Targeting DNA repair defects in gynecologic cancers: BRCA, BRCAness and beyond Panagiotis...

Targeting DNA repair defects in gynecologic cancers:

BRCA, BRCAness and beyond

Panagiotis Konstantinopoulos MD, PhD

Assistant Professor of Medicine

Harvard Medical School

Medical Gynecologic Oncology Program

Dana Farber Cancer Institute

1. Defective DNA repair pathways in

gynecologic cancers

Aziz et al. / Pharmacology & Therapeutics 133 (2012) 334–350

DNA Damage Repair Pathways

Homologous Recombination DNA Repair Pathway

Hereditary Breast Ovarian Cancer (HBOC) Syndrome

Associated with germline mutations in BRCA1/2 genes and characterized by a

familial clustering of breast and epithelial ovarian cancers (EOCs)

Accounts for 10-15% of all ovarian cancers, although its frequency is much

higher among Ashkenazi Jewish women with EOC (29%-41%)

The National Comprehensive Cancer Network guidelines for breast and ovarian

genetic risk assessment currently recommend referral for genetic testing for

HBOC syndrome for every woman diagnosed with ovarian, fallopian tube or

primary peritoneal serous cancer

Other cancers that may be part of HBOC syndrome are gastric, pancreatic,

prostate and uterine cancers (BRCA1 carriers) and melanoma, gastric,

pancreatic, prostate and biliary duct cancers (BRCA2 carriers)

As many as 50% of high

grade serous ovarian

cancers have defective HR

DNA repair pathway

Ovarian Cancer and HR defects

Fingerprint of HR pathway alterations in ovarian cancer

Cancer Genome Atlas Research Network.

Nature, 2011 Jun 29;474(7353):609-15

Platinum damage and DNA repair

Cisplatin

Intrastrand Interstrand cross-links

Nucleotide

Excision

Repair (NER)

Homologous

Recombination

(HR)

NER pathway alterations are present in 8% of high grade serous tumors.

NER alterations confer a clinical phenotype of platinum sensitivity similar to that

of BRCA1/2-mutations in ovarian cancer.

NER alterations are functionally associated with platinum sensitivity but do not

confer sensitivity to PARPis or other double strand break inducing agents.

NER alterations is a novel mechanism of platinum sensitivity in ovarian cancer.

NER pathway alterations

Mismatch Repair Pathway

HNPCC (Lynch) Syndrome

Associated with development of multiple cancer types at an early age,

particularly colon, uterine and ovarian cancer

Caused by a germline mutation in MSH2, MLH1, MSH6, PMS2 genes

MSH2 or MLH1 mutations account for 90% of Lynch syndrome, MSH6 most of

the rest and PMS2 are very rare 

Lynch syndrome accounts for 2-5% of all uterine carcinomas and about 1-2% of

ovarian cancers

The majority of Lynch syndrome-associated uterine cancers are endometrioid

histology

Lynch syndrome has been associated with all subtypes of ovarian cancer

Risks of uterine and ovarian cancer in Lynch syndrome

Uterine Cancer and Mismatch Repair Defects

Defective MMR occurs in 20-

35% of all uterine tumors (i.e.

not only Lynch syndrome)

This can happen through

various mechanisms that

usually do not involve mutations

in MMR genes

Uterine Cancer and BRCA1/2

There have been some reports of an increased risk of the serous

subtype of uterine cancer in BRCA carriers.

In one report, 4 of 20 Ashkenazi Jewish women with USC had

BRCA1 germline mutations

In another, three BRCA1 and three BRCA 2 germline mutations were

identified among 22 Jewish women with USC

2. Targeting defective DNA repair pathways in

gynecologic cancers

Development of PARP inhibitors

Interaction between BER and HR repair pathways

A cell CAN survive if ONLY the homologous recombination (HR)

pathway OR ONLY the base excision repair pathway (BER) is

defective

BUT

CANNOT survive if BOTH pathways are defective

Synthetic lethality between HR and BER

HR pathway BER pathway

Base Excision Repair (BER)

PARP-inhibitors (Synthetic Lethality)

Selected trials of olaparib in BRCA carriers in EOC

Agent Design Patients Results

Olaparib Phase I 15 BRCA carriers8/15 (53%) had objective response per RECIST

criteria and 1 had stable disease for 6 months

Olaparib Phase I 50 BRCA carriers

40% ORR and/or CA125 (>50% decline)

Clinical benefit in platinum-sensitive, resistant, and

refractory subgroups (69%, 45%, and 23%,

respectively)

Olaparib Phase II

33 BRCA carriers

(400mg po bid)

24 BRCA carriers

(100mg po bid)

ORR: 33% at 400 mg bid and 13% at 100 mg bid

Median PFS : 5.8 mos at 400mg bid and 1.9 mos

at 100mg bid

Olaparib

versus

Doxil

Randomized

Phase II97 BRCA carriers

Objective response rate per RECIST was 25% for

200mg po bid dose and 31% for 400mg po bid.

PFS was 6.5 and 8.8 months respectively

Fong et al. NEJM, 2009; Fong et al. JCO, 2010; Audet et al. Lancet, 2010; Kaye et al. JCO, 2012

Concept of “BRCAness”

A subset of sporadic ovarian tumors appear to share defects in

homologous recombination (HR) DNA repair with tumors that arise in

BRCA1/2 germline mutation carriers

Such sporadic tumors may behave similarly to those with BRCA germline

mutations and are referred to as having a “BRCAness” phenotype

characterized by:

Heightened sensitivity to platinum analogues and PARP inhibitors

(PARPis)

Improved survival compared to their sporadic counterparts

Turner et al Nat Rev Cancer. 2004 Oct;4(10):814-9

As many as 50% of high

grade serous ovarian

cancers have defective HR

DNA repair pathway

Ovarian Cancer and HR defects

Olaparib in pts with negative or unknown BRCA-status

Agent Design Patients / Dose Results

Olaparib

Phase II, open

label, multicenter,

non randomized

study

17 BRCA-associated EOCs

46 sporadic EOCs

(400mg twice daily)

BRCA-associated EOCs ORR: 41%

(Plat Sens: 60%, Plat Res: 33%)

Sporadic-EOC ORR: 24%

(Plat Sens: 50%, Plat Res: 4%)

Olaparib

Maintenance

Vs

Placebo

Randomized,

double-blind,

placebo-

controlled, phase

2

265 high grade EOC patients

with unknown BRCA-status

who had received two or

more platinum based

regimens and had had a

partial or complete response

to their most recent

platinum-based regimen

136: olaparib 400mg twice

daily

129: placebo

Adverse events with an incidence that was at least 10%

higher in the olaparib group than in the placebo group,

were nausea, fatigue, vomiting, and anemia

A complete response (vs. partial response) to the final

platinum-based therapy was associated with longer

progression-free survival, regardless

of study group

Interim OS analysis no difference between two arms

Biomarkers of BRCAness (Genomic Scars)

Lord et al Nature. 2012;481:287-294

Combinations of PARP inhibitors with other drugs

Combination of PARPis with antiangiogenic drugs

Tentori et al Eur J Cancer 2007; 43:2124-33

Combination of PARPis with PI3K inhibitors

Juvecar et al Cancer Discovery. 2012; 2:1048-63

Development of resistance to PARP inhibitors

1. Secondary mutations in BRCA1-associated tumors

Swisher et al. Cancer Res 2008

2. Secondary mutations in BRCA2-associated tumors

Sakai et al. Nature 2008

3. Loss of 53BP1 in BRCA1-associated tumors

4. Increased expression of p-glycoprotein efflux

transporter mediating multi-drug resistance

Is it possible to use PARPis in patients that have

intact HR or those who have developed resistance to

PARPis?

Evaluation of synergism between 17AAG and olaparib

36M2 w/ Olaparib + 17AAG

0

20

40

60

80

100

120

140

0 5 10 15 20

Olaparib (uM)

Cell V

iabilit

y (%

)

NO 17AAG

0.01uM 17AAG

OVCAR5 w/ Olaparib + 17AAG

0

20

40

60

80

100

120

0 5 10 15 20

Olaparib (uM)

Cell V

iabilit

y (%)

NO 17AAG

0.01uM 17AAG

IC501.

2.IC50

BRCA1 mut / PARPi resistant

CDKN2A loss

CDKN2A loss

CCNE1 amplification

Targeting cell cycle checkpoints

Conclusions (I)

DNA damage repair pathways are frequently deregulated in gynecologic cancers

both as hereditary cancer syndromes as well as sporadic tumors

Defective DNA damage repair offers cancer cells genomic instability that allows

them to break and reform chromosomes, generate new oncogene fusions and

mutations, inactivate tumor suppressor genes, and consequently become more

malignant and progress

At the same time, defective DNA repair pathways provide exciting opportunities

for anticancer therapies (e.g. chemotherapy, XRT, etc)

Conclusions (II)

PARP inhibitors are exciting new drugs that target DNA repair pathways and

have shown promising activity in ovarian cancer

Identifying patients who benefit from PARP inhibitors is an active area of

investigation

Combinations of PARP inhibitors with other drugs may enhance sensitivity and

overcome resistance to these agents

Checkpoint inhibitors are exciting novel agents against ovarian cancer