1. TRIPLE NEGATIVE BREAST CANCER: an overview 10 th ESO-ESMO Masterclass in Clinical Oncology 2-7 April 2011, Ermatingen (Lake Constance), Switzerland Joseph Gligorov, MD APHP Tenon

3. Find a drug before I have breasts

6. Breast Cancer Biology Key Dates 1970s 1980s 1990s

12. Algorithm for HER2 and/or HER2 testing by IHC and/or FISH Wolff AC et al. JCO 2007

15. Caveats 3: molecular ≠ pathological ≠ clinical definition « Basal-like » cancers are associated with bad prognosis and are frequently ER and HER2 negative: Triple negative ?

16. Correspondence between Molecular Class and Clinicopathological Features of Breast Cancer Sotiriou V, Pusztai L. NEJM 2009

17. BRCA1 downregulation High histological grade Medullary histological type Basal-like immunophenotype TN Hanneman et al EBCC6

18. TNBC overlaps with BLBC a subgroup that expresses cytokeratins and other non-luminal (basal) genes. Breast cancers occurring in patients with germline BRCA1 mutations are often TNBC & BLBC, bringing the hypothesis that BRCA1 defects or deficiency may be involved in sporadic TNBC and BLBC Carey L et al. Nat Rev Clin Oncol 2010

20. Clinical-pathological characteristics of the current intrinsic subtypes of breast cancer Prat A, Perou CM. Molecular Oncology 2011

21. Intrinsic subtype distribution within the triple-negative tumor category shown with and without Claudin-low tumors. Prat A, Perou CM. Molecular Oncology 2011

23. Part of prognosis is always driven by pathology Basal-like and Triple Negative Breast Cancers High grade tumours Medullary breast cancer Metaplastic breast cancer Grade 3 – IDC-NST Low grade tumours Secretory carcinoma Adenoid cystic carcinoma Courtesy F Penault LLorca

24. Natural Histoty & Prognosis Prat A, Perou CM. Molecular Oncology 2011

25. Characteristics of triple-negative versus other breast cancers Dent R et al. Clin Canc Res 2007

26. Tumor size by nodal status in the triple-negative and other groups Dent R et al. Clin Canc Res 2007 Method of breast cancer detection in the triple-negative and other groups

27. Local Reccurence, Distant Reccurence and Death HRs in the TNBC group compared with the other group Dent R et al. Clin Canc Res 2007

29. Local Reccurence, Distant Reccurence and Death HRs in the TNBC group compared with the other group Dent R et al. Clin Canc Res 2007

30. Rates of distant recurrences and breast-specific survival in TNBC and other breast cancers. RFS OS Dent R et al. Clin Canc Res 2007

31. Rates of distant recurrences following surgery in triple-negative and other breast cancers. Dent R et al. Clin Canc Res 2007

35. Local Reccurence, Distant Reccurence and Death HRs in the TNBC group compared with the other group Dent R et al. Clin Canc Res 2007

38. There are limited single-arm prospective data for certain patient populations regarding the use of accelerated partial breast irradiation, including those with negative ES receptor satus.

39. Natural Histoty & Prognosis Prat A, Perou CM. Molecular Oncology 2011

41. pCR and OS relationship Rastogi P et al. JCO 2008 NSABP B18 NSABP B27

42. Liedtke C et al. JCO 2008 pCR and OS relationship in TNBC

47. Importance of Alkylating agents for TNBC MA5 Study - 710 patients - CMF vs CEF The interaction between basal status and treatment is borderline significant (p=0.06) Test of main hypothesis: comparison of overall survival in core basal patients versus all other subtypes in MA5, stratified by treatment arm Evaluation immunohistochimique de ER, PR, HER2, Ki67, CK5/6, EGFR Cheang M et al. ASCO 2009 Biological subtype and treatments N 5-Year OS (95% CI) P-value Hazard ratio (95% CI) Log-rank Wilcoxon CEF Core basal 35 51% (35-68) 0.02 0.002 1.84 (1.09-3.11) All others 209 80% (74-85) CMF Core basal 35 71% (56-86) 0.72 0.74 0.90 (0.50-1.60) All others 232 71% (64-76)

51. TNBC platin compounds – refractory patients 1 Baselga et al. ESMO 2010; 2 O ’ Shaughnessy et al. ESMO 2010; 3 Carey et al. ASCO 2008 Study Platin arm Doses N First line ORR (%) PFS BALI-1 1 Cisplatin 75 mg/m 2 q3w 58 73% 6 (10.3%) 1.5 months BSI-201 2 Carbo - Gem AUC 2 d1, 8 q3w 1000 mg/m 2 d1, 8 62 60% 20 (32,2%) 3.6 months TBCRC-001 3 Carbo – Cetuximab AUC 2 d1, 8, 15 q4w 71 46% 13 (18%) 2.0 months

52. Docetaxel RFS : meta-analyis Laporte S. et al, SABCS 2009

53. et al.

54. et al.

56. FINXX TRIAL Time to any recurrence: Patients with triple-negative cancer (n=202) HR = 0.43 (p = 0.024) 95% CI 0.21 – 0.90 HR: 0.43, 95% CI 0.21–0.90 P = 0.024 TX + CEX, n=93 T + CEF, n=109 Courtesy H Joensuu

60. « Targeted » therapies Gluz O et al. Ann Oncol 2009

62. Antiangiogenic drugs: Bevacizumab meta-analysis O’Shaugnessy J et al. ASCO 2010

63. Miles D et al. ESMO 2010

64. Structural and Functional characteristics of PARP1 Rouleau et al. Nat Rev Cancer 2010 10- to 500-fold increase in PARP1 activity PARP1 is active in a homodimeric form The dense negative charge of pADPr succeeds has the loss of affinity of PARP1 for DNA and allowes the recruitement of repair proteins

66. Strategies to target PARP1 ionizing radiation DNA-methylating agents NAD + Catalytic inhibition Nicotinamide

67. Strategies to target PARP1 ionizing radiation DNA-methylating agents Catalytic inhibition Other PARPs Mono-ADP-ribosyl-transferase Sirtuins … NAD + Nicotinamide

68. Strategies to target PARP1 ionizing radiation DNA-methylating agents PARP activity must be inhibited by > 90% to detectably impair DNA repair

69. Clinical development approaches of PARP inhibitors Targeting cells genetically predisposed to die when PARP activity is lost Combining PARP inhibitors with DNA-damaging agents

70. Targeting cells genetically predisposed to die when PARP activity is lost

73. Perspectives Rouleau et al. Nat Rev Cancer 2010; 10: 293-301. Underhill C et al. Ann Oncol 2010; Epub of a print. > 30 ongoing clinical trials with PARPi & DNA-damaging agents > 10 ongoing clinical trials with PARPi alone > 10 ongoing clinical trials with PARPi alone > 10 ongoing clinical trials with PARPi & DNA-damaging agents Unselected Population BRCA mutant BRCAness

75. P ersonalizing C ancer C are

76. I Bergman The 7th Seal

77. The complexity of TNBC treatment strategies Thanks