1. Medical Oncology Training Program Resident Teaching Friday January 7th, 2011 @ PMH, 5-223 Locally Advanced and Inflammatory Breast Cancer Eitan Amir Medical Oncology Princess Margaret Hospital

2. Challenges/Objectives in the Management of Locally Advanced Breast Cancer Surgical oncology Who to send for preoperative therapy? Role of breast conservation Role of SLN surgery Surgery on relapse Medical oncology What drugs to give for preoperative therapy? How can we improve response rates? What to give on relapse? Radiation oncology Combined chemo-rads? Role of breast conservation Radiotherapy for inoperable/progressive disease despite NAT Radiotherapy on relapse

3. What is LABC? LABC –10 -15% of all new Breast Cancers Prognosis is poor –local recurrence –systemic relapse –overall survival –15 yr OS 20% IBC, 40% NIBC

4. Inoperable Improve surgical options Deliver adequate “adjuvant” chemotherapy Provide in vivo anti- tumour assessment Assess surrogate biologic endpoints for response & survival GoalOperable What are the indications for neoadjuvant therapy?

5. What is the current systemic treatment standard? Challenges in the Management of LABC

6. Clinical response and pathologic response are currently used as a surrogate of survival and as a tool to compare chemotherapy regimens % Surviving Years after Surgery TRTNDeaths Non pCR1899396 pCR40931 HR=0.33 p<0.0001 NSABP B-27: Overall Survival - pCR vs. non-pCR patients (Bear JCO 2003)

7. Operable Breast Cancer Stratification Age Age Clinical Tumor Size Clinical Tumor Size Clinical Nodal Status Clinical Nodal Status Operation + TAM if >50 yrs AC x 4 + TAM if >50 yrs. AC x 4 Operation Operable Breast Cancer: NSABP B-18 No difference in DFS and OS Lumpectomy Rates 60% vs 68% Preop AC cCR pCR 36% 13%

8. 0 20% 40% 60% 80% 100% 2468 Year P=0.00005 pINV cPR cNR pCR 2468 pINV cPR cNR pCR P=0.0008 Wolmark N: CDC, 2000 Clinical response predicts overall survival Pathologic response predicts overall survival Pathologic response predicts overall survival Neoadjuvant therapy - Operable Breast Cancer B-18 DFS by responseB-18 OS by response

9. B-27 Schema (n=2,411) Operable Breast Cancer Randomization AC x 4 Tam X 5 Yrs AC x 4 Tam X 5 Yrs AC x 4 Tam X 5 Yrs Surgery Docetaxel x 4 Surgery Surgery

10. B-27 Pathologic Response (pCR) in Breast P < 0.001 AC Docetaxel (718 pts) AC (1,492 pts) 3.9% 9.8% No Tumor Non-Invasive 6.9% 18.7% 13.7% 25.6% 20% 10% 0 30%

11. B-27: Nodal Down-staging Rastogi P, et al. J Clin Oncol 2008;26:778-85

12. EORTC-NCIC-SAKK Multi-centre Trial in LABC: Patient Population (n = 448) –40% T4a-c –45% T4d –Locoregional treatment variable RANDOMIZATIONRANDOMIZATIONRANDOMIZATIONRANDOMIZATION C 75 mg/m 2 po q d days 1–14 E 60 mg/m 2 IV days 1 and 8 q 4 wk x 6 F 500 mg/m 2 IV days 1 and 8 E 120 mg/m 2 IV day 1 q 2 wk x 6 C 830 mg/m 2 IV days 1 with G-CSF day 2-13 Therasse P et al. J Clin Oncol 2003;21:843-50

13. Adapted from Therasse P, et al. J Clin Oncol 2003;21:843-50 In exploratory analysis: DFS worse in IBC (median 23.5 m) vs LABC (median 44 m)

16. Current “standard” neoadjuvant chemotherapy regimens: anthracycline & taxane combination – Her2 neg RegimenTrial pCR (%) Anthracycline (adriamycin / epirubicin)15 Anthracycline plus taxane (taxol or taxotere) 28

17. What is the “standard” Her2- at PMH? AC-T (dose dense)8 (16%) FEC-D38 (79%) Endocrine2 (4%) In Ontario: AC-taxotere FEC-taxotere Dose dense AC-Taxol

18. Breast Cancer Biological Subtypes as Predictive Subtypes

19. NOAH: the largest neoadjuvant trial in HER2-positive breast cancer a Hormone receptor-positive patients receive adjuvant tamoxifen; LABC, locally advanced breast cancer; H, trastuzumab (8 mg/kg loading then 6 mg/kg); AT, doxorubicin (60 mg/m 2 ), paclitaxel (150 mg/m 2 ); T, paclitaxel (175 mg/m 2 ); CMF, cyclophosphamide, methotrexate, fluorouracil HER2-positive LABC (IHC 3+ and / or FISH+) n=113 H + AT q3w x 3 H + T q3w x 4 H q3w x 4 + CMF q4w x 3 Surgery followed by radiotherapy a H continued q3w to Week 52 T q3w x 4 CMF q4w x 3 Surgery followed by radiotherapy a n=115 AT q3w x 3 T q3w x 4 CMF q4w x 3 Surgery followed by radiotherapy a n=99 HER2-negative LABC (IHC 0/1+)

20. Patient characteristics HER2-negative IBC, % Total pop IBC pop (n=99) (n=14) ER, oestrogen receptor; PgR, progesterone receptor Characteristic 43 5750 64 36 29 50 21 100 0 Age group <50 years >50 years Menopausal status Pre Post Hormonal receptors ER+ and / or PgR+ Both negative Axillary nodes N0 N1 N2 Ipsilateral supraclavicular nodes No Yes HER2-positive IBC, % -H Total pop IBC pop (n=113) (n=31) +H Total pop IBC pop (n=115) (n=31) 42 5850 35 65 16 47 37 96 4 32 68 55 45 16 84 19 55 26 90 10 46 54 52 48 35 65 13 44 43 94 6 55 45 42 58 23 77 26 52 23 100 0 51 49 55 45 64 36 17 38 44 96 4

21. Significant improvement of pCR in IBC by adding trastuzumab +H-H Patients (%) HER2 negative +HHER2 negative -H p=0.004 p=0.002 HER2 positive tpCRpCR 4 (29%) 6 (19%) 17 (55%) 4 (29%) 4 (13%) 15 (48%) p=0.49 p=0.20 eradication of invasive cancer in the breast eradication of invasive cancer in the breast plus axillary nodes

23. Good cardiac safety profile No change (LVEF >55%) Absolute decrease >10-<20% Absolute decrease >20% CHF responsive to treatment +H (n=31) 77 23 0 -H (n=31) 84 13 3 0 86 14 0 HER2-positive IBC, % CHF, congestive heart failure; LVEF, left ventricular ejection fraction HER2-negative IBC, % (n=14) LVEF worst value

25. Pathologic Complete Response (pCR) Untch M et al. EBCC 2008

26. What is the “standard” Her2+ at PMH? MUGA FEC MUGA Taxotere + herceptin In Ontario: AC-TaxotereH FEC-TH AC-TaxolH TCH

27. Anything new in 2010?

28. Baselga J et al, SABCS 2010

32. Gianni L et al, SABCS 2010

37. Winer EP, SABCS 2010

39. Should patients with LABC have a lumpectomy if good response to chemotherapy? Challenges in the Management of LABC

40. Pre-Treatment MRI of Breast Cancer with Septal Spread After Neo-Adjuvant Chemotherapy Tumour shrunk to lesser volume along septa

41. Pathologic Response to Neoadjuvant Chemotherapy (TSRCC) StudyDefinitionpCR rate (n=117) (%) NSABPpCR in breast only No microinvasive disease Can have DCIS 10.3 AberdeenpCR in breast/axilla No microinvasive disease Can have DCIS 8.6 TSRCCpCR in breast and axilla No microinvasive disease Can have DCIS 8.6 ChevallierpCR in breast and axilla No microinvasive disease No DCIS 4.3

42. Why such low pCR rates? 1)Advanced nature of patients selected for neoadjuvant chemotherapy in a LABC dedicated program 1)this is a VERY different pt population than preoperative systemic therapy for Stage I and II pts that is becoming more common in USA 2)High incidence of ER + tumors (71%) 3)Strict definition of pCR

43. How effective is Neoadjuvant Chemotherapy in ER+ Breast Cancer Chemotherapy is less effective in ER+ disease vs ER- disease (but doesn’t mean some patients don’t benefit) Luminal A cohort do not benefit vs luminal B? Other predictive markers needed

44. Phase III SWOG 8814 (TBCI 0100) Postmenopausal, N+, ER+ RANDOMIZE n = 1477 tamoxifen x 5 yrs CAF x 6, then tamoxifen CAF x 6, with concurrent tam Albain, et al. Breast Cancer Res Treat 2007 Superior Disease-Free Survival (DFS) and Overall Survival (OS) over 10 Years (n = 361) (n = 550)(n = 566)

47. Our most successful therapies target self- sufficiency in growth signals Growth Factor Estrogen/ER HER2 Therapy SERMs, AIs, oophorectomy, fulvestrant Trastuzumab –Lapatinib

48. Should we treat patients with residual lymph node involvement after neoadjuvant chemotherapy with further adjuvant chemotherapy? Challenges in the Management of LABC

49. Should we treat patients with residual lymph node involvement after neoadjuvant chemotherapy with further adjuvant chemotherapy? % Surviving Years after Surgery Nodal StatusN Deaths Negative884112 1-3 Positive587113 4-9 Positive308107 10+ Positive10254 3-31-04 NSABP B-27: Overall Survival nodal Status; Patients without pCR (Bear JCO 2003)

50. Systemic therapy – when more is less! LABC patients not responding to chemotherapy –More or different chemo is not always the answer –Chemo is toxic –Importance of multidisciplinary team –Unique area for further study: Role of RT Role of biologics Understanding chemo-resistance Response predictors Response Assessment Tools

51. Our most successful therapies target self- sufficiency in growth signals Growth Factor Estrogen/ER HER2 Therapy SERMs, AIs, oophorectomy, fulvestrant Trastuzumab –Lapatinib

52. Surely neoadjuvant chemotherapy is the best? Semiglazov et al. 2004 –Neoadjuvant treatment in women aged >70 with ER + breast cancer Doxorubicin and Paclitaxel (q3 weeks, 4 cycles) (n=60) 3 months treatment with anastrozole or exemestane (n=59) There was a trend towards more breast conservation in the AI arms. chemotherapyanastrozoleexemestane pathological CRs 7.4%3.3%6.8% overall clinical RRs 76%75%81%

55. Summary Preoperative vs. Postoperative –OS = DFS =  BCS Clinical and pathologic response predicts overall survival Standard chemo is an anthracycline & taxane regimen For older HR+ pts consider endocrine therapy Currently no role for more chemo for patients with residual disease after preoperative therapy

56. Challenges in the Management of Locally Advanced Breast Cancer Surgical oncology Who to send for preoperative therapy? –In the setting of LABC – we are hoping to make surgery feasible –This is different from using NAT as the standard for ALL patients Role of breast conservation –Not common for LABC population –Can be done when feasible Role of SLN surgery –Very high rate of nodal involvement Surgery on relapse –Palliation in the setting of very poor prognosis

57. Challenges in the Management of Locally Advanced Breast Cancer Medical oncology What drugs to give for preoperative therapy? –Anthracycline and taxane (± herceptin) –Endocrine therapy How can we improve response rates? –More than chemo! –radiotherapy, biological agents What to give on relapse? –Very difficult as survival is often short