1. 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

2. 1. Defective DNA repair pathways in gynecologic cancers

4. DNA Damage Repair Pathways
Aziz et al. / Pharmacology & Therapeutics 133 (2012) 334–350

5. Homologous Recombination DNA Repair Pathway

6. 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)

7. Ovarian Cancer and HR defects
As many as 50% of high grade serous ovarian cancers have defective HR DNA repair pathway

8. Fingerprint of HR pathway alterations in ovarian cancer
Cancer Genome Atlas Research Network.
Nature, 2011 Jun 29;474(7353):609-15

9. Platinum damage and DNA repair
Cisplatin
Intrastrand Interstrand
cross-links
Nucleotide Excision Repair (NER)
Homologous Recombination
(HR)

10. NER pathway alterations
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.

11. Mismatch Repair Pathway

12. 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

13. Risks of uterine and ovarian cancer in Lynch syndrome

14. 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

15. 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

16. 2. Targeting defective DNA repair pathways in gynecologic cancers

17. Development of PARP inhibitors

18. 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

19. Synthetic lethality between HR and BER
HR pathway BER pathway

20. Base Excision Repair (BER)

21. PARP-inhibitors (Synthetic Lethality)

22. Selected trials of olaparib in BRCA carriers in EOC
Agent
Design
Patients
Results
Olaparib
Phase I
15 BRCA carriers
8/15 (53%) had objective response per RECIST criteria and 1 had stable disease for 6 months
50 BRCA carriers
40% ORR and/or CA125 (>50% decline)
Clinical benefit in platinum-sensitive, resistant, and refractory subgroups (69%, 45%, and 23%, respectively)
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
versus
Doxil
Randomized Phase II
97 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

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

24. Ovarian Cancer and HR defects
As many as 50% of high grade serous ovarian cancers have defective HR DNA repair pathway

25. 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%)
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

26. Biomarkers of BRCAness (Genomic Scars)
Lord et al Nature. 2012;481:

27. Combinations of PARP inhibitors with other drugs

28. Combination of PARPis with antiangiogenic drugs
Tentori et al Eur J Cancer 2007; 43:

30. Combination of PARPis with PI3K inhibitors
Juvecar et al Cancer Discovery. 2012; 2:

32. Development of resistance to PARP inhibitors

33. 1. Secondary mutations in BRCA1-associated tumors
Swisher et al. Cancer Res 2008

34. 2. Secondary mutations in BRCA2-associated tumors
Sakai et al. Nature 2008

35. 3. Loss of 53BP1 in BRCA1-associated tumors
4. Increased expression of p-glycoprotein efflux transporter mediating multi-drug resistance

36. Is it possible to use PARPis in patients that have intact HR or those who have developed resistance to PARPis?

37. Evaluation of synergism between 17AAG and olaparib

38. 1.
IC50 2.
IC50

40. BRCA1 mut / PARPi resistant
CDKN2A loss
CDKN2A loss
CCNE1 amplification

41. Targeting cell cycle checkpoints

47. 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)

48. 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