dna repair therapies for ovarian cancer

Alan D’Andrea, MDDana-Farber Cancer Institute

Elizabeth Swisher, MDUniversity of Washington School of

Medicine

DNA Repair Therapies for Ovarian Cancer

SU2C-OCRF-OCNA-NOCC Ovarian Cancer Dream Team Grant

DNA Repair Dream TeamImpacting Ovarian Cancer Mortality Through Novel Therapies and Prevention

Therapy Prevention

TEAM SCIENCE

Advocacy

University of Washington • Dana Farber Cancer Institute • Mayo Clinic • University of Chicago • MD Anderson • Memorial Sloan-Kettering

CDKi + PARPiPI3Ki + PARPiATRi + PARPi

MAGENTAWISDOM

Crase • Polinsky • Gavin

Elizabeth Swisher Alan D’Andrea Scott Kaufmann Gini Fleming Karen Lu Maria Jasin

Alan D’Andrea, MD Elizabeth Swisher, MD

Gini Fleming, MD Maria Jasin, PhD Scott Kaufmann, MD, PhD

Karen Lu, MD

OVARIAN CANCERDREAM TEAM

DNA RepairA Crucial Cellular Function


DNA Repair

• Defective DNA repair allows cells to accumulate mutations which leads to cancer

• Defects in DNA repair pathways impact how a cancer responds to therapy

A Crucial Cellular Function


DNA RepairA Crucial Cellular Function


• DNA repair pathways are complicated and redundant

• Many genes associated with an inherited risk of cancer are DNA repair genes, including BRCA1 and BRCA2


DNA Repair Dream TeamIntroduction

• Ovarian cancer (OC) has few druggable targets

• Up to half of OC have defective DNA repair

• Defective DNA repair makes it harder for the cancer to repair DNA damage caused by chemotherapy

• Some newer targeted drugs, such as PARP inhibitors, are lethal to cells with specific types of defective DNA repair

• Defective DNA repair is an Achilles heel that provides therapeutic opportunities

Aim 1Mechanisms of Sensitivity and Resistance to PARPi


Rationale:• Most OC have some type

of defect in DNA repair• Olaparib is a PARP inhibitor approved for OC with BRCA1/2 mutations, but most develop resistance

• Other patients may also respond

Goal: • To develop predictors of response

and resistance to PARP inhibitors

Novel Drug Combinations to Extend PARPi Use

Rationale:• OC with normal DNA repair are not sensitive to PARPi• BRCA1/2-mutated OC eventually develop PARPi

resistance, through restoration of DNA repair • New drugs which inhibit DNA repair could be combined

with PARPi

DNA Repair Proficient

DNA Repair Deficient

+ PARPiAgent that Inhibits HR

Synthetic Lethality

First Two Clinical Trials in Ovarian SU2C

PARPi and Dinaciclib• Currently in final part of Phase I: Dose finding• Will open Phase II later this year: Recurrent OC• Veliparib vs. veliparib + dinaciclib• Will enroll 90 at Dana-Farber, Mayo, MSKCC

PARPi and PI3Ki• Currently in final part of phase I: Dose finding• Will open phase II later this year: Recurrent OC• Olaparib vs. olaparib + BYL719 • Will enroll 90 at Dana-Farber, MSKCC, MD Anderson

Third TrialATRi + PARPi, Preclinical & Phase 1 Trial


• ATR inhibitor enhances killing of OC cell lines concurrently treated with veliparib

• ATRi synergizes with PARPi (olaparib) • Currently testing strategy in mice with human OC (PDX)• Aim to start phase I trial in 2017

Fourth Trial (added)Pembro/Niraparib Phase 1/2 Trial


• Preclinical DataImproved therapeutic efficacy with Niraparib and immune checkpoint inhibitor combination

• Phase 1 6 per dose level (n=18) (yr 1-2)

• Phase 2 Expansion Cohort 96 platinum-resistant OC, 48 HGSC, 48 clear cell (yr 2-3)– 48 HGSC – 48 clear cell

• Enrolling shortly at multiple centers…

Can we predict who will get Ovarian Cancer?

• How much breast and ovarian cancer is hereditary and which genes are involved?

• Watch Mary-Claire King on Moth Radio ( ) http://themoth.org/posts/storytellers/mary-claire-king

Dr. Mary-Claire King, PhD, discovers BRCA1 in 1990Took many scientists 4 years to sequence this one gene!

Is it in your genes?

2 Genes: BRCA1 BRCA2

Hereditary Ovarian Carcinoma


Wildtype 80%

BRCA1 9.5%BRCA2 5.1%

Other OC gene 4%

• 20% of OC caused by inherited risk• BRCA1 and BRCA2 are the most important genes• 9 other genes cause 4% of cases,

¼ of mutations occur in non-BRCA genes

• 1 of 5 ovarian cancers occur in women with identifiable risk and could be prevented!

• If we identified all genetic risk of OC, we could save many lives

BRCA1 and BRCA2Important DNA Repair Genes


• 15% of ovarian cancer is caused by inherited mutations

in BRCA1 and BRCA2• BRCA1 mutations 40% lifetime risk of OC• BRCA2 mutations 20% lifetime risk of OC• Both 50–80% lifetime risk of breast cancer• BRCA1 and BRCA2 mutations also increase the risk

of male breast, pancreatic and early onset prostate cancer• Olaparib is a PARP inhibitor approved for recurrent OC

with BRCA1/2 mutations (after 3 previous lines of treatment)

Why do we care about Familial cancer risk?

These cancers can be prevented!

Know your family history and share that knowledge with relatives

A Family Gift

• PERSONAL and FAMILY HISTORY are the mainstays in identifying inherited cancer risk

• Early onset cancers– Premenopausal breast cancer– Colon cancer age <50

• Multiple affected relatives• Individuals with multiple primary

cancers– Bilateral breast cancer– Multiple melanomas

• Rare or unusual cancers– Male breast cancer

Red Flags of Hereditary Cancer

Rationale for Genetic Testing• Accurately identifies risk• Identifies cancer risk to other organs• Appropriate interventions for those at risk,

avoids interventions for those not at risk• Eliminates uncertainty

Br ca 35Ov Ca 55

Br ca 42

The daughter wants to know her risk

Br 42Ov 66

Br 49

The best person to test is the relative with cancer

Br 42Ov 66BRCA1/2 neg

Br 49


V = BRIP1 mutation

NVBr 42Ov 66BRCA1/2 neg

Br 49


Once you identify the mutation in the family, you can give definitive risk information to women without cancer

V = BRIP1 mutation

NVBr 42Ov 66BRCA1/2 neg

Br 49

Hereditary OC risk can come from the dad’s side

Ov 54

Br 45

Hereditary OC risk can come from the dad’s side

Ov 54BRCA1

Br 45BRCA1

BRCA1

FT 52BRCA1/2 WT

Hereditary OC?

BRCA1 and BRCA2 negative on genetic testing

BRCA1 and BRCA2 negative on genetic testing

Hereditary OC can occur with no cancer family history

FT 52BRCA1/2 WT

FT 52BRCA1/2 WT

CF 1659

V = BARD1 2148delCA

TNBC 52

BARD1 BARD1

Hereditary OC can occur with no cancer family history

CF 1659Once the family mutation is identified, you can determine who is at risk

Sisters, mothers, daughters have a 50% chance of having the same mutation

FT 52BRCA1/2 WT

V = BARD1 2148delCA

TNBC 52

BARD1 BARD1

CF 1659Once the family mutation is identified, you can determine who is at risk

Gene mutations will not skip generations

FT 52BRCA1/2 WT

V = BARD1 2148delCA

TNBC 52

BARD1 BARD1

WT BARD1

Ov 79

BRCA1, BRCA2 negative

Ov 54

Ov 45

94 87BRCA1/2 negative

CF 2959Not all women with an OC gene mutation get cancer

RAD51C mutation: Only 10% of women with the mutation will get cancer; risks differ for each gene

Aim 3OC Risk Assessment and Prevention


Defining OC Gene Risk Genetic Risk Assessment Surgical Prevention

Wildtype 80%

BRCA1 9.5%BRCA2 5.1%

Other OC gene 4%

(Walsh et al, PNAS, 2011)

Rationale:• 20% of OC caused by germline

mutations in OC genes• Preventive surgery can decrease

OC mortality in high-risk women• Genetic testing underutilized• Not all women willing to undergo

RRSO prior to menopause

Aim 3ADefining OC Risk (Swisher, King)


Gene

Mutations Minus CNVs

N=1915

Mutations in Adjusted ESP EA

N=4300OR (95% CI)

Cases vs. ESP P ValueMedian Age

(Range) BRIP1 24 (1.3%) 5 (0.12%) 10.9 (4.2–28.6) <0.0001 65.5 (43–79)

PALB2 10 (0.52%) 2 (0.05%) 11.3 (2.5–51.6) 0.0007 56 (49–65)

RAD51C 10 (0.52%) 1 (0.02%) 22.6 (2.9–176) <0.0001 64 (47–70)

RAD51D 9 (0.47%) 2 (0.05%) 10.2 (2.2–47) <0.0001 54 (34–75)

BARD1 5 (0.26%) 0 24.8 (1.4–448) 0.003 53 (47–60)

• 11 OC genes: BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, PALB2, BARD1, PMS2, MSH6, MLH1, MSH2

• Test 20,000 WHI controls, and the number of cases to 4000• Generate more precise risk estimates for OC genes• Identify new OC genes

Aim 3B MAGENTA (Swisher, Lu, Fleming, Olopade)


Goal:• Develop a new

paradigm for genetic testing that would increase access to OC risk assessment

MAking GENetic Testing Accessible

Barriers to widespread OC Risk Identification:• Identification of target patients by physicians• Availability of genetic counselors• Lack of knowledge• Inconvenience• Cost

MAGENTA

Relative with known mutationCascade testing (Group 2, N=750)

TARGET Population:

Personal history BCor family history BC/OC

(Group 1, N=2,250)

• Women without ovarian cancer• Age ≥30• No prior genetic testing


Assess how well we can deliver genetic testing for breast and ovarian cancer risk to women in their living room?

GOAL

MAGENTA

Subject Study Flow


• Screening

• E-consent• Baseline questionnaires • Randomization, 2 x 2 design,

comparing online education vs. telephone counseling, pre- and post-test

• Saliva test kits • Color Genomics

sequences 19 breast and OC genes

• Results disclosed

Subject passes pre-screen criteria


GOAL

MAGENTA

Outcomes: PrimaryIncrease in distress


GOAL

Secondary• Completion rate• Satisfaction with web-

based genetic services• Anxiety, depression, QOL• Decisional conflict• How information used:

– Communication tofamily members

– Utilization of OCprevention


Not all women want preventive surgery


• Risk-reducing salpingo-oophorectomy (RRSO) mortality for women with BRCA1 and BRCA2 mutations

• RRSO has negative impact on: – health

– sexual function

– well-being

The Tubal HypothesisA majority of serous ovarian and peritoneal carcinomas are actually seeded from cancer cells from the tubal epithelium

WISDOM


Women choosing Interval Salpingectomy with Delayed Oophorectomy to postpone Menopause

• A large fraction of OC in women with BRCA1/2 mutations arises in the fallopian tube

• Salpingectomy could be useful to risk in 2 high-risk groups:Those who have completed childbearing but are younger than recommended age for RRSOThose delaying RRSO beyond recommended ageto avoid menopause

• 34% of high-risk women in FORCE survey were interestedin salpingectomy

• MD Anderson completed enrollment of pilot trial of 40 women who chose ISDO vs. standard RRSO

WISDOMSU2C-OCRF-OCNA-NOCC Ovarian Cancer Dream Team Grant

Inclusion Criteria: • Age 30–50• Premenopausal• Known mutation in OC gene

Scripted counseling on recommended age for oophorectomy

SafetyStop Rules

DSMB

IntervalSalpingectomy

DelayedOophorectomy

RRSO

SECONDARY Outcomes: • Vasomotor symptoms (MRS)• Psychological symptoms (HADS)• Pathological results (TIC, carcinoma)

PRIMARY Outcome: Sexual Function (FSFI)


Ovarian CancerDecreasing Mortality

Defining OCGene Risk

Genetic RiskAssessment

SurgicalPrevention321

• Developing a new paradigm for OC preventionrequires addressing all three areas:

• Advocacy is critical:• Clinical trial design• Recruitment• Interpretation of results• Publicizing results to patients and providers


DNA Repair Dream TeamStrengths of DNA Repair Dream Team

• Diverse, complementary team of investigators from six world class institutions

• Novel therapeutic interventions for delivering near-term patient benefit

• Potential for reducing OC mortality through prevention

• Industry collaborations• Committed advocates


Alan D’Andrea, MD Elizabeth Swisher, MD

Gini Fleming, MD Maria Jasin, PhD Scott Kaufmann, MD, PhD

Karen Lu, MD

OVARIAN CANCERDREAM TEAM

dna repair therapies for ovarian cancer

Health & Medicine