DREAM TEAM

DREAM NO SMALL DREAMS GOETHE

TIME

MAGAZINE

WOMEN’S CANCER MOONSHOT

Ovarian Cancer

Karst and Drapkin et al Faculty 1000 Medicine

High Grade Serous Ovarian Cancer

Is Probably Fallopian Tube Cancer

• 22,000 new cases and 15,500 deaths in the USA • Low grade and high grade tumors have distinct genomic

aberrations • Low grade and high grade tumors do not interconvert • HGSEOC is the most common and aggressive form of ovarian cancer

DIFFERENT HISTOLOGICAL SUBTYPES OF OVARIAN CANCER INDICATE DIFFERENT THERAPEUTIC OPPORTUNITIES

Serous

Endometrioid

Mucinous

Clear cell

High grade low grade

High grade low grade

Low grade serous

KRAS

Clear Cell

PIK3CA mutations

Endometrioid

ARID1A mutation and deletion

Mucinous

Probably metastatic colon

High grade serous

p53, BRCA1/2 copy number

long tail of actionable mutations

Targeted agents

Bevaczumib

PARP inhibitors have now been

FDA approved

Chris Sander

Rab25 Adar1

PIK3CA PIK3CB PKCi Mecom mir 569, 551 Snon Cldn 7 Tert

HER2

PTEN

Ovarian Cancer

Myc

High grade serous ovarian cancer is driven by copy number changes with low frequency of recurrent mutations

Copy number changes may provide

opportunity for immunotherapy

HGSEOC is primarily driven by DNA copy number abnormalities with

p53 and BRCA1/2 pathway mutations

Gene % of mutations

TP53 96.4

CSMD3 4.8

FAT3 4.8

NF1 3.2

BRCA1 2.7

BRCA2 2.5

CDK12 2.2

RB1 1.5

GABRA6 1.5

Somatic Mutated Genes in HGSEOC

TCGA Ovarian Network Joe Gray

Rab25 PRKCI, MECOM Snon,PIK3CA, TERT mir551 569

MYC PVT1

Cyclin E

BRCA1/2 germline mutations and loss in 20-

25% of of ovarian cancers Improved patient outcomes

Opportunities associated with genomic aberrations in high grade serous ovarian cancer

• P53 – Wee1 inhibitors have increased activity in p53 mutated tumors

– P53 is frequently retained but unfolded and non-functional • Can be normalized by a number of compounds

– COTI2, ZMC1, Prima1

– P53 loss is common • Can result in loss of nearby genes

– POL2RA heterozygous loss can sensitize to alpha amanitin

• Homologous Recombination (HR) defects – Almost half of HGSEOC have evidence for defective HR

– A number of assays have been developed to identify patients likely to benefit from targeting HRD

– Sensitize to platinum based therapy

– PARP therapy is demonstrating activity • Rational Combinations with PARP therapy

• Almost half of all HGSEOC have a mutation in an actionable gene – Are these drivers or passengers Will targeting these genes benefit patients

The Impact Of Residual Tumor: What Is Optimal Debulking?

Progression-free survival Overall Survival

Dubois et al, Cancer, 2009: Mar 15; 115(6): 1234-44

R0 R0

R0 25%

0 < R1 <1 cm 50%

R2 > 1cm 25%

Rates of R0 resection

Nick et al., Nature Rev Clin Oncol, 2015

Opportunity For Quality Improvement: Personalized Surgical Therapy

Implementation of evidence-based patient care guidelines

Multidisciplinary approach

Improvement in the quality of surgical care

Standardized care

Improvement in rates of complete gross resection (R0) with reciprocal improvement in patient overall survival

Developing a personalized surgical approach that translates across different clinical practice settings

Women w/ suspected ovarian cancer

Primary Assessment

Laparoscopy: Validated score

Intraoperative agreement

R0 not feasible

Neo-adjuvant chemotherapy

R0 feasible

Primary tumor reductive surgery

Tissue

Immune & molecular analyses

Opportunity For Quality Improvement: Personalized Surgical Therapy

Primary cytoreduction 20% 88% (n = 87)

NACT → Interval cytoreduction 60% 76% (n = 65)

Surgical Outcomes (R0 Rates) since implementation of Flagship 2A

Pre- implementation

Post- implementation

Major effort focused on R0 resection included education, clinical retreats (consensus among all 21 gynecologic oncologists), and engaging other specialties (e.g., thoracic, GI surgery)

Compliance is over 98%

Flagship 2B: Novel Clinical Interventions

Develop integrated predictors of response to standard chemotherapy

Assess tumor heterogeneity and molecular evolution to determine adaptive responses to standard therapeutics

Novel clinical trial designs

New Moonshot Projects - FP2B HGSOC Fl

agsh

ip P

roje

ct 2

LSC

Score <8

FP2b Phase 0 “Window” trials

1-2 wks Single Agents “POSITION” Trial

Debulking

Tissue acquisition

Novel therapy vs. Std therapy

Score >8

FP2b Phase Ib-2 Treatment Trials

NACT

Pac/Carbo + novel Debulking

Adjuvant

Pac/Carbo + novel

Tissue acquisition

Tissue acquisition

Clinical Trial Standard of Care

Matched sites Ovary/Primary Omentum Diaphragm Other peritoneum

Ovarian Cancer Window of Opportunity Trial

Analysis: • HRD assessment

• DNA, RNA, Protein • Immune profile • Generation of PDX and lines

Flagship 2C: PDX Models - Transition to the clinic

Development of breast and ovarian cancer patient-derived xenograft models:

• Molecularly characterized (DNA, RNA, protein)

• Therapy naïve

• TNBC: >10 (6 genomically characterized)

• HGSOC: 10

• Post-therapy/resistant

• TNBC: 5

Project 2A/B – Agents

• DNA Damage

– PARPi: BMN-673, olaparib,

– Wee1 AZD-1775

– CHK1/2

– ATR, ATM

– BRD4

• PI3K pathway: BKM120, BYL219, AZD2014, AZD5363, Copelesib

• Angiogenesis: Dll4 (demcizumab), TAMs (AC708)

• Immune: PD-1 (MK-3475) PDL-1 (Medimune)

• P53: AZD-1775, COTI-2

• Others: Prolanta (PrL), KPT-330

Expanding our Program

Regional care centers in the greater Houston area • Katy, The Woodlands, Sugarland,

Bay Area and Pearland • LBJ Hospital (Houston, TX) • MDACC Cancer Network

MD Anderson Cancer Center at Banner and Cooper National and International Sister

Institutions Other national and international

centers

Building a Pipeline for Future • Translational biology

• P53 based approaches – synthetic lethality

• New animal models and imaging to prioritize the massive numbers of potential new targets and drugs

• Rational combination therapy: new combinations of kinase inhibitors; identify synergistic combinations with PARP inhibitors

• Immune modulation/inflammation as therapy targets

• Re-define “druggable” targets – co-extinction strategies

• Survivorship

• Identify and validate predictors of long-term survival

• Predictors of toxicity

• Early Detection and prevention

• New biomarkers for screening and drugs for prevention

WOMEN’S CANCER MOONSHOT

BRCA1 and BRCA2

10% of TNBC or HGSOC

Family history

TNBC or HGSOC

Predisposition to breast and

ovarian cancer

BRCA2 Male breast cancer

Prevention decreases risk by at

least 80%

New therapy (PARPi) effective

for patients

Germline BRCA-1 and -2 testing

(>10% will be positive)

FP1A Active Outreach

FP1C Screening Prevention

Offer genetic testing to all patients

with TNBC or HGSOC

NCCN Guidelines

No charge to patient or MDACC

Making Cancer History for the Family

SCOPE OF PROBLEM: PREVENTING FUTURE OVARIAN CANCERS IN FIRST DEGREE RELATIVES BY TESTING

FOR BRCA MUTATIONS

Reference strategy 0 tested 0 test+

SGO criteria 4,005 tested

900 test+

Test serous CA 9,337 tested 1,252 test+

Test all 14,000 tested

1,481 test+

14,000 women with ovarian cancer in U.S. (index cases)

0 FDR tested

0 test+

216 Ov Ca

1,800 FDR tested

988 test+

157 Ov Ca

2,504 FDR tested

1,288 test+

137 Ov Ca

2,962 FDR tested

1,418 test+

121 Ov Ca

27% 37% 44% Kwon et al, JCO 2009

Despite this, less than 50% of patients offered testing at MDACC and less than 25% elsewhere

Breast Ovarian Number of patients 2458 680 Number of pts. tested at MDA 1729 389 Percentage tested 72% 57% BRCA⁺ among TNBC/HGSOC 51 73 Percent positive 14% 19%

FAMILY OUTREACH PROTOCOL (REACH) Total number of family members 121 Contacted 47 (50%)

Current Reporting Metrics for TNBC/HGSOC Patients (9/1/2012 – 3/31/15)

IMPACT: Increased testing rate from 25% to 65%!!

Making Cancer History for the Family

Previvors • Surgical Prevention • Chemoprevention • Screening

• Recently Funded-SU2C • CHECMATE Trial - CHance to End

hereditary ovarian Cancer by MAking Testing better and Easier

• WISDOM Trial - Women choosing Interval Salpingectomy with Delayed Oophorectomy to postpone Menopause

Best way to improve

outcomes is to prevent the

disease

5 years

80% decrease in deaths in

family members

12% improvement in

survival

Making Cancer History for the Family

20-50% of patients will

have a defect BRCA1 or

BRCA2 function

PARP-inhibitor based

therapy

8 fold improvement

Offer genetic testing to all

patients with TNBC or

HGSOC

HELPING THE PATIENT

Academic Industrial

Collaboration

Other moonshots

Identification of patients

likely to benefit

HELPING THE PATIENT

Rational combination therapy

with PARPi

7 new trials

Improving

outcomes

across

Houston,

Texas and the

world

PARADIGM SHIFT

Patient

Family

Current state-of-knowledge Front-line Therapy:

- Surgery

• Comprehensive staging or cytoreduction for metastatic disease

• Tumor residuum is the strongest prognostic factor

- Adjuvant therapy

• Nearly all cases

• Platinum-taxane based

Recurrence Therapy:

– Chemo-sensitive disease

• Approach like frontline therapy

• Surgery (+/-)

• Platinum based

– Chemo-resistant disease

• Emergence is cause of death

• Multiple agents of poor response

Roles of biologic and maintenance therapy are evolving

Som

e a

re c

ure

d! N

on

e are

cure

d!