherapy

Chambers JT, et al. Obstet Gynecol 1987; 69:109

WHOLE ABDOMINAL RADIATION THERAPY IN USC (YNHH 1987-1988)

FIGO Stage (2009) No. Pts.

IA 4

IB 1

II 2

IIIA 2

Total 9

Frank AH, et al. Cancer 1991; 68:1516

CHEMOTHERAPY REGIMENS USED AT YNHH 1983-1997

Dates Chemo Total No. Pts.

1983-1991 CAP 19

1991-1994 CA + IP Plat 13

1994-1997 EPA 21

Total 53

CAP: I.V. cyclophosphamide, adriamycin, cisplatin CA + IP plat: IV cyclophosphamide, adriamycin +

intraperitoneal cisplatin EPA: etoposide, cisplatin, adriamycin

USC TREATED WITH PLATINUM-BASED CHEMOTHERAPY 1983-1997 AT YNHH

FIGO Stage

No. Pts

NED

DOD

DOC

AcD

IA IB IC

6 8 3

6 7 3

― ― ―

― 1

― ― ―

IIA IIB

2 5

2 ―

― 4

― ―

― ―

IIIA IIIC

7 7

1 3

4 11

― ―

― 1

IVA IVB

3 12

― 2

― 6

1 ―

― ―

Total 53 25 25 2 1

Uterine Serous Cancer Treated with Adjuvant Cisplatin, Doxorubicin and Etoposide

Chambers JT, ET AL. INT J GYNECOL CANCER 1998; 8:193

FIGO STAGE I USC TREATED WITH HIGH DOSE RATE VAGINAL BRACHYTHERAPY (1985-1993)

Treatment No. Pts.

HDR vaginal brachytherapy 18

Chemotherapy 5 (28%)

WART 1 (6%)

WPRT 2 (11%)

Surgical staging 15 (83%)

Turner BC, et al. Int J Rad Oncol Biol Phys 1998; 40:77

Actuarial Overall Survival Surgical Stage I for 18 USC Patients Whose Treatment Included HDR Vaginal Apex Brachytherapy

(YNHH)

Turner BC, ET AL. INT J RAD ONCOL BIOL PHYS 1998; 40:77

EARLY STAGE UPSC (YNHH)

ADJUVANT TREATMENT YNHH 1987-2006 Observation Abdominopelvic radiation High dose rate vaginal cuff radiation

Platinum-based chemotherapy and brachytherapy

(“chemoradiation.”)

Kelly MG, et al. Gynecol Oncol 2005; 98:353 Schwartz PE. Int Gynecol Cancer Soc 2006

EARLY STAGE UPSC (YNHH)

ADJUVANT THERAPY

Stage None Chemo+Brachy Other Total

IA (no residual) IA (residual) IB IC IIA IIB

10 14 4 1 0 0

3 7

22 12 1 6

1 0 8 4 3 3

14 21 34 17 4 9

Total 29 51 19 99

Kelly MG, et al. Gynecol Oncol 2005; 98:353 Schwartz PE. Int Gynecol Cancer Soc, 2006

STAGE I UTERINE PAPILLARY SEROUS CARCINOMA: Postoperative Platinum-based Chemotherapy vs. No Chemotherapy

OVERALL SURVIVAL

1.0

0.8

0.6

0.4

0 30 60 90 120 150

TIME (months)

Cum

ulat

ive

Surv

ival

0.2

Kelly MG et al. Gynecol Oncol 2005; 98:353

All Stage I Chemo (n=32)

All Stage I no chemo (n=42)

P<0.01

1.0

0.8

0.6

0.4

0 40 60 80 100 120 140 TIME (months)

Cum

ulat

ive

Surv

ival

0.2

20

Kelly MG et al. Gynecol Oncol 2005; 98:353

STAGE I UTERINE PAPILLARY SEROUS CARCINOMA: Postoperative Platinum-based Chemotherapy vs. No Chemotherapy

OVERALL SURVIVAL

All Stage I Chemo (n=32)

All Stage IA+RUD no chemo (n=14)

All Stage IB no chemo (n=13)

(All Stage IC no chemo (n=5) P<0.01

EARLY STAGE USC (YNHH)

RECURRENT CANCER Adjuvant Therapy

Stage

Chemo+Brachy

Other

Survival (DFS +OS)

IA (no residual) IA (residual) IB IC IIA IIB

0/3 0/7 0/22 1/12 0/1 0/6

0/11 6/14

10/12 4/5 1/3 3/3

<0.05 <0.01 <0.01

Total 1/51 (2%) 24/48 (50%)

Kelly MG, et al. Gynecol Oncol 2005; 98:353 Schwartz PE. Int Gynecol Cancer Soc 2006

EARLY STAGE USC (YNHH)

Sites of Recur.

OBS

(n=29)

Brachy (n=12)

Cesium Pack (n=1)

WART (n=8)

Chemo +Brachy (n=51)

Vaginal Cuff

4 0 1 1 0

Pelvis 2 1 0 2 1

Abdomen 2 4 1 6 0

Total 8 5 1 8 1

Kelly MG, et al. Gynecol Oncol 2005; 98:353 Schwartz PE. Int Gynecol Cancer Soc, 2006

HAZARD RATIOS OF TREATMENT MODALITIES IN STAGE I USC PATIENTS (YNHH, n=74)

Analysis Treatment HZ 95% CI P

Univariate Brachytherapy WART Chemo ± Brachytherapy

1.135 3.984 0.069

0.361-3.567 1.371-11.579 0.008-0.584

0.828 0.011 0.014

Multivariate* Brachytherapy

WART Chemo ± Brachytherapy

0.663 1.521 0.032

0.196-2.246 0.403-5.743 0.004-0.300

0.509 0.536 0.003

*Controlled for sub-stage

Kelly MG, et al. Gynecol Oncol 2005; 98:353

RECOMMENDED MANAGEMENT OF SURGICAL STAGE IA-IIB UPSC

Stage IA (No residual disease in

hysterectomy specimen)

Observe

Stage IA (Residual) – Stage IIB Disease

Platinum-based chemotherapy + Vaginal apex brachytherapy

UTERINE SEROUS CANCER (YNHH – 1983-2009 n=334)

Patient Characteristic N (%)

Age, mean years (37-91) Race: Caucasian African-American Other

69

282 (88) 32 (10) 6 (2)

HRT Use: Negative Positive

257 (86) 42 (14)

UTERINE SEROUS CANCER (YNHH – 1983-2009 n=334)

Patient Characteristic N (%)

BMI: <25 25-29 30-39 40-49 >50

88 (30) 72 (25 95 (32) 31 (11) 6 (2)

Medical History Hypertension Diabetes Mellitus

177 (80) 69 (32)

Prior Cancer: Breast Colon

35 (10) 5 (1.5)

UTERINE SEROUS CANCER (YALE-NEW HAVEN HOSPITAL 1983-2009)

FIGO Stage No. Pts. (%)

IA 121 (36.2) IB 36 (10.8) II 27 (8.1)

IIIA 39 (11.7) IIIB 2 (0.6)

IIIC1 32 (9.6) IIIC2 9 (2.7) IVA 28 (8.4) IVB 40 (12.0) Total 334

UTERINE SEROUS CANCER (YNHH 1983 – 2009)

Pathology No. Pts (%)

Pure USC 190 (57.1)

>10% USC + EAC 85 (25.5)

>10% USC + CCC 46 (13.8)

>10% USC + MMT 10 (3.0)

>10% USC +EAC + CCC 3 (0.9)

Kaplan-Meier disease progression free survival curves stratified by stage

0 50 100 150 200 250 300

1.00

0.75

0.50

0.25

0.00

Sur

viva

l Fun

ctio

n

Time (months)

P=4.98E-38

Stage IA/ΙB (n=157) Stage II (n=36) Stage IIIA/IIIB (n=34)

Stage IIICI/IIIC2 (n=41)

Stage IVA/IVB (n=68)

Kaplan-Meier overall survival curves stratified by Stage

0 50 100 150 200 250 300

1.00

0.75

0.50

0.25

0.00

Sur

viva

l Fun

ctio

n

Time (months)

Stage IA/ΙB( n=157) Stage II (n=36) Stage IIIA/IIIB (n=34)

P=2.56E-37

Stage IIICI/IIIC2 (n=41) Stage IIIV A (n=68)

5-YEAR SURVIVAL FOR STAGE IA-IVB USC (YNHH 1983-2009)

Stage 5-year DFS OS

IA/IB 82% 82%

II 68% 70%

IIIA/B 56% 64%

IIIC1/C2 24% 36%

IVA/B 6% 9%

5-YEAR SURVIVAL FOR STAGE IA/IB USC BASED ON TREATMENT

(YNHH 1983-2009)

Treatment DFS OS

- Platinum-based chemo + Vag brachytherapy

89% 94%

- Observation 82% 90%

-Platinum-based chemo - Vag Brachytherapy - Whole Abdominal XRT

86% 72%

0

75% 65%

0

5-YEAR SURVIVAL FOR STAGE II-IVB USC BASED ON TREATMENT

(YNHH 1983-2009)

Treatment DFS OS

- Platinum-based Chemo + Vag Brachytherapy

42% 51%

- Observation 0 0

- Platinum-based Chemo 17% 23%

- Whole Abdominal XRT 13% 20%

RE EmGD Serous EIC UPSC

1 2 3 4 5

EmGD frequently shows LOH at multiple chromosomal loci, particularly at 17p (TP53) and 1p. In addition, a significantly high concordant LOH pattern between EmGD and serous EIC or UPSC is seen.

TP53

PRECURSOR FORMS OF ENDOMETRIAL CANCER

TYPE 1 TYPE 2 Complex hyperplasia without atypia

Endometrial glandular dysplasia (EmGD)

Complex hyperplasia with atypia

Endometrial intraepithelial carcinoma (EIC)

Well-differentiated adenocarcinoma

Uterine papillary serous carcinoma (UPSC)

Liang SX, et al. Int J Surg Pathol 2004; 12:319

MINIMAL UTERINE SEROUS CARCINOMA

FIGO Stage No. Pts. IA IB IC

20 0 0

IIA IIB

2 0

IIIA IIIB IIIC

3 0 1

IVA IVB

0 14

Total 40 Hui P, et al. Mod Pathol 2005; 18:75

MINIMAL UTERINE SEROUS CARCINOMA

Histology

Extrauterine Spread

Total

EIC 3 9

Superficial serous carcinoma

15 31

Total 18 40

Hui P, et al. Mod Pathol 2005; 18:75

MINIMAL UTERINE SEROUS CARCINOMA

EXTRAUTERINE DISEASE (n=18)

Macrometastases: - Omentum

10

Micrometastases: - Ovarian surfaces and/or omentum - Tubal and omental surfaces - Pelvic lymph nodes - Positive peritoneal washings Positive peritoneal washings + metastases

5 1 1 1

13 Hui P, et al. Mod Pathol 2005; 18:75

MINIMAL UTERINE SEROUS CARCINOMA OVERALL SURVIVAL

1.0

0.8

0.6

0.4

0 20 30 40 50 60 70

TIME (months)

Cum

ulat

ive

Surv

ival

0.2

10

Hui P et al. Mod. Pathol 2005; 18:75

Stage III - IV (n=18)

Stage I - II (n=19)

High Grade Endometrial Carcinoma in Tamoxifen-Treated Breast Cancer Patients

Breast Cancer Patients YNHH: 1980-1990

n=3467

No Tamoxifen N=38

Received Tamoxifen N=15

Not Evaluable N=4

Uterine Cancer N=57

Magriples U, ET AL. J CLIN ONCOL 1993; 485

HIGH GRADE ENDOMETRIAL CARCINOMA IN TAMOXIFEN-TREATED BREAST CANCER PATIENTS

Parameter Tamoxifen No Tamoxifen

No. Cases 15 38 Mean age (yrs) 72.3 68.5

Mean interval From breast cancer

5.33 12.26

Endometrioid ca Low grade High grade

6 3

26 5

Uterine serous ca 3 2 Clear cell ca 1 0

Mixed mesodermal tumor 2 2

Sarcoma 0 3

Magriples U, et al. J Clin Oncol 1993; 11:485

GENE-EXPRESSION PROFILING OF USC

Gene Expression

P53 CDKN2a Claudin-3 Claudin-4

Kallikrein-6 Kallikrein-10

C-erb B2

Overexpressed Overexpressed Overexpressed Overexpressed Overexpressed Overexpressed Overexpressed

Santin A, et al. Br J Cancer 2005; 92:1561

INTERLEUKIN-6 (IL-6) SERUM LEVELS IN USC PATIENTS

1. HER2/neu ↑ → IL6 ↑

2. IL6 ↑ → Activation p38 mitogen-activatived protein kinase signaling pathway →

3. Resistance to chemotherapy

Bellone S, et al. Gynecol Oncol 2005; 98:92

SERUM AMYLOID A (SAA)

An HDL – associated lipoprotein known to have a major role as a modulator of inflammation and in the metabolism and transport of cholesterol Up-regulated in gastric, nasopharyngeal and lung cancer

Cocco E, et al. Br J Cancer 2009; 101:335

Distribution of Serum Amyloid A (SAA) in Advanced Stage (III, IV) and Low Stage (I, II) USC

Cocco E, ET AL. BRIT J CANCER 2009; 101:335

Serum SAA µg/ml

Stage III, IV

Stage I, II

HER2/neu EXPRESSION IN PRIMARY UTERINE SEROUS CARCINOMA CELL LINES

Specimen

IHC

FISH

RT-PCR mRNA Copy No.

Control ▬ ▬ 1

ARK-1 3+ 2.5 373

ARK-2 3+ 5.2 607

ARK-3 3+ 4.7 677

ARK-4 0 1.6 7

ARK-5 0 1.4 13

ARK-6 1+ 0.9 6

Cross SN, et al. Am J Obstet Gynecol 2010; 162.ei

Log10 Values for HER-2/neu Over-expressors vs. Low Expressors Treated with Single-Agent Chemotherapy

Cross SN, ET AL. AM J OBSTET GYNECOL 2010; 203:162.e1

Log10 Values for USPC Cell Lines Treated with Drug Combinations

Cross SN, ET AL. AM J OBSTET GYNECOL 2010; 203:162.e1

HER2/neu EXPRESSION IN PRIMARY UTERINE SEROUS CARCINOMA CELL LINES

USC cell lines overexpressing HER2/neu compared to low HER2/neu-expressing cell lines

– Have higher proliferation rates – Significantly more sensitive to platinum compounds in

vitro – May more rapidly recover from the cytoxic effects of

chemotherapy drugs in vivo due to increased cell proliferation

Cross SN, et al. Am J Obstet Gynecol 2010; 203; 162.e1

PATUPILONE (EPOTHILONE B, EPO 906)

Competitively inhibits the binding of paclitaxel to

microtubules and in particular, to β-tubulin III.

Exhibits a 3 to 20 fold higher in vitro cytotoxic potency

than paclitaxel.

Has cytotoxic activity in a broad range of paclitaxel-

sensitive and resistant cells that overexpress the P-

glycoprotein efflux pump.

Paik D, et al. Gynecol Oncol 2010; 119:140

Dose Response Curves of USC Primary Cell Lines Exposed to Patupilone and Paclitaxel with High Versus Low

HER-2/neu Expression

Piak D, ET AL. GYNECOL ONCOL 2010; 119:140

PATUPILONE (EPOTHILONE B, EPO 906)

There is a significant increase in the expression of P-glycoprotein and β-tubulin III in USC cells that overexpress HER2/neu The sensitivity to patupilone must be at least partially mediated by its interaction with β-tubulin III

Paik D, et al. Gynecol Oncol 2010; 119:140

PATUPILONE (EPOTHILONE B, EPO 906)

HER2/neu positive cells may be significantly more sensitive to patupilone than paclitaxel when used alone or in combination with a platinum compound.

Paik D, et al. Gynecol Oncol 2010; 119:140

EpCAM mRNA Expression Levels in Primary and Metastatic/Recurrent USPC Compared with Normal

Endometrial Cells (NEC)

EL-Sahwi k,, ET AL. MOL CANCER THER 2010; 9:57

EpCAM - Positive Cell Link (USPC ARK-2) Response to MT201 (Adecatumumab) - Mediated Antibody-Dependent

Cellular Cytotoxicity In Vitro

EL-Sahwi, ET AL. MOL CANCER THER 2010; 9:57

PROSPECTIVE RANDOMIZED TRIAL HER2/neu POSITIVE ADVANCED AND RECURRENT USC

STAGE III,IV, RECURRENT USC

RANDOMIZE

CARBOPLATIN, PACLITAXEL, RADIATION THERAPY

CARBOPLATIN, PACLITAXEL,

TRASTUZUMAB RADIATION THERAPY

Advanced Stage USC

HER2/neu

Positive Negative

Chemo + Trastuzumab +

Radiation

Chemo + Radiation

Recurrent USC

PI3K+ mTOR + Tubulin β3 +

PI3K + Inhibitors

mTOR Inhibitors

Ixabepilone + Bevacizumab

BIOMARKERS TO BE PROSPECTIVELY EVALUATED IN FUTURE USC STUDIES

KALLIKREIN – 6

KALLIKREIN – 10

SOLUBLE FORMS OF Erb/Β2

SERUM – AMYLOID

INTERLEUKIN-6