1. Highlights in the management of breast cancer How to improve the outcome of Triple-Negative Breast Cancer Claudia Bighin IRCSS – AOU S. Martino – IST Genova

2. «From benchside to bedside»

3. Bed-side

7. Dissecting the Heterogeneity of TNBC Metzger-Filho et al, JCO 2012 CK5/6, CK17

9. Lips et al, BJC 2013 76% of the TNBC had a BRCA1-like aCGH profile

12. Good news from earlier stages?

13. Cheang et al, ASCO 2009

16. A-based vs CMF according to molecular subgroup (meta-analysis of 4 phase III trials) 1 0.820.83 1.06 0.77* 0.67 *Triple negative disease A-based vs CMF HR: 0.77 95% CI 0.54-1.09 P value = 0.13 CMF A-based Di Leo et al, Lancet Oncol 2011

18. TNBC/Basal-likeHER2 + Luminal BLuminal A Hugh J et al. JCO 2009

19. Future perspective Joensuu et al, Ann Oncol 2012

20. SABCS 2012

23. pCR predicts favourable outcome in TNBC Liedtke C, et al. J Clin Oncol 2008 pCR rates RegimensTNBCNon- TNBC FAC/FEC/AC20%5% TFAC/TFEC28%17% Single agent Taxane 12%2% The Paradox of higher sensitivity to neoadjuvant chemotherapy in poor prognosis subtype (TNBC) is explained by the high relapse among pts with residual disease

24. TNBC and pCR von Minckwitz et al, JCO 2012

25. Ongoing neoadjuvant trial von Minckwitz et al, Ann Oncol 2012

26. Bevacizumab

27. von Minckwitz et al, NEJM 2012

28. Bear et al, NEJM 2012

29. Phase II study: FEC  wPaclitaxel + Bevacizumab Clavarezza et al, The Breast 2013 (in press)

30. ASCO 2013 Breast Cancer Oral Session Abstract #1003 – PrECOG 0105: Final efficacy results from a phase II study of gemcitabine (G) and carboplatin (C) plus iniparib (BSI-201) as neoadjuvant therapy for triple- negative (TN) and BRCA1/2 mutation-associated breast cancer. (Melinda L. Telli) Abstract #1004 – A randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple- negative and HER2-positive early breast cancer (GeparSixto). (Gunter Von Minckwitz)

32. Median survival with distant metastases Luminal A: 2.2 yrs Luminal B: 1.6 yrs Luminal/HER2: 1.3 yrs HER2 enriched:0.7 yrs Basal-like:0.5 yrs 3,732 EBC diagnosed between 1986-1992 Basal-like treated with adj CT: 48%

33. TNBC: Annual Hazard Rate of Distant Recurrence Dent R, et al. Clin Cancer Res 2007 Peak of recurrence TN: 1 to 3 years Non-TN: steady risk over time

34. Foulkes et al, NEJM 2010

35. Re-biospy?

36. Cardoso et al, The Breast 2012

37. TNBC: “…Cytotoxic chemotherapy remains the mainstay of treatment in this group…» Cardoso et al, Ann Oncol 2012

38. Newly approved drugs in TNBC AgentPhase trialTNBC ptsSettingResults Ixabepilone 1 III433+ CapeSuperior ORR and PFS ORR: 31% vs 15% PFS: 4,2 mo vs 1,7 mo Bevacizumab 2 III (ECOG2100, AVADO, RIBBON) 621+ CTSuperior ORR and PFS ORR: 42% vs 23% PFS: 8,1 mo vs 5,4 mo OS: 18,9 mo vs 17,5 mo Eribulin 3 III144Mono vs TPC Superior OS HR=0,71 1 Rugo, SABCS 2008 2 O'Shaughnessy, ASCO 2011 3 Twelves, ESMO 2010

39. Targeted therapies

40. BALI-1 Trial Baselga, SABCS 2010

41. The difference between the arms was not significant (p=0.11) and the ORR in the cetuximab plus cisplatin arm did not exceed 20% (p=0.50; one-sided Z-test with a significance level of alpha/2=0.05), therefore the simultaneous null hypothesis could not be rejected. Baselga, SABCS 2010

43. Carey et al, JCO 2012 ORR < 20%

44. Targeted therapies

45. Tutt et al, Lancet 2010

47. O'Shaughnessy et al, NEJM 2011

48. [TITLE] ORR 30 vs 34% O'Shaughnessy et al, ASCO 2011

49. [TITLE] O'Shaughnessy et al, ASCO 2011

50. Chuang et al, BCRT 2012 Olaparib Iniparib

52. Can we find the Achille heel of TNBC?

53. Can we sub-classify TNBC? Pietenpol, SABCS 2012

56. Subtypes Characteristics SubtypeGene OntologyIHC analysis Hysto typePossible sensitivity Basal-like 1Cell cycle and cell division DNA damage response High Ki67--Cisplatin PARP-Inhibitors Basal-like 2Growth gactor signaling (EGFR, MET) --MedullaryAnti-EGFR Immuno- modulatory Immune cell processes-- Mesenchymal- like Cell motility and cell differentation (TGF-β, Src); GF patways -- Metaplastic PI3K-mTOR Inh (BEZ235) Src-Inhibitors (Dasatinib) Mesenchymal Stem-like Angiogenesis Low levels prolif genes Claudin-low --Anti-angio Luminal ARHormonally regulated pathways AR +Molecular Apocrine AR antagonist Lehmann et al, J Clin Inv 2011

57. TNBC subtypes differ in RFS RFS decreased in LAR subtype compared with BL-1, IM and MSL (p<0,005) Better RFS in BL-1 Lehmann et al, J Clin Inv 2011

58. Pietenpol, SABCS 2012

60. Shah et al, Nature 2012

61. Pietenpol, SABCS 2012

62. AR positive AR negative

63. West et al, BMJ 2013

64. ASCO 2013 Poster Discussion Session Abstract #1010 – Next-generation sequencing to find predictors for chemotherapy response in triple-negative breast cancer (TNBC). (Esther H. Lips) Abstract #1011 – Molecular identification of basal-like breast cancer through genomic analyses across five cancer types. (Aleix Prat) Abstract #1012 – NFKBIA deletion in triple-negative breast cancer. (Markus Bredel)

65. Aparicio, SABCS 2012

66. How to improve the outcome of TNBC?...at bedside Adjuvant setting – Anthra plus Taxanes Neoadjuvant setting – Anthra plus Taxanes Metastatic setting – Re-biospy – Bevacizumab – Platinum salts – Eribulin CLINICAL TRIALS!!!