Personalized Medicine for Ovarian Cancer Patients

Setsuko K. Chambers, MD Member, Institute of Medicine

Professor and Bobbi Olson Endowed Chair in Ovarian Cancer Research Vice Chair and Section Head, Gynecologic Oncology

Department of Obstetrics and Gynecology and the Arizona Cancer Center University of Arizona

Conflicts to declare: none

Plenary session, Ovarian Cancer National Alliance

National Conference, July 2015

Personalized Medicine

Where we are-- towards moving to where we need to be-to apply precise management plans tailored for the individual patient for risk assessment, prevention, treatment, and/or avoidance of excessive toxicity

Graphic from Transatlantic conference on Personalized Medicine, 2015

What about an individual is unique which can be potentially used to design personalized medicine approaches?

• Germline, or inherited mutations in the DNA

• Molecular abnormalities in the individual cancer tissue

• Components circulating in the bloodstream such as tumor cells, miRNA, cell-free DNA, protein..

• Molecular imaging of tumors in patients

• Chemo-resistance assays using the patient’s tumor cells

• Patient-derived ovarian cancer xenografts

Abnormalities in DNA can be inherited (germline)

or arise during an individual’s lifetime, found in the tumor (somatic)

Either way, these abnormalities lead to altered pathways and

functions which can be exploited directly as targets

or indirectly as it provides a context

wherein an approach could be more successful

Focus first on germline, inherited mutations

2 main hereditary cancer syndromes

BRCA 1/2

• breast

• ovary, tube, peritoneal

• others

Lynch Syndrome

• colon

• endometrial

• ovary, tube, peritoneal

• others

BRCA1/2 and Lynch Syndrome Genes

• These genes have roles in DNA repair, specifically homologous recombination and mismatch repair

• BRCA1/2 mutations, account for the majority of hereditary ovarian cancer cases, but not all

• ~6% of hereditary ovarian cancer cases –due to mutations in the Fanconi anemia pathway genes—leading to homologous recombination DNA repair deficiency

• Lynch Syndrome cases account for a much smaller fraction • These inherited mutations collectively account for ~24% of ovarian

cancer cases overall

Collaborative Oncological Gene-environment Study (COGS), Nature Genetics 2013,

Walsh T, PNAS 2011

The University of Arizona High-risk clinic: a unique diverse database rich with Hispanic and Native American ancestry

• Significantly higher proportion of BRCA2 mutations than BRCA1

• Novel BRCA2 mutations not previously reported • Certain to find other new genetic susceptibility

loci for ovarian cancer risk in these populations

Familial Cancer, 2012

More common genetic loci are being identified which are

associated with risks for hormonally sensitive cancers –

these mutations may account for up to 4% of inherited

ovarian cancer cases, if validated

Findings pertain mainly to persons of European ancestry

COGS, Nature Genetics 2013

Inherited common genetic loci (mutations) not generally validated yet to correlate

with clinical outcomes, such as excessive toxicity, or lack of response

Inherited genetic loci to help predict response or toxicity

--Pharmacogenomics not yet ready

for prime-time

“Normal” ovary and fallopian tube:

• Appearance of normal, pre-cancer

• Appearance in general population and those at high-risk

Molecular abnormalities arise in these tissues sight unseen

Switching gears to the study of molecular abnormalities in the tumors

The Cancer Genome Atlas:

Epithelial Ovarian Cancer

Epithelial Ovarian Cancer is not one disease

Significant genomic complexity with many different mutations, and driver genes

Multiple Pathways activated including those which drive proliferation, metastasis, drug resistance, toxicity

Such complexity leads to challenges in early detection, chemoprevention, as well as in targeted treatment of ovarian cancer patients

Nature, 2011

How does molecular information about the tumor help develop a management plan for the

patient? • There are many clinical trials now which triage based on

the characteristics of the patient's tumor. Several examples of such personalized therapies will follow.

• Tremendous value to this knowledge to research, as new genes/pathways help in the design of combination therapies pertinent to the subtype of ovarian cancer. The knowledge helps uncover the basis of many tumor behaviors, such as drug resistance, tumor metastasis, tumor development...

Common locations of metastatic spread from ovarian cancer, with different molecular abnormalities seen within and

between tumors and between primary and metastatic sites

Serous ovarian cancer with heterogeneity for

expression of a growth factor, CSF-1

Drilling down to the cellular level, heterogeneity of

gene expression is seen even within a single region

of a tumor

Tumor Heterogeneity in the context of targeted therapy is a challenge

Analysis of sample from one tumor at a single point in time limits relevant information

Sampling of primary tumor and metastasis, with serial samples taken over time is optimal, but feasibility and costs could be limiting

Ma X, PLOS one 2008

Mapping of Genetically compensatory biologic

pathways in yeast

Imagine the genomic complexity and redundant pathways

present in the healthy human, further convoluted in an

ovarian cancer specimen: alter one pathway, another one

becomes more dominant

Graphics from the University of Arizona

Precision Health effort

• Inhibiting target may have

little effect

• Tumor heterogeneity

• Redundant pathways

• Target may be present and

have function in normal

tissues

• Side effects limit dose

and efficacy

Examples of ovarian cancer clinical trials using a personalized medicine approach

• BRCA mutations, Homologous recombination defects, and PARP inhibitors

• Defective p53 pathway

• Folate Receptor imaging and directed treatment

• Patient specific directed immunotherapy

• Potential of patient-derived ovarian cancer xenografts

Theme: interface between germline mutations, molecular

abnormalities in the tumor, and the tumor microenvironment

PARP inhibitors in high-grade serous ovarian cancer; they take advantage of the DNA repair (homologous recombination, or HRD)

defect in the tumors Tumor profiling of high-grade serous carcinomas on Clovis clinical trial with Rucaparib has shown so far:

From Clovis Oncology and McNeish et al, ASCO 2015

Germline BRCA mutation

20%

“BRCA-like”—somatic mutations consistent

with HRD signature

40%

Biomarker neg

34%

Unclassified

6%

Grouping correlates nicely with tumor response

Taking advantage of p53 mutation in the tumor; deficient p53 pathway

• Some epithelial ovarian cancers may arise in the background of germline p53 mutation

• Almost all epithelial ovarian/tubal serous cancers have p53 mutation, which leads to deficiency in DNA repair among many other defects

• Targeting a different cell-cycle checkpoint takes advantage of this p53 deficient pathway in tumors

• Example of this approach is the Astrazeneca SMI—Wee 1 tyrosine kinase inhibitor-- used for chemo-sensitization, among other agents in clinical trials

Tubal serous carcinoma,

courtesy of Chris Crum

Molecular Imaging: a way to characterize one aspect of the patient’s tumors as a whole

• Nuclear medicine SPECT scan overlaid on CT scan, visualizing folate receptor expressing tumors in ovarian cancer

• Can triage those patients whose tumors are less or more likely to respond to folate receptor targeted therapy

• Example: pipeline of folate receptor targeted drugs from Endocyte, with active clinical trials

Courtesy of Phil Kuo and Endocyte, Inc

Folate receptor+ omental disease

Targeted immunotherapy has come a long way, with improved understanding of the immune landscape in the ovarian cancer microenvironment

• Recognition that T cell infiltration of ovarian cancer enhances survival, because of its innate anti-tumor effect

• NY-ESO-1 target or other ovarian tumor targets: Dendritic cell vaccine trials: patient’s dendritic cells ex vivo is loaded

with tumor antigen(s), and re-infused into the patient Adoptive T cell therapy trials ongoing: re-engineer patient’s T cells ex

vivo to better recognize the ovarian cancer cells and re-infuse into the patient

• Immune checkpoint inhibitor—many trials in ovarian cancer Inhibition of PD-1 and CTL4 receptor/ligand interaction Combination therapies with low dose chemo, durability of response

• Targeted therapy generally modulates innate immune response favorably

CD8+ T cells infiltrating ovarian cancer

High T cells Low T cells

Courtesy of K. Odunsi

Taking advantage of mutation-prone tumors: such as those with microsatellite instability, including

cancers in patients with Lynch syndrome

Tumors with DNA mismatch repair defects and microsatellite instability including those associated with Lynch Syndrome, have a high proportion of infiltrating T cells, upregulation of the PD-1 pathway, and are particularly susceptible to immune checkpoint inhibitor therapy

Ovarian cancer patient with incidental

early endometrial cancer: MSH6 protein

loss in the patient’s tumor

Genetic testing confirms

germline MSH6 mutation

= Lynch Syndrome

patient’s tumor + control

Le DT, NEJM 2015; Howitt B, ASCO 2015

Patient-derived ovarian cancer xenografts • Patient-derived cell line chemo-resistance assays rely on clonal cells which

grow out–tumor heterogeneity a real issue

• Xenografts from patient tumors in mice preserve much of the heterogeneity but improvement still needed—need human stroma, etc

• These xenografts poorly predictive for immune responses

• High take rate of ovarian cancers

• Not proven yet to be able to consistently predict response to targeted therapy, but encouraging!

Figure from Tentler JJ 2012 Nat Rev Clin Oncol

What could help us in the future? • Define more precisely the potential of success and the limitations of targeted

approaches in precision medicine of ovarian cancer. Combination approaches are more likely to be successful given the: many redundant molecular pathways and evolution of compensatory pathways found in

the tumor tumor heterogeneity impact of the tumor microenvironment increasing repertoire of germline mutations

• Characterize among those many genomic loci proposed to be associated with an increased risk of ovarian cancer, those which are validated to contribute to clinically relevant risk, so that an informed risk-modifying plan can be created for the patient

• Quality of life is an important focus during much of the ovarian cancer path. Despite

previous large effort in the area of pharmacogenomics, loci in genes which may predispose the patient to altered toxicity from the drugs we commonly use have not been validated. Different approaches need to be investigated in order to overcome prior obstacles.

University of Arizona Cancer Center

Tucson, AZ

Thank you!