Michael BirrerMichael Birrer

Ian McNeishIan McNeish

New Developments in Biology andTargets of

Epithelial Ovarian Cancer

Ovarian CancerOvarian CancerHistoric PerspectiveHistoric Perspective

All serous tumors thought to arise from surface All serous tumors thought to arise from surface epithelium/inclusion cysts.epithelium/inclusion cysts.

75%75% patients present with advanced stage disease. patients present with advanced stage disease. 80%80% respond to chemotherapy. respond to chemotherapy. Vast majority of patients relapse and eventually develop Vast majority of patients relapse and eventually develop

drug resistant disease.drug resistant disease. MinimalMinimal increase in overall survival over last 30 years. increase in overall survival over last 30 years. All patients treated with surgery and chemotherapy.All patients treated with surgery and chemotherapy.

New Development in New Development in BiologyBiology

OriginsOrigins

Integrating the models of Integrating the models of serous carcinogenesis – a serous carcinogenesis – a

binary modelbinary model

Levanon, Crum, and Drapkin, JCO, 2008

How does it affect How does it affect screening?screening?

Is the target lesion a 1mm lesion Is the target lesion a 1mm lesion in the fallopian tube?in the fallopian tube?

How rapidly do these progress? How rapidly do these progress? What about tumors arising from What about tumors arising from

the surface of the ovary? the surface of the ovary?

How does it affect treatment?

Two types of Serous Tumors?Two types of Serous Tumors?

Surface Epithelium versus Surface Epithelium versus Fallopian tubeFallopian tube

Are they biologically the Are they biologically the same?same?

Is Ovarian Cancer a Is Ovarian Cancer a Homogenous Disease?Homogenous Disease?

HistologyHistology

OVARIAN AND ENDOMETRIAL CANCER OVARIAN AND ENDOMETRIAL CANCER SUBTYPESSUBTYPES

OVARIAN AND ENDOMETRIAL CANCER OVARIAN AND ENDOMETRIAL CANCER SUBTYPESSUBTYPES

SEROUSSEROUS ENDOMETRIOIDENDOMETRIOID CLEAR CELLCLEAR CELL

OV

AR

YO

VA

RY

EN

DO

ME

TR

IUM

EN

DO

ME

TR

IUM

OVARIAN & ENDOMETRIAL OVARIAN & ENDOMETRIAL CANCER CANCER

OVARIAN ENDO & SEROUS

ENDOMETRIAL ENDO & SEROUS

OVARIAN CLEAR CELL ENDOMETRIAL CLEAR

CELL

QuickTime™ and aCinepak decompressor

are needed to see this picture.

Zorn et. al. Clinical Cancer Research 2005

CLEAR CELL CANCER CLEAR CELL CANCER

OVARIAN ENDOMETRIAL RENAL

Zorn et. al. Clinical Cancer Research 2005

QuickTime™ and aCinepak decompressor

are needed to see this picture.

Clinical Impact of Genomic Clinical Impact of Genomic Characterization of Clear Cell Characterization of Clear Cell

CancersCancers Remove clear cell tumors from Remove clear cell tumors from

ovarian cancer phase III trials.ovarian cancer phase III trials. Create clear cell specific phase II Create clear cell specific phase II

trials.trials. Utilize understanding of molecular Utilize understanding of molecular

pathways of clear cell cancers from pathways of clear cell cancers from other organs to better treat ovarian other organs to better treat ovarian cancer.cancer.

Expression Profiling of Expression Profiling of Clear Cell Tumors of the Clear Cell Tumors of the

OvaryOvary 15 clear cell cancers of the ovary15 clear cell cancers of the ovary Whole genome profilingWhole genome profiling Supervised clusteringSupervised clustering Pathway identificationPathway identification

Cell Cycle Progression

Glycolysis

HIF1alpha degradation

Angiogenesis

Clear Cell Ovarian Cancer HIF1 alpha Pathway

Cell Migration

Is ovarian cancer a Is ovarian cancer a homogenous homogenous

disease?disease?GradeGrade

Unsupervised Hierarchical Clustering of Serous Unsupervised Hierarchical Clustering of Serous Ovarian CancersOvarian Cancers

Ovarian CancerOvarian Cancer

Normal Cells

Papillary Serous Ovarian Tumors

LMP/Low GradeLMP/Low Grade

High GradeHigh GradeP53-

P53+

B-raf, rasBonome et al Cancer Research 2005

Low Grade Phase II Trials

GOG 239 AZ MEK InhibitorGOG 239 AZ MEK Inhibitor

What About Papillary Serous Ovarian Cancer?What About Papillary Serous Ovarian Cancer?

90% of ovarian cancers are papillary serous tumors.All tumors high grade tumors treated with surgery and chemotherapy.Activated pathways remain unknown.

Copyright ©2008 American Association for Cancer Research

Tothill, R. W. et al. Clin Cancer Res 2008;14:5198-5208

Figure 5">

Optimally Debulked Suboptimally Debulked

Gene signatures predicts survival only for suboptimally debulked tumors

Co-regulated Signaling Events In Sub-optimal Patient Subgroups

TCGATCGA

200 high grade serous ovarian 200 high grade serous ovarian cancerscancers

6000 genes sequenced6000 genes sequenced Expression profilingExpression profiling Copy number differencesCopy number differences Methylation statusMethylation status

Future DirectionsFuture Directions

Histo/grade specific trials and Histo/grade specific trials and regimens.regimens.

Identification of sub-groups of Identification of sub-groups of patients based upon genomic patients based upon genomic patterns and activated pathways.patterns and activated pathways.

Future ChallengesFuture Challenges Validation of prognostic and predictive Validation of prognostic and predictive

biomarkers.biomarkers. Larger numbers of carefully annotated Larger numbers of carefully annotated

specimensspecimens FFPE technologiesFFPE technologies

Identification and validation of small Identification and validation of small molecule inhibitors targeting pathwaysmolecule inhibitors targeting pathways Integrated biomarkers will be mandated.Integrated biomarkers will be mandated.

Molecular basis for resistanceMolecular basis for resistance Recurrent tumor biopsies should be a Recurrent tumor biopsies should be a

requirement.requirement.

Michael J. Birrer M.D. Ph.D.Michael J. Birrer M.D. Ph.D.

Professor of Medicine Harvard Medical SchoolProfessor of Medicine Harvard Medical School

Director Gynecologic Medical OncologyDirector Gynecologic Medical Oncology

Massachusetts General HospitalMassachusetts General Hospital