1. Elżbieta Senkus-Konefka Dept. of Oncology and Radi otherapy , Medical University of Gdańsk, Poland ESO Masterclass 2011 15th century painting in Santa Maria della Grazia in Milan Breast cancer - neoadjuvant therapy and t reatment of metastatic disease

2. Neoadjuvant therapy of breast cancer

5. Efficacy = adjuvant therapy Wolmark, JNCI Monogr 2001, Mauri, JNCI 2005

6. Other outcomes… mastectomy rate Mieog, Br J Surgery 2007

7. no increase in postoperative complications ? less cardiotoxicity and infections Mieog, Br J Surgery 2007

8. but… Mauri, JNCI 2005 less aggressive local therapy after tumor shrinkage due to systemic therapy???

9. more recurrences in patients with „downstaged” vs „preplanned” BCS Mieog, Br J Surgery 2007

10. Who benefits from neoadjuvant treatment? Wolmark, JNCI Monogr 2001

11. Which patients benefit most? Colleoni, BCRT 2009 invasive ductal carcinoma invasive lobular carcinoma

12. Which patients benefit most? Huober, BCRT 2010

13. How important is pCR in relation to other prognostic factors? Liedtke, JCO 2008

14. Can treatment results be improved? von Minckwitz, BCRT 2010 ?correlation with long term outcomes

15. Is chemotherapy indispensable? Semiglazov, Cancer 2007

16. Is chemotherapy indispensable? Semiglazov, Cancer 2007

17. HTH for ER + Targeted therapy MD Anderson study Buzdar , JCO 2005 Trastuzumab weekly x 24 Paclitaxel q3w x 4 FEC x 4 Paclitaxel q3w x 4 FEC x 4 n=23 n=19 Stage II Her2 + IHC 3+ / FISH +

19. NOAH: trastuzumab in the neoadjuvant setting in ErbB2+ LABC Gianni , Lancet 2010 AP P CMF AP P CMF T + P T + CMF T continued R n= 1 15 n=99 n= 1 13 Surgery + RT Surgery + RT Surgery + RT T + AP ErbB2 ( + ) ErbB2 ( - )

20. NOAH: pathological complete response Gianni , Lancet 2010 0 10 20 30 40 50 With H Without H HER2 negative With H Without H HER2 negative Patients, % HER2 positive HER2 positive BREAST ONLY BREAST AND NODES 43% 22% 17% 38% 19% 16% p=0.37 p=0.002 p=0.003 p=0.43

21. NOAH study results (HER2+) Gianni , Lancet 2010 0 6 12 18 24 30 36 Patients Events HR 95% CI p T + C T 1 17 18 0.62 0.34–1.23 0.11 C T 1 18 26 0.25 0.50 0.75 1.00 0.00 Months Patients Events HR 95% CI p T + C T 1 17 36 0.59 0.36–0.85 0.013 C T 1 18 51 0 6 12 18 24 30 36 42 0.25 0.50 0.75 1.00 Overall survival 0.00 Months 42 Event-free survival Probability, EFS Probability, overall survival

22. New targeted agents ↑ pCR -> ??? long term outcome

24. Does pCR translate into long term outcome??? Gianni , Lancet 2010 EFS: HER2 + (without trastuzumab) vs HER2 - NOAH pCR rates 1.00 0.75 0.50 0.25 0.00 0 6 12 18 24 30 36 42 Probability, EFS Months CT, HER2 + CT, HER2 - 0 10 20 30 40 50 With H Without H HER2 - With H Without H HER2 - Patients, % HER2 + HER2 + BREAST ONLY BREAST AND NODES 43% 22% 17% 38% 19% 16% p=0.37 p=0.002 p=0.003 p=0.43

26. Metastatic breast cancer

27. … for metastatic breast cancer there are few approved standards of care…

29. (1) The management of metastatic breast cancer (MBC) is complex; therefore, involvement of all appropriate specialties in a multi/interdisciplinary team (medical, radiation, surgical and imaging oncologists, palliative care, psycho-social, among others) is crucial.

30. Systemic management of breast cancer supportive care chemo- therapy hormono- therapy targeted therapy

31. (2) From the first diagnosis of MBC, patients should be offered personalised appropriate psychosocial, supportive, and symptom-related interventions as a routine part of their care.

32. disease and treatment sequelae antiemetics colony-stimulating factors bisphosophonates analgesics psychotropics

33. (3) Following thorough assessment and confirmation of MBC, the realistic treatment goals must be specified and discussed. Patients and family members should be invited to participate in all decision-making.

35. Management of Advanced Breast Cancer: Efficacy vs Toxicity

36. (4) A small but very important subset of MBC patients, for example, those with a solitary metastatic lesion, can achieve complete remission and a long survival. For these selected patients, a more aggressive and multidisciplinary approach should be considered .

38. Surgery for primary in MBC? 0.67 ND 5179/9197 (56.3%) Khan 2003 0.53 surgery: 26.8 no surgery: 12.6 187/409 (45.7%) Fields 2007 0.5 not reached predicted: 54 82/224 (37%) Babiera 2006 Rao 2008 0.71 surgery: 27.1 no surgery: 16.8 242/395 (61.3%) Blanchard 2008 0.63 surgery: 27 no surgery: 12 4578/9734 (47%) Gnerlich 2007 margin (-): 0.6 margin (+): NS margin (-): 26 margin (+): 17 no surgery: 13 127/300 (42%) Rapiti 2006 margin (-): 0.61 margin (+): 0.75 total mastectomy: 31.9 partial mastectomy: 26.9 no surgery: 19.3 9162/16023 (57.2%) Khan 2002 HR for OS (surgery vs not) median OS (months) N° patients: operated/all (%) Author

39. Surgery for primary in MBC? 0.67 ND 5179/9197 (56.3%) Khan 2003 0.53 surgery: 26.8 no surgery: 12.6 187/409 (45.7%) Fields 2007 0.5 not reached predicted: 54 82/224 (37%) Babiera 2006 Rao 2008 0.71 surgery: 27.1 no surgery: 16.8 242/395 (61.3%) Blanchard 2008 0.63 surgery: 27* no surgery: 12* 4578/9734 (47%) Gnerlich 2007 margin (-): 0.6 margin (+): NS margin (-): 26* margin (+): 17* no surgery: 13* 127/300 (42%) Rapiti 2006 margin (-): 0.61 margin (+): 0.75 total mastectomy: 31.9 partial mastectomy: 26.9 no surgery: 19.3 9162/16023 (57.2%) Khan 2002 HR for OS (surgery vs not) median OS (months) N° patients: operated/all (%) Author

40. Surgery for primary in MBC? Rapiti, JCO 2006 only selection bias?

42. (5) Minimal staging work-up for MBC includes a history and physical examination, complete haematology and biochemistry, and imaging of the chest, abdomen and bone.

43. (5) – contd. The clinical value of tumour markers is not well established for diagnosis or follow-up; however, their use as an aid to evaluate response to treatment, particularly in patients with nonmeasurable disease, is acceptable.

44. Should we rebiopsy the tumor? Liedtke, Ann Oncol 2009

45. Should we rebiopsy the tumor? Liedtke, Ann Oncol 2009, Wilking 2011 biology or suboptimal treatment???

47. systemic treatment of breast cancer previous treatments anthracycline dose taxane use late sequelae tumor organ involvement biology tumor bulk patient age performance status co-morbidities clinical trial ? treatment toxicity efficacy preference impact on QoL Optimal treatment choice DFI cardiac damage

48. (7) Endocrine therapy is the preferred option for hormonal receptor-positive disease, unless there is concern or proof of endocrine resistance. Endocrine therapy of breast cancer is a very old targeted treatment…

50. The optimal first-line hormonal treatment for postmenopausal patients is an aromatase inhibitor ; however, tamoxifen remains a viable option. Optimal post-aromatase inhibitor treatment is uncertain, but tamoxifen , fulvestrant or a different aromatase inhibitor are possible options .

52. (8) Trastuzumab should be offered early to all HER-2-positive MBC patients, either combined with chemo or endocrine therapy or as a single agent .

53. Trastuzumab + chemotherapy Slamon, NEJM 2001 H0648g study probability of survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 25.4 20.3 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 trastuzumab + ChT ChT p=0.025 overall survival ( mths ) 5,1 mths

54. Trastuzumab + chemotherapy DFS Marty , J Clin Oncol. 2005 overall survival M77001 study Docetaxel + trastuzumab Docetaxel alone/crossover Docetaxel alone Estimated probability 1.0 0.8 0.6 0.4 0.2 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months 19.1 31.2 24.5 Estimated probability Months 6.1 11.7 Docetaxel + trastuzumab Docetaxel 0 0.2 0.4 0.6 0.8 1.0 0 3 6 9 12 15 18 21 24 27 30 33 36 p=0.0001 5,6 mths 12,1 mths

55. Trastuzumab + chemotherapy – subgroup analysis Marty, JCO 2005 M77001 study 0.1 1 10 100 Docetaxel better Trastuzumab + docetaxel better no difference Whole patient population Measurable disease and IHC 3+/FISH positive No previous anthracyclines Previous anthracyclines Age <50 years Age  50 years <24 months disease-free interval  24 months disease-free interval 1–2 metastatic organ sites >2 metastatic organ sites Visceral (lung or liver) metastases Non-visceral metastases ER and/or PgR positive ER and PgR negative/unknown ECOG performance status 0 ECOG performance status  1

56. time-to-progression Di Leo, ASCO 2007 Lapatinib – I line treatment p=0.007

57. overall survival Lapatinib – I line treatment Di Leo, ASCO 2007

58. Anti-HER2 therapy in combination with endocrine therapy is superior to endocrine therapy alone for HER-2 positive/ER positive disease .

59. ER – HER2 crosstalk Arpino , Endocr Rev 2008

60. 73 / 104 patients (70%) were crossed-over to trastuzumab on progression 0.4 PFS Mackey, SABCS 2006 Trastuzumab + hormonotherapy TAnDEM study months 0 5 10 15 20 25 30 35 40 45 50 55 60 overall survival p 0.325 Median OS 28.5 mths 23.9 mths 1.0 0.8 0.6 0.2 0.0 4.6 mths 2.4 mths 1.0 0.8 0.6 0.4 0.2 0 5 10 15 20 25 30 35 40 45 50 55 60 p 0.0016 Median PFS 4.8 mths 2.4 mths 0.0 HR 0.63 months

61. Trastuzumab + hormonotherapy Overall survival for patients on T + A vs A, excluding patients who crossed over to T Kaufman, JCO 2009

62. Lapatinib + letrozole Johnston , JCO 2009 HR-positive, HER2-positive patients PFS overall survival

63. Lapatinib + letrozole Johnston , JCO 2009 HER2(–) patients with <6 months since discontinuation of adjuvant tamoxifen

64. Patients progressing on an anti-HER-2 therapy combined with a cytotoxic agent should be offered a second combination of agents since it is important to keep blocking the HER-2 pathway in these tumours. Lapatinib combined with a cytotoxic agent is a viable option for patients progressing on trastuzumab .

65. GBG-26 Von Minckwitz, JCO 2009 Continuing trastuzumab beyond progression… capecitabine + trastuzumab (n=78) MBC HER2 + progressing on trastuzumab capecitabine (n=78) R

66. Continuing trastuzumab beyond progression… 54.0% 75.3% 27.0% 48.0% CR + PR p = 0.011 clinical benefit p = 0.0068 Von Minckwitz, JCO 2009

67. Von Minckwitz, JCO 2009 Continuing trastuzumab beyond progression… PFS 40 0 0.0 0.2 1.0 0.8 0.6 0.4 10 20 30 HR=0.69 p=0.015 8.2 5.6 capecitabine + trastuzumab (n=78) capecitabine (n=78) 20.4 40 0 0.0 0.2 1.0 0.8 0.6 0.4 10 20 30 HR=0.76 p=0.26 + + + + + + + + + + + + + 25.5 overall survival

69. Targets for anti-HER2 compounds trastuzumab lapatinib

70. Lapatinib – active in p95 ErbB2 (+) tumors Scaltriti , J NCI 2007

71. Scaltriti, Clin Cancer Research 2010 Lapatinib – active in p95 ErbB2 (+) tumors Lapatinib +capecitabine

72. EGF100151 Cameron, BCRT 2008 , Oncologist 2010 Lapatinib – post trastuzumab failure overall survival (weeks) time-to-progression (weeks)

73. PFS ( weeks ) Blackwell, JCO 2010 Combining targeted therapies…

74. Combining targeted therapies… Blackwell, JCO 2010 OS ( weeks )

75. (9) Both combination and sequential single agent monotherapy are reasonable first-line chemotherapy options. I n the absence of rapid clinical progression, life-threatening visceral metastases, or the need for rapid symptom and/or disease control sequential monotherapy i s the preferred choice in MBC.

76. (9) – contd. Patient- and disease-related factors should be used to choose between combination and sequential single-agent chemotherapy for MBC. Duration of each regimen and number of regimens should be tailored to each individual patient. Efficacy Toxicity

77. Median PFS/TTP (mths) Combination vs single agent? Pacilio 2006 9 months 0 2 4 6 8 10 Mu-oz 2006 Zielinski 2005 Albain 2004 O’Shaughnessy 2002 Jassem 2001 Mu-oz 2006 Seidman 2004 Chan 1999 Chan 1999 ET Gem + Vin Flu + Epi GT TX AT Vinorelbine Paclitaxel Doxorubicin Docetaxel

78. Combination vs single agent? m edian OS (mths) O’Shaughnessy 2002 Melemed 2007 Sledge 2003 Seidman 2004 Jones 2005 24 months 0 5 10 15 25 30 20 paclitaxel q3w paclitaxel q1w TX GT docetaxel

80. Combination vs single agent? randomized studies with planned cross-over Cardoso, JNCI 2009

83. Duration of chemotherapy Gennari, ESMO 2010

84. (10) There are few proven standards of care in MBC management. Therefore, inclusion of patients in well-designed, independent, prospective randomised trials must be a priority whenever available. Every proposed option must have a sound scientific rationale, preferably evidence-based.

85. (11) The medical community is aware of the problems raised by the cost of MBC treatment. Balanced decisions should be made in all instances, but the patient’s well-being, length and quality of life must always be the main decision factors.

87. Bewacizumab Miller, NEJM 200 7 E2100 – overall survival no effect on survival!!! Months 1.0 0.8 0.6 0.4 0.2 0 HR=0.869 Log-rank test: p=0.1374 Paclitaxel + Avastin: median OS 26.5 months Paclitaxel: median OS 24.8 months OS estimate 0 6 12 18 24 30 36 42 48 54 60

88. Bewacizumab AVADO – progression free survival Mile s , ASCO 2008 BEV 7.5 mg/kg BEV 15 mg/kg Median 8.0 vs 8.7 mths HR 0 .79 (.63–.98) P = .0318 Mos PFS estimate 0 0.2 0.4 0.6 0.8 1.0 0 6 12 18 HR 0 .72 (.57–.90) P = .0036 Mos PFS estimate 0 0.2 0.4 0.6 0.8 1.0 0 6 12 18 Bev + Docetaxel (n = 248) Placebo + Docetaxel (n = 241) Median 8.0 vs 8.8 mths

89. (12) Formal (not just informal) quality of life assessments provide useful information and should be encouraged. If collected, such information should be integrated with that from clinic assessments to allow management decisions on initiating, changing, or stopping drug therapy.

90. Difficult issues triple-negative breast cancer

91. Inhomogenous disease „ triple negative” BC basal-like BC BRCA1 -related BC no single treatment is going to be effective high-grade ductal Ca metaplastic Ca apocrine Ca secretory Ca adenoid cystic Ca myoepithelial Ca medullary Ca high-grade lobular Ca neuroendocrine Ca

97. Byrski, JCO 2010 Neoadjuvant treatment of 102 consecutive BRCA1 (+) breast cancer pts 83% 10 12 Cisplatin 8% 2 25 AT 21% 6 28 FAC 22% 5 23 AC 7% 1 14 CMF % pCR No of pCR No treated Regimen

100. PARP-inhibitors O’Shaughnessy , NEJM 2011 „ triple negative„ BC 0–2 prior chemotherapy regimens for MBC

102. Thank you for your attention