(1) Neoadjuvant therapy for breast cancer can improve operability and allow for breast-conserving surgery, though some studies have found higher recurrence rates in patients who undergo less aggressive local therapy after tumor shrinkage from neoadjuvant treatment. (2) The NOAH study found that adding trastuzumab to neoadjuvant chemotherapy significantly improved pathological complete response rates and event-free survival in HER2-positive breast cancer compared to chemotherapy alone. (3) Multiple studies have found a survival benefit for surgery in selected metastatic breast cancer patients, such as those with a solitary metastasis or intact primary tumor, suggesting a more aggressive multidisciplinary approach may be warranted in these cases.

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

3. POSSIBLE Earlier treatment of distant micrometastases In vivo sensitivity test of systemic agents Improvement of survival vs. local therapy alone PROVEN Improved operability rates of initially inoperable tumors Improved rates of breast-conserving surgery Translational correlative studies POSSIBLE DISADVANTAGES T umour progression i f no response to systemic therapy Loss of pathological prognostic information ADVANTAGES

4. Candidates for neoadjuvant therapy LOCALLY ADVANCED or INFLAMMATORY BC „ LARGE” OPERABLE BC Primary systemic therapy = treatment of choice Primary systemic therapy = option

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 +

18. Targeted therapy MD Anderson study pCR DFS Buzdar , JCO 2005, Clin Cancer Res 2007

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

23. Meaning of pCR surrogate for cure? selection of best prognosis patients? will higher pCR rate translate into improved 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

25. NSABP B-27 Does pCR translate into long term outcome??? Rastogi, JCO 20 08 pCR rate DFS overall survival

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.

34. Primary goals in the treatment of MBC Maintenance of quality of life and function Reduction of cancer related symptoms and complications Prolongation of survival

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 .

37. Is MBC curable? RATIONALE: in the era of improved systemic control with new therapies a removal of intact primary or oligometastatic foci may prevent further tumor spread and allow for long-term disease control

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?

41. Resection of metastases? 467 cases of the international registry of lung metastases Friedel , Eur J Cardio-Thor Surg 2002

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???

46. (6) Treatment choice should take into account: endocrine responsiveness, HER-2 status, menopausal status, disease-free interval, previous therapies and response obtained, tumour burden (defined as number and site of metastases), biological age and co-morbidities (including organ dysfunctions), performance status, need for rapid disease/symptom control, socio-economic and psychological factors, patient’s preference and available therapies in the patient’s country (this list is not exhaustive).

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…

49. For pre-menopausal women, tamoxifen combined with ovarian suppression/ablation is the first choice except for tamoxifen-resistant tumors.

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 .

51. Maintenance of hormonal treatment after chemotherapy is not established, but is reasonable. Concomitant chemo + endocrine therapy should be discouraged.

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

68. Trastuzumab resistance p95 ErbB2 ~ 30% HER2 (+) breast cancers

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

79. Combination vs single agent? E1193 Sledge, JCO 2003 doxorubicin vs paclitaxel vs doxo + paclitaxel time to treatment failure p=0.011 overall survival p=0.77

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

81. Optimal therapy choice? monotherapy slow natural history older age poor PS patient’s choice (continuing to work, etc.) combination chemotherapy rapid progression need for rapid symptom control visceral involvement good PS

82. in the past Chemotherapy – paradigm change now progression progression progression

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.

86. Bewacizumab E2100 – progression free survival Miller, NEJM 200 7 0 20 40 60 80 100 Time (months) Progression-free survival estimate 0 10 20 30 40 6.7 13.3 HR=0.48; p<0.0001 99% increase in median PFS Median PFS (months) 15 10 5 0 Avastin + paclitaxel Paclitaxel Paclitaxel (n=354) Avastin + paclitaxel (n=368)

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

92. Choice of ChT anthracyclines? theory – ideal compounds frequent overexpression of Topo II  BRCA mutation/dysfunction -> aberrant DNA repair

93. Anthracyclines? clinical data conflicting Di Leo, SABCS 2008, Cheang , ASCO 2009 NCIC-CTG MA5 A better CMF better HER2 amplified Triple negative Highly horm-sensitive Moderately horm-sensitive Metaanalysis British Columbia population-based

94. Choice of ChT taxanes? theory 80% of TNBC are p53 mutant – potential benefit of taxanes?

95. Taxanes? clinical data conflicting Hayes, NEJM 2007, Ellis, Lancet 2009 CALGB 9344 all patients N+ patients TACT DFS

96. Choice of ChT platinum? theory platinum -> double strand DNA damage TNBC - deficiency in BRCA associated DNA repair

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

98. Platinum in TNBC few prospective data exist metronomic cyclophosphamide and methotrexate ± cisplatin in anthracycline and taxane pretreated TNBC pts Bhattacharyya, ECCO 2009 12 months 16 months OS 7 months 13 months PFS 30 % 62% RR no cisplatin cisplatin

99. synthetic lethality PARP-inhibitors Wild BRCA DNA damage BRCA PARP DNA repair DNA damage BRCA PARP DNA repair Inactive BRCA Wild BRCA DNA damage BRCA PARP DNA repair DNA damage BRCA PARP Inactive BRCA cell death

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

102. Thank you for your attention