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OPEN ISSUES IN MULTIDISCIPLINARY BREAST CANCER MANAGEMENT Mediterranean School of Oncology

OPEN ISSUES IN MULTIDISCIPLINARY BREAST CANCER MANAGEMENT Mediterranean School of Oncology Rome, March 30, 2012. NEOADJUVANT THERAPY. Lucia Mentuccia Oncologia Medica, Sora. Goals of Neoadjuvant Theapy in Breast Cancer. To improve surgical outcomes and options

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OPEN ISSUES IN MULTIDISCIPLINARY BREAST CANCER MANAGEMENT Mediterranean School of Oncology

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  1. OPEN ISSUES IN MULTIDISCIPLINARY BREAST CANCER MANAGEMENT Mediterranean School of Oncology Rome, March 30, 2012 NEOADJUVANT THERAPY Lucia Mentuccia Oncologia Medica, Sora

  2. Goals of Neoadjuvant Theapy in Breast Cancer • To improve surgical outcomes and options • For operable breast cancer, the aim is to increase the chance of breast conserving surgery in patients who would otherwise require mastectomy • For inoperable locally advanced breast cancers, the aim is to achieve operability • To gain information on tumor response • To define short-term surrogate markers of response

  3. NSABP B-18 1523 pts with clinical T1-3, N0-N1 breast cancer Stratification • Age • Clinical Tumor Size • Clinical Nodal Status Operation AC x 4 AC x 4 Operation Wolmark N t al; J Natl Cancer Inst Monogr. 2001

  4. NSABP B-18: Clinical and Pathologic Breast Tumor Response pCR (63 pts) 9% 36% cCR (249 pts) 4% pNon-Inv (26 pts) 23% cPR (296 pts) 43% pInv (160 pts) cSD + cPD (140 pts) 20% Wolmark N t al; J Natl Cancer Inst Monogr. 2001

  5. NSABP B-18: Surgery Performed 100 40 32 80 Mast Lump 60 % 40 60 68 P < 0.01 20 0 Preop- Chemo Postop-Chemo Wolmark N t al; J Natl Cancer Inst Monogr. 2001

  6. Wolmark N t al; J Natl Cancer Inst Monogr. 2001

  7. NSABP B-27 Pts with T1c-3 N0 or T1-3N1 breast cancer 2411 pts Randomization AC x 4 Tam X 5 Yrs AC x 4 Tam X 5 Yrs AC x 4 Tam X 5 Yrs Surgery Taxotere x 4 Surgery Taxotere x 4 Surgery Bear HD, et al. J ClinOncol. 2006;24(13):2019-2027.

  8. NSABP B-27 Pathologic Complete Response in Breast Bear HD, et al. J ClinOncol. 2006;24(13):2019-2027.

  9. pCR to Neoadjuvant Chemotherapy is correlated with improved DFS & OS (NSABP B-27) Disease free-survival Overall Survival Bear HD, et al. J ClinOncol. 2006;24(13):2019-2027.

  10. NSABP B-27: Overall Survival Nodal Status Pts with pCR Pts without pCR

  11. NSABP B-27: OS, DFS, RFS

  12. Preoperative vs postoperative, Overall Survival The Cochrane Library, Issue 3, 2008

  13. pCR vs residual disease, Overall Survival The Cochrane Library, Issue 3, 2008

  14. Intrinsic sub-types have different prognosis and different response to primary CT

  15. Response Rates with Neoadjuvant Trastuzumab Study Pernas et al 2006, n=16 T → FEC + H Buzdar et al 2007, n=64 T → FEC + H Coudert et al 2005, n=33 D + H X + D + H Lybaert et al 2006, n=89 Gianni et al 2007, n=115 AT → T → CMF + H Limentani et al 2007, n=31 D + V + T (including IBC) Trastuzumab D + H Griggs et al 2005, n=18 NOAH, all patients D + cisplatin + H (including IBC) Hurley et al 2002, n=48 NOAH, IBC only Lapatinib V + H (including IBC) Harris et al 2003, n=40 AC → T + H (including IBC) Kelly et al 2006, n=37 T + H (including IBC) Burstein et al 2003, n=40 D + H Bines et al 2003, n=32 Baselga et al 2007, n=31 AT → T → CMF + H (IBC only) T + L (IBC only) Christofanilli et al 2006, n=30 0 10 20 30 40 50 60 70 80 90 100 pCR (%) L, lapatinib; V, vinorelbine; X, capecitabine; FEC, 5-fluorouracil, epirubicin, cyclophosphamide

  16. The MD Anderson Study Paclitaxel q3wk x 4 N=19 FEC x 4 BC pts M0, T1-3, No-1, HER2+ (FISH or ICH 3+) N=42 R Paclitaxel q3wk x 4 + H x 12 N=23 FEC x 4 + H x 12 FEC, 5-fluorouracil, epirubicin, cyclophosphamide H, trastuzumab Additional 22 pts Buzdar AU, Clin Cancer Res 2007

  17. pCR with CT  Trastuzumab 75 66% 50 % of patients 26% 20 0 T-FEC T-FEC + Tras Buzdar AU, Clin Cancer Res 2007

  18. MD Anderson Neoadjuvant Trial DFS at 72 months FU Buzdar AU, Clin Cancer Res 2007 Buzdar A et al ASCO Breast 2009

  19. NOAH HER2-negative LABC(IHC 0/1+) (n=99) ATq3w x 3 cycles Tq3w x 4 cycles CMFq4w x 3 cycles Surgery followed byradiotherapya HER2-positive LABC(IHC 3+ or FISH+) (n=115) (n=113) H + ATq3w x 3 cycles ATq3w x 3 cycles H + T q3w x 4 cycles Tq3w x 4 cycles H q3w x 4 cycles+ CMF q4w x 3 cycles CMFq4w x 3 cycles Surgery followed byradiotherapya Surgery followed byradiotherapya 19 crossed over to H H continued q3wto week 52 Gianni L et al. Lancet 2010; 375: 377–84

  20. pCR rates in the NOAH trial:intent-to-treat population Patients (%) 50 p=0.002 40 39% 30 20 20% 10 0 With H Without H HER2 positive Gianni L et al. Lancet 2010; 375: 377–84

  21. EFS: HER2-positive population L. Gianni et al., The Lancet, 2010

  22. … Future Clinical Practice….

  23. Anti-HER2 Treatment: mechanisms of action

  24. Three Neoadjuvant Trials Using Targeted Therapies for HER-2 Positive BC

  25. San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8-12, 2010 Lapatinib vstrastuzumab in Combination with NeoadjuvantAnthracycline-Taxane-Based CHEMOTHERAPY: Primary Efficacy Endpoint Analysis of The GEPARQUINTO study (GBG 44) Untch M, LoiblS, Bischoff J, EidtmannH, Kaufmann M, BlohmerJU, HilfrichJ, StrumbergD, Fasching P, KreienbergR, TeschH, HanuschC, Gerber B, RezaiM, JackischC, HuoberJ, KühnT, Nekljudova V, von MinckwitzG for the GBG /AGO study group This presentation is the intellectual property of the author/presenter  Contact them for permission to reprint and/or distribute.

  26. Conclusions from Run-in Phase(N=60) * von Minckwitz, M. Untch et al, Ann Oncol 2010 • Neutropenia Grade III/ IV in 82% • G-CSF made mandatory together with L • Treatment discontinuations in 34.5% • L dose reduced from 1250 to 1000 mg/ d • Diarrhea Grade III/ IV in 6.9% • Loperamide given as stand-by medication for L

  27. Breast Conservation Rate

  28. Conclusions • Anthracycline-taxane based CT + T achieved a pCR (ypT0/is ypN-/+) rate of 50% in HER2-positive patients, confirming our previous findings (TECHNO, GeparQuattro) • CT + L (1250/ 1000 mg) resulted in a significantly lower pCR rate of 35% (Caveat: 10% more discontinuations with L). • Compliance of L with EC and Docetaxel was lower than with T. • Results should be seen in the context of other studies like Neo-ALTTO, which usesa higher dose of L (1500 mg/d) but a shorter pre-operative treatment duration.

  29. First results of the Neo-ALTTO trial (BIG 01-06 / EGF 106903): A phase III, randomized, open label, neoadjuvant study of lapatinib, trastuzumab, and their combination plus paclitaxel in women with HER2-positive primary breast cancer José Baselga, Ian Bradbury, Holger Eidtmann, Serena Di Cosimo, Claudia Aura, Evandro de Azambuja, Henry Gomez, Phuong Dinh, Karine Fauria, Veerle Van Dooren, Paolo Paoletti, Aron Goldhirsch, Tsai-Wang Chang, Istvan Lang, Michael Untch, Richard D. Gelber and Martine Piccart-Gebhart on behalf of the Neo-ALTTO Study Team December 10, 2010

  30. Study Design Invasive operable HER2+ BC T > 2 cm (inflammatory BC excluded) LVEF  50% N=450 lapatinib lapatinib paclitaxel R A N D O M I Z E S U R GE R Y FEC X 3 trastuzumab trastuzumab paclitaxel • Stratification: • T ≤ 5 cm vs. T > 5 cm • ER or PgR + vs. • ER & PgR – • N 0-1 vs. N ≥ 2 • Conservative surgery • or not lapatinib lapatinib trastuzumab trastuzumab paclitaxel + 12 wks 6 wks 34 weeks 52weeks of anti-HER2 therapy

  31. Efficacy – pCR and tpCR

  32. Efficacy – Overall (Clinical) Responseat 6 weeks (w/o chemo) and at surgery L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab

  33. Safety Number (%) of patients with AEs at Grade ≥ 3 * Includes 2 patients with Hy’s Law criteria in T, and one patient in L L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab • No major cardiac dysfunction • One death in L+T immediately after end of treatment

  34. CHER LOB Trial: study plan TXL 80 mg/m2   RANDOMI ZATI ON A CORE BI OPSY S URGE RY Chemotherapy   B  Lapatinib 1500 mg/daily   C Lapatinib 1000 mg/daily 5 FU 600 mg/m2 Epi 75 mg/m2 CTX 600 mg/m2 Trastuzumab 2 mg/kg 121 paz Guarneri V, ASCO 2011

  35. CHER-LOB: EFFICACY OUTCOMES 90 80 70 60 50 40 30 20 10 0 Arm A:CT + trastuzumab Arm B: CT + lapatinib Arm C: CT + trastuzumab/lapatinib Breast conservation Node negativity pCR (breast & axilla) Guarneri V, ASCO 2011

  36. NeoSphere: study design FEC q3w x 3 trastuzumab q3w cycles 5–17 FEC q3w x 3 trastuzumab q3w cycles 5–17 docetaxel q3w x 4→FEC q3w x 3 trastuzumab q3w cycles 5–17 FEC q3w x 3 trastuzumab q3w cycles 5–21 TH (n=107)docetaxel + trastuzumab S U R G E R Y Patients with operable or locally advanced /inflammatory* HER2-positive BC Chemo-naïve & primary tumors >2cm (N=417) THP (n=107)docetaxel + trastuzumab +pertuzumab HP (n=107)trastuzumab + pertuzumab TP (n=96)docetaxel + pertuzumab Study dosing: q3w x 4 BC, breast cancer; FEC, 5-fluorouracil, epirubicin and cyclophosphamide*Locally advanced=T2–3, N2–3, M0 or T4a–c, any N, M0; operable=T2–3, N0–1, M0; inflammatory = T4d, any N, M0H, trastuzumab; P, pertuzumab; T, docetaxel Gianni L et al. SABCS 2010

  37. NeoSphere pCR rates: ITT population summary p = 0.0198 p = 0.0141 p = 0.003 50 40 pCR, %  95% CI 45.8 30 20 29.0 24.0 10 16.8 0 H, trastuzumab; P, pertuzumab; T, docetaxel TH THP HP TP 6 Gianni L et al. SABCS 2010

  38. NEOSPHERE: pCR and hormone receptors status ER or PR pos ER and PR neg 70 60 50 63.2 40 pCR, %  95% CI 30 20 36.8 30.0 29.1 10 26.0 20.0 17.4 5.9 0 H, trastuzumab; P, pertuzumab; T, docetaxel TH THP HP TP Gianni L et al. SABCS 2010

  39. pCR by hormone receptor status L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab pCR pathologic complete response HR: hormone receptors Baselga J et al. SABCS 2010

  40. CHER-LOB: pCR rate by HR 60 56.2% 50 40 35.7% 35.7% 30 26.6% 25% 22.7% 20 10 HR+ HR- HR+ HR- HR+ HR- 0 Arm A (CT + T) Arm B (CT +L) Arm C (CT + T + L) T: trastuzumab; L: lapatinib; T+L: trastuzumab plus lapatinib

  41. HORMONE RECEPTOR STATUS AND pCR

  42. Neoadjuvant therapy in HER2+ operable breast cancer: Key Findings • Patient selection is mandatory for the integration of novel agents in cancer treatment • Chemotherapy + trastuzumab is the gold standard • Double-HER2 blockade increases the pCR rate • Endocrine pathway is still important even in presence of HER2 co-expression • The preoperative setting is ideal to test new combinations through the “window of opportunity model”

  43. Neo Adjuvant Systemic Therapy 87.2% 8.5% 4.3% Yes No A • IsdualHER2-targeting a reasonable option for the preoperative setting for HER2 disease? 21.7% 67.4% 10.9% Yes No A Should neoadjuvant regimens for HER2-positive disease always contain anti-HER2 drug? St Gallen 2011

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