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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
SU2C-OCRF-OCNA-NOCC Ovarian Cancer Dream Team Grant
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
SU2C-OCRF-OCNA-NOCC Ovarian Cancer Dream Team Grant
DNA RepairA Crucial Cellular Function
SU2C-OCRF-OCNA-NOCC Ovarian Cancer Dream Team Grant
• DNA repair pathways are complicated and redundant
• Many genes associated with an inherited risk of cancer are DNA repair genes, including BRCA1 and BRCA2
SU2C-OCRF-OCNA-NOCC Ovarian Cancer Dream Team Grant
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
SU2C-OCRF-OCNA-NOCC Ovarian Cancer Dream Team Grant
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
SU2C-OCRF-OCNA-NOCC Ovarian Cancer Dream Team Grant
• 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
SU2C-OCRF-OCNA-NOCC Ovarian Cancer Dream Team Grant
• 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
SU2C-OCRF-OCNA-NOCC Ovarian Cancer Dream Team Grant
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
SU2C-OCRF-OCNA-NOCC Ovarian Cancer Dream Team Grant
• 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
The best person to test is the relative with cancer
V = BRIP1 mutation
NVBr 42Ov 66BRCA1/2 neg
Br 49
The best person to test is the relative with cancer
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
SU2C-OCRF-OCNA-NOCC Ovarian Cancer Dream Team Grant
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)
SU2C-OCRF-OCNA-NOCC Ovarian Cancer Dream Team Grant
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)
SU2C-OCRF-OCNA-NOCC Ovarian Cancer Dream Team Grant
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
SU2C-OCRF-OCNA-NOCC Ovarian Cancer Dream Team Grant
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
SU2C-OCRF-OCNA-NOCC Ovarian Cancer Dream Team Grant
• 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
Assess how well we can deliver genetic testing for breast and ovarian cancer risk to women in their living room?
GOAL
MAGENTA
Outcomes: PrimaryIncrease in distress
Assess how well we can deliver genetic testing for breast and ovarian cancer risk to women in their living room?
GOAL
Secondary• Completion rate• Satisfaction with web-
based genetic services• Anxiety, depression, QOL• Decisional conflict• How information used:
– Communication tofamily members
– Utilization of OCprevention
SU2C-OCRF-OCNA-NOCC Ovarian Cancer Dream Team Grant
Not all women want preventive surgery
SU2C-OCRF-OCNA-NOCC Ovarian Cancer Dream Team Grant
• 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
SU2C-OCRF-OCNA-NOCC Ovarian Cancer Dream Team Grant
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)
SU2C-OCRF-OCNA-NOCC Ovarian Cancer Dream Team Grant
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
SU2C-OCRF-OCNA-NOCC Ovarian Cancer Dream Team Grant
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
SU2C-OCRF-OCNA-NOCC Ovarian Cancer Dream Team Grant
Alan D’Andrea, MD Elizabeth Swisher, MD
Gini Fleming, MD Maria Jasin, PhD Scott Kaufmann, MD, PhD
Karen Lu, MD
OVARIAN CANCERDREAM TEAM