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Medical Oncology Training Program Resident Teaching Friday January 7th, 2011 @ PMH, 5-223

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. Surgical oncology Who to send for preoperative therapy? Role of breast conservation

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Medical Oncology Training Program Resident Teaching Friday January 7th, 2011 @ PMH, 5-223

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  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. 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? Challenges/Objectives in the Management of Locally Advanced Breast Cancer • 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. What are the indications for neoadjuvant therapy? Inoperable Goal Operable • Improve surgical options • Deliver adequate “adjuvant” chemotherapy • Provide in vivo anti-tumour assessment • Assess surrogate biologic endpoints for response & survival

  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 • TRTNDeaths • Non pCR 1899 396 • pCR 409 31 HR=0.33 p<0.0001 Years after Surgery NSABP B-27: Overall Survival - pCR vs. non-pCR patients (Bear JCO 2003)

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

  8. Neoadjuvant therapy - Operable Breast Cancer • Clinical response predicts overall survival • Pathologic response predicts overall survival B-18 DFS by response B-18 OS by response 100% 80% 60% pCR pCR pINV pINV P=0.0008 40% P=0.00005 cPR cPR 20% cNR cNR 0 Year 2 4 6 8 2 4 6 8 Wolmark N: CDC, 2000

  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 Docetaxel x 4

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

  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 RANDOMIZATION C 75 mg/m2 po q d days 1–14E 60 mg/m2 IV days 1 and 8q 4 wk x 6F 500 mg/m2 IV days 1 and 8 E 120 mg/m2 IV day 1 q 2 wk x 6C 830 mg/m2 IV days 1 with G-CSF day 2-13 Therasse P et al. J Clin Oncol 2003;21:843-50

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

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

  15. What is the “standard” Her2- at PMH? • In Ontario: • AC-taxotere • FEC-taxotere • Dose dense AC-Taxol

  16. Breast Cancer Biological Subtypes as Predictive Subtypes

  17. NOAH: the largest neoadjuvant trial in HER2-positive breast cancer HER2-negative LABC(IHC 0/1+) HER2-positive LABC(IHC 3+ and / or FISH+) n=99 n=113 n=115 H + ATq3w x 3 ATq3w x 3 ATq3w x 3 Tq3w x 4 Tq3w x 4 H + Tq3w x 4 CMFq4w x 3 CMFq4w x 3 H q3w x 4 + CMF q4w x 3 Surgery followed by radiotherapya Surgery followed by radiotherapya Surgery followed by radiotherapya H continued q3w to Week 52 aHormone 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/m2), paclitaxel (150 mg/m2); T, paclitaxel (175 mg/m2); CMF, cyclophosphamide, methotrexate, fluorouracil

  18. Patient characteristics Characteristic HER2-positive IBC, % HER2-negative IBC, % +HTotal pop IBC pop(n=115) (n=31) -HTotal pop IBC pop(n=113) (n=31) Total pop IBC pop(n=99) (n=14) 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 46 54 5248 3565 134443 946 3268 5545 1684 195526 9010 4258 5050 3565 164737 964 5545 4258 2377 265223 1000 5149 5545 6436 173844 964 4357 5050 6436 295021 1000 ER, oestrogen receptor; PgR, progesterone receptor

  19. Significant improvement of pCR in IBC by adding trastuzumab p=0.004 p=0.002 Patients(%) 17 (55%) 15 (48%) p=0.49 p=0.20 4 (29%) 4 (29%) 6 (19%) 4 (13%) +H -H HER2negative +H -H HER2negative HER2 positive HER2 positive pCR tpCR eradication of invasive cancer in the breast plus axillary nodes eradication of invasive cancer in the breast

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

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

  22. What is the “standard” Her2+ at PMH? • In Ontario: • AC-TaxotereH • FEC-TH • AC-TaxolH • TCH

  23. Anything new in 2010?

  24. Baselga J et al, SABCS 2010

  25. Gianni L et al, SABCS 2010

  26. Gianni L et al, SABCS 2010

  27. Gianni L et al, SABCS 2010

  28. Gianni L et al, SABCS 2010

  29. Winer EP, SABCS 2010

  30. Winer EP, SABCS 2010

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

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

  33. Pathologic Response to Neoadjuvant Chemotherapy (TSRCC)

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

  35. 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

  36. 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 (n = 361) (n = 550) (n = 566) Superior Disease-Free Survival (DFS) and Overall Survival (OS) over 10 Years Albain, et al. Breast Cancer Res Treat 2007

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

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

  39. Should we treat patients with residual lymph node involvement after neoadjuvant chemotherapy with further adjuvant chemotherapy? • Nodal StatusNDeaths • Negative884112 • 1-3 Positive 587 113 • 4-9 Positive 308 107 • 10+ Positive 102 54 % Surviving Years after Surgery NSABP B-27: Overall Survival nodal Status; Patients without pCR 3-31-04 (Bear JCO 2003)

  40. 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

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