Mucinous ovarian carcinoma -...

Mucinous Ovarian

Carcinoma

Professor Timothy Perren

Leeds Institute of Cancer Medicine & Pathology

St James’s Institute of Oncology

University of Leeds and St James’s University Hospital

Leeds UK

Mucinous ovarian tumours

Continuum from benign borderline

malignant

benign mucinous cystadenoma ≈ 10-15%

mucinous tumours of low

malignant potential (mucinous

borderline tumours)

≈ 67%

invasive mucinous

adenocarcinoma

≈ 4%

tumours metastatic to the ovary

15% of all ovarian neoplasms

Mucinous Tumour - Ovary

Pseudomyxoma peritonei

Appendix

• Metastatic

– Bilateral

– If Unilateral <10 cm

• Primary

– Unilateral

– >10cm

Seidman J.D. et al

Am J Surg Pathol

2003; 27: 985

The Leeds Teaching Hospitals

NHS Trust

Mucinous Carcinoma

Mucinous carcinoma

MC rarely bilateral

Usually present as Stage Ia

Grade 1 or 2 treated by surgical resection and no

adjuvant chemotherapy

Recurrent or metastatic MC associated with poor

prognosis

Unusual sites for mets (lung/bone)

Mucinous carcinoma (show reduced mucin cf

borderline mucinous tumours)

Most of “intestinal type”

“endocervical (Mullarian type)” rare

Distinction between primary ovarian

carcinoma and metastases to the ovary (1)

Feature Primary Metastatic

Laterality Unilateral Bilateral

Size Max diameter > 12 cm Max diameter < 10 cm

Extensive intra-

abdominal spread

Unlikely More likely

Multinodular growth

pattern with intervening

normal parenchyma

Not usual Characteristic

Surface involvement Not usual (other than

background

endometriosis)

Characteristic

Hilar involvement Absent/not typical Typical

Extensive vascular

invasion

Not usual Favours metastasis

Singh, N; 2014

Distinction between primary ovarian

carcinoma and metastases to the ovary (2)

Feature Primary Metastatic

Patterns specifically

favouring primary or

metastatic carcinoma

Associated benign,

borderline and malignant

appearing areas

Beware phenomenon of

“maturation of ovarian

metastases – may result

in similar gradation of

features

Complex papillary

architecture

Signet ring carcinoma

Association with

background changes

such as endometriosis,

Brenner tumour, mature

cystic teratoma, Sertoli-

Leydig cell tumour,

adenofibroma

Pseudomyxoma

peritoneii or ovarii;

Colloid carcinoma;

Infiltrative pattern of

small glands with

desmoplastic reaction;

Single cell infiltrate

Singh, N; 2014

Decision tree for differential diagnosis of primary

ovarian versus metastatic carcinoma

Kelemen, L. E. and M. Köbel (2011) Lancet Oncology 12(11): 1071-1080.

Immunohistochemistry profileMarker Ovary

intestinal

Ovary

Mullarian

Colorectal Appendix Pancreas &

biliary

Stomach Cervix

CK7 Usually

diffuse

Diffuse Negative

(except

rectal)

Usually

negative

Usually

diffuse

Usually

diffuse

Diffuse

CK20 Usually

focal

Negative Diffuse Usually

negative

Usually

negative

Usually

negative

Usually

negative

CEA Focal or

diffuse

Negative Diffuse Diffuse Diffuse or

focal

Diffuse or

focal

Diffuse or

focal

CA19.9 Diffuse Negative or

focal

Diffuse Diffuse Diffuse Diffuse Diffuse

CDX2 Focal Negative Diffuse Diffuse Focal Focal Negative or

focal

CA125 Negative Diffuse Negative Negative Negative Negative Diffuse

ER Negative Diffuse Negative Negative Negative Negative Negative or

focal

DPC4/

SMAD4

Diffuse Diffuse Diffuse Diffuse Negative in

50%

Diffuse Diffuse

P16 Negative or

focal

Negative or

focal

Negative or

focal

Negative or

focal

Negative or

focal

Negative or

focal

Diffuse

PAX8 Usually

negative

Positive Negative Negative Negative Negative Positive

Beta-

catenin

Sometimes

pos

Sometimes

pos

Positive Usually

positive

Variable Positive Variable

Singh, N; 2014

Falling incidence of primary mucinous

ovarian carcinoma diagnosis

• better recognition of the clinical importance of making the

distinction

– stage I mucinous ovarian carcinoma has an excellent prognosis

– metastasis from upper GI / pancreatic primary very poor prognosis

– treatment quite different

• better histological distinction between metastases to the

ovary and primary mucinous ovarian carcinoma

– pattern recognition

– cytokeratin and other immunohistochemical staining

• better preoperative work-up with imaging, and tumour

markers coupled with MDT discussion

Mucinous epithelial ovarian cancer: a

separate entity requiring specific treatment

Patients & methods

• Cases: 27 of 50 evaluable pts

with stage III/IV mEOC from

RMH 1992-2001

• Controls: 54 pts stage III/IV

non-mEOC matched for date

of Dx and stage

• First line treatment:

– 1/3rd all pts single agent platinum;

– 2/3rd platinum containing

combinations

Results

mEOC

(n=27)

Control

(n=54)

Prog on Rx 63%

CR+PR (measurable

disease)

1 + 4

(26%)

6 + 18

(65%)

Median

PFS

5.7 mos 14.1 mos

Median OS 12.0 mos 36.7 mos

Hess et al: J Clin Oncol 2004; 22(6): 1040-4

Mucinous epithelial ovarian cancer: a

separate entity requiring specific treatment

Hess et al: J Clin Oncol 2004; 22(6): 1040-4

PFS OS

P

Retrospective analysis of GOG182

[ICON5]

• 54 of 3435 (1.5%) pts entered by

GOG classified as mucinous

carcinoma

• 10 had insufficient material for

review or not mucinous

• 44 reviewed independently by 3

pathologists according to 2

classification systems (no IHC)

• 16 to 18% judged primary mEOC

• 57 to 63% judged metastatic

• No difference in OS between

primary and metastatic mucinous

Survival of primary mEOC

substantially worse than serous

• Median OS 14 mos vs 42 mos

P < 0.001

Cancer 2011;117:554–62

Mucinous ovarian carcinoma responds

poorly to platinum based chemotherapy

Harrison et al; Int J Gynecol Cancer 2008: 209-214

Mucinous ovarian carcinoma may

respond preferentially to oxaliplatin & 5FU

• mEOC cell lines ‒ MN-1, OMC-1, RMUG-L, RMUG-S, TU-OM-1

• All resistant to platinum & Paclitaxel

• All sensitive to oxaliplatin & FU with additive or synergistic effect

• In a xenograft model treatment with oxaliplatin & FU increased survival over PBS or either drug alone

Sato et al; Cancer Science 2009 March, 100 (3) 546-551

A GCIG Intergroup multicentre trial of open label carboplatin and paclitaxel +/-bevacizumab compared with oxaliplatin and capecitabine +/- bevacizumab as first line chemotherapy in patients with mucinous

Epithelial Ovarian Cancer (mEOC)

[GOG241]

Cancer Research UK & UCL Cancer Trials Centre

mEOC [GOG 0241]

Trial Design – 2x2 Factorial

Randomise (332 patients – 83 patients in each arm)

Carboplatin & Paclitaxel 6 x 21-day cycles

Oxaliplatin & Capecitabine 6 x 21-day cycles

Carboplatin & Paclitaxel 6 x 21-day cycles

Bevacizumab given every 3 weeks for 5 or 6* cycles

Oxaliplatin &Capecitabine6 x 21-day cycles


Clinical assessment every 6 weeks for 36 weeksTelephone call between visits

Bevacizumab given every 3 weeks for 12 cycles

Clinical assessment every 6 weeks for 36 weeks

Follow-up

mEOC Trial Timelines and

Recruitment• MHRA approval – September

2008

• MREC approval – October 2008

• Launch meeting – 6th Feb 2009

• Start date December 2009

• Trial stopped early (2013) due to poor accrual

• 50 pts recruited

• Median follow up 23 months

• 31 progressions/deaths

mEOC (GOG 0241)Recruitment

Aim to randomise (332 patients – 83 patients in each arm)Recruitment – 50 pts [End 09 to Early 2013]

[A]Carboplatin & Paclitaxel 6 x 21-day cycles

N=13

[B]Oxaliplatin & Capecitabine 6 x 21-day cycles

N=13

[C]Carboplatin & Paclitaxel 6 x 21-day cycles


N=11

[D]Oxaliplatin &Capecitabine6 x 21-day cycles


N=13

[A&C] vs [B&D]n=24 n=26Carbo/Paclitaxel vs Oxaliplatin/Capecitabine

[A&B] vs [C&D]

n=26 n=24

No Bevacizumab vs addition of Bevacizumab

Target Statistics

332 pts required to detect 5 month

increase in median PFS:

• oxaliplatin/capecitabine [B+D]

• adding bevacizumab [C+D]

Abstract submitted to ASCO 2015

Gore et al

mEOC• Data submitted to ASCO 2015

• Specialist pathology review n = 36

− 19 were considered to not have primary

mEOC

− (many metastatic disease)

• Setting up & conducting this international trial

was challenging in this rare group

• Correctly assigning histological diagnosis was

difficult.

• Primary mEOC is rare so different approaches

are needed to evaluate new therapies.

A dualistic approach to the

classification of ovarian carcinoma

Kurman RJ, Shih IM: Hum Pathol 2011, 42:918-931

Ovarian Cancer Genotyping

• EORTC GCG and EORTC GCG Translational Research Group

• 262 high risk stage I and stage II-IV from University Hospitals

Leuven and EORTC 55971

• Genotyped for hotspot mutations in KRAS, BRAF, NRAS, PIK3CA,

PTEN, AKT2, AKT3, and FOXL2, using Sequenom MassARRAY

– Type 1 tumours (13%): 49% were KRAS or PIK3CA mutant

– Type 2 tumours (87%): 2.9% were KRAS or PIK3CA mutant

– Mucinous subtypes significantly more KRAS mutations than all

nonmucinous tumours (50% vs 4%, P < 0.001)– PIK3CA mutations were predominantly found in clear cell carcinomas (46.2%) and

endometrioid carcinoma (20%) and were frequently associated with endometriosis

– Low-grade serous tumours were more frequently KRAS or BRAF mutated (44%) than high-

grade serous tumours (0.6%)

– Mutations in NRAS, PTEN, FBXW7, AKT2, AKT3, and FOXL2 were rare (<1%)

• KRAS or PIK3CA mutation did not correlate with progression-free

survival or overall survival

Despierre et al (2014). Int J Gynecol Cancer 24(3): 468-477.

Molecular alterations in ovarian and

colorectal mucinous carcinomas


Molecular alterations in ovarian and

colorectal mucinous carcinomas


Alterations in KRAS, BRAF or HER2 tend to be mutually exclusive

So

Alterations in MAPK 60% 40% 38%

(Ras/Raf/MEK/ERK)

Molecular characterisation of mEOC supports

stratified approach with HER2 targeting

• Cases from Mayo Clinic, Australian

Ovarian Cancer Study Group,

Toronto PMH & General, Alberta

Cancer Research biorepository

• HER2 amplification & KRAS

mutation status investigated in189

mEOC & 199 mucinous BOT

• HER2 investigated by IHC, with

FISH & CISH as appropriate

• KRAS mutation investigated by

Sanger Sequencing

Anglesio et al, J Pathol 2013; 229: 111–120

• KRAS mutation:• 26/33 (79%) MBOT

• 31/71 (44%) mEOC

• HER2 amplification• 11/176 (6%) MBOT

• 29/154 (19%) mEOC

• HER2 and KRAS mutation

status both known in 74

mucinous carcinomas

Prognostic significance of HER2

and HER2/KRAS expression

HER2 PFS

HER2 OS

---- KRAS + HER2 +

---- KRAS + HER2 –

---- KRAS wt HER2 +

---- KRAS wt HER2 -


Potential treatment algorithm for

primary mucinous ovarian carcinoma


Cetuximab in mucinous ovarian

cancer cell lines• EGFR & KRAS mutation status investigated in 5

ovarian cell lines

– MN-1, OMC-1, RMUG-L, RMUG-S, MCAS

– EGFR expressed in all but MN-1

– KRAS at codon 12 only in MCAS

• Evaluated in vivo & in vitro effects of cetuximab

– inhibited RMUG-L & OMC-1 growth in vitro

– completely blocked RMUG-L tumour in vivo

– no effect on MCAS in vitro & only partial growth reduction in vitro

Sato et al 2012, Oncology Reports; 27: 1336-1340

HER2 targeting in mucinous

ovarian carcinoma• HER2 status investigated in

– 33 mEOC & 16 mBOTs

– 5 cases of documented recurrence with tissue avail

– 3 prospectively documented HER2 pos recurrent

mEOC

• HER2 amplification observed in

– 6/33 (18%) mEOC

– 3/16 (19%) mBOT

• 1/3 HER2 amplified recurent mEOC had

dramatic response to trastuzumab

McAlpine J et al. BMC Cancer 2009; 9(1): 433

Possible approaches to management of metastatic

or recurrent mucinous ovarian carcinoma

Molecular

phenotype

First line Second line

HER2+, KRAS wt Anti HER2 therapy Add anti EGFR

thrapy

HER2+, KRAS mut

(very rare)

Anti HER2 therapy GI chemotherapy

option or trial

KRAS mut, HER2- Gi chemotherapy or

trial

Gi chemotherapy or

trial

HER2-, KRAS wt Anti EGFR therapy Gi chemotherapy or

trial

P53 gene mutation ? Platinum based

chemotherapy

Adapted from Anglesio et al J Patho, 2013; 229: 111-120

Potential new approaches for

mucinous ovarian carcinoma• Anti HER2 therapy:

– Trastuzumab, MGAH22, lapatinib, TDM-1,

• Anti EGFR therapy for KRAS wt

– cetuximab, panitumumab

• KRAS mut

– Targeting Src and Tubulin in Mucinous Ovarian Carcinoma: Liu T et al; Clin

Cancer Res 2013; 19(23): 6532-43

– Phase 1 selumetanib + MK-2206: Durable response in 1 of 2 low grade ovarian

with RAS mutation. Tolcher 2014

• Chemotherapy

– phase II Japanese study of women with advanced or recurrent are undergoing

treatment with oxaliplatin and S1, an orally active drug combining tegafur,

gimeracil, oteracil

Mucinous ovarian carcinoma

conclusions• Probably the most challenging subtype of ovarian cancer

due to its rarity and diagnostic difficulty

• Large phase disease orientated 3 trials seem unlikely to

succeed (mEOC)

• Would a broader study enroling patients with advanced

stage mucinous tumours involving the ovary whether

primary or secondary be more likely to succeed?

• ?Adaptive trial design platform study with a series of single

arms or randomised phase 2 trials defined by molecular

phenotype. Clinical & translational endpoints

• Monitoring & reporting strategy: SMART [Shared Access

Medicine an Approach to Rare Tumours]

– http://www.smartcancerproject.com

• Broad international cooperation

http://www.smartcancerproject.com/

Thank you

Acknowledgments:

Dr Nafisa Wilkinson for histology slides and guidance

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