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 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
1523 pts with clinical T1-3, N0-N1 breast cancer 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 3
Clinical and Pathologic Breast Tumor Response 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 4
NSABP B-18: Surgery Performed 100 40 32 80 Mast Lump 60 % 40 60 68 P < 0.01 20 Postop-Chemo Preop- Chemo Wolmark N t al; J Natl Cancer Inst Monogr. 2001
Wolmark N t al; J Natl Cancer Inst Monogr. 2001
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Pts with T1c-3 N0 or T1-3N1 breast cancer NSABP B-27 2411 pts Pts with T1c-3 N0 or T1-3N1 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 Taxotere x 4 Surgery Surgery Taxotere x 4 Bear HD, et al. J ClinOncol. 2006;24(13):2019-2027.
Complete Response in Breast NSABP B-27 Pathologic Complete Response in Breast Bear HD, et al. J ClinOncol. 2006;24(13):2019-2027.
Disease free-survival 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.
NSABP B-27: Overall Survival Nodal Status Pts with pCR Pts without pCR
NSABP B-27: OS, DFS, RFS
Preoperative vs postoperative, Overall Survival The Cochrane Library, Issue 3, 2008
pCR vs residual disease, Overall Survival The Cochrane Library, Issue 3, 2008
Intrinsic sub-types have different prognosis and different response to primary CT
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 Lybaert et al 2006, n=89 X + D + H Gianni et al 2007, n=115 AT → T → CMF + H Limentani et al 2007, n=31 D + V + T (including IBC) Trastuzumab Griggs et al 2005, n=18 D + H NOAH, all patients Hurley et al 2002, n=48 D + cisplatin + H (including IBC) NOAH, IBC only Harris et al 2003, n=40 V + H (including IBC) Lapatinib Kelly et al 2006, n=37 AC → T + H (including IBC) Burstein et al 2003, n=40 T + H (including IBC) Bines et al 2003, n=32 D + H Baselga et al 2007, n=31 AT → T → CMF + H (IBC only) Christofanilli et al 2006, n=30 T + L (IBC only) 10 20 30 40 50 60 70 80 90 100 pCR (%) L, lapatinib; V, vinorelbine; X, capecitabine; FEC, 5-fluorouracil, epirubicin, cyclophosphamide 19
Buzdar AU, Clin Cancer Res 2007 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
pCR with CT Trastuzumab 75 66% 50 % of patients 26% 20 T-FEC T-FEC + Tras Buzdar AU, Clin Cancer Res 2007 21 21
MD Anderson Neoadjuvant Trial DFS at 72 months FU Buzdar AU, Clin Cancer Res 2007 Buzdar A et al ASCO Breast 2009 22 22
NOAH HER2-positive LABC (IHC 3+ or FISH+) AT q3w x 3 cycles T q3w x 4 cycles CMF q4w x 3 cycles HER2-negative LABC (IHC 0/1+) Surgery followed by radiotherapya (n=99) (n=115) (n=113) H + AT q3w x 3 cycles AT q3w x 3 cycles H + T q3w x 4 cycles T q3w x 4 cycles H q3w x 4 cycles + CMF q4w x 3 cycles CMF q4w x 3 cycles Surgery followed by radiotherapya Surgery followed by radiotherapya H continued q3w to week 52 19 crossed over to H Gianni L et al. Lancet 2010; 375: 377–84 23 23 23 23
pCR rates in the NOAH trial: intent-to-treat population Patients (%) 50 p=0.002 40 39% 30 20 pCR and tpCR 20% 10 With H Without H HER2 positive Gianni L et al. Lancet 2010; 375: 377–84 24 24
EFS: HER2-positive population L. Gianni et al., The Lancet, 2010 25
… Future Clinical Practice….
Anti-HER2 Treatment: mechanisms of action
Three Neoadjuvant Trials Using Targeted Therapies for HER-2 Positive BC
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8-12, 2010 Lapatinib vs trastuzumab in Combination with Neoadjuvant Anthracycline-Taxane-Based CHEMOTHERAPY: Primary Efficacy Endpoint Analysis of The GEPARQUINTO study (GBG 44) Untch M, Loibl S, Bischoff J, Eidtmann H, Kaufmann M, Blohmer JU, Hilfrich J, Strumberg D, Fasching P, Kreienberg R, Tesch H, Hanusch C, Gerber B, Rezai M, Jackisch C, Huober J, Kühn T, Nekljudova V, von Minckwitz G 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. Materiale di training ad escliusivo uso interno
Conclusions from Run-in Phase (N=60) 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 * von Minckwitz, M. Untch et al, Ann Oncol 2010 Materiale di training ad escliusivo uso interno
Breast Conservation Rate
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 uses a higher dose of L (1500 mg/d) but a shorter pre- operative treatment duration. Materiale di training ad escliusivo uso interno
on behalf of the Neo-ALTTO Study Team 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 36
52 weeks of anti-HER2 therapy Study Design S U R G E Y A N D O M I Z E lapatinib trastuzumab paclitaxel + 12 wks 6 wks 34 weeks 52 weeks of anti-HER2 therapy lapatinib trastuzumab FEC X 3 Stratification: T ≤ 5 cm vs. T > 5 cm ER or PgR + vs. ER & PgR – N 0-1 vs. N ≥ 2 Conservative surgery or not Invasive operable HER2+ BC T > 2 cm (inflammatory BC excluded) LVEF 50% N=450 37 37
Efficacy – pCR and tpCR
Efficacy – Overall (Clinical) Response at 6 weeks (w/o chemo) and at surgery L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab
Safety Number (%) of patients with AEs at Grade ≥ 3 L (N= 154) T (N= 149) L+T (N= 152) Diarrhea 36 (23%) 3 (2%) 32 (21%) Hepatic * 20 (13%) 2 (1%) 13 ( 9%) Neutropenia 24 (16%) 4 (3%) Skin disorders 10 (7%) * Includes 2 patients with Hy’s Law criteria in T, and one patient in L No major cardiac dysfunction One death in L+T immediately after end of treatment L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab
CHER LOB Trial: study plan RANDOMI ZATI ON Lapatinib 1000 mg/daily Lapatinib 1500 mg/daily CORE BI OPSY S URGE RY Chemotherapy A B C TXL 80 mg/m2 Trastuzumab 2 mg/kg 5 FU 600 mg/m2 Epi 75 mg/m2 CTX 600 mg/m2 121 paz Guarneri V, ASCO 2011 41
CHER-LOB: EFFICACY OUTCOMES 10 20 30 40 50 60 70 80 90 Arm A:CT + trastuzumab Arm B: CT + lapatinib Arm C: CT + trastuzumab/lapatinib pCR (breast & axilla) Node negativity Breast conservation Guarneri V, ASCO 2011 42
NeoSphere: study design TH (n=107) docetaxel + trastuzumab S U R G E Y FEC q3w x 3 trastuzumab q3w cycles 5–17 trastuzumab q3w cycles 5–21 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 docetaxel q3w x 4→FEC q3w x 3 trastuzumab q3w cycles 5–17 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, M0 H, trastuzumab; P, pertuzumab; T, docetaxel Gianni L et al. SABCS 2010 43
NeoSphere pCR rates: ITT population summary 50 p = 0.003 40 pCR, % 95% CI 45.8 30 20 29.0 24.0 10 16.8 H, trastuzumab; P, pertuzumab; T, docetaxel TH THP HP TP Gianni L et al. SABCS 2010 6 44
NEOSPHERE: pCR and hormone receptors status 70 60 ER or PR pos ER and PR neg 50 63.2 40 pCR, % 95% CI 30 . 20 36.8 30.0 10 29.1 26.0 20.0 5.9 17.4 H, trastuzumab; P, pertuzumab; T, docetaxel TH THP HP TP Gianni L et al. SABCS 2010 45 45
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 46 46
CHER-LOB: pCR rate by HR 25% 22.7% 10 20 30 40 50 60 Arm A (CT + T) Arm B (CT +L) Arm C (CT + T + L) 26.6% 35.7% 56.2% HR+ HR- T: trastuzumab; L: lapatinib; T+L: trastuzumab plus lapatinib 47 47
HORMONE RECEPTOR STATUS AND pCR Trial/author pts # Regimen HR + % % pCR HR- HR+ Kemeny 54 FACVb 66 20.0 7.7 Ring 435 CMF, A/E 71 21.6 8.1 Bear 1211 AC 59 13.6 5.7 565 AC+T 57 22.8 14.1 GEPARDO 250 ddAD+/-T 56 15.4 1.1 GEPARDUO 913 ddAD/CA-D 74 6.2 GEPARTRIO 286 TAC/TAC-NX 68 36.6 10.1 Guarneri 1731 FAC+/-P 23.8 7.8 Gianni 438 A+/P/CMF 63 42.2 11.6 201 FEC/ET/GET 16.6 3.5 Colleoni 399 ECF/EC/ET/ViFuP 33.3 7.6 48 48
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”
Neo Adjuvant Systemic Therapy Should neoadjuvant regimens for HER2-positive disease always contain anti-HER2 drug? 87.2% 8.5% 4.3% Yes No A Is dual HER2-targeting a reasonable option for the preoperative setting for HER2 disease? 21.7% 67.4% 10.9% Yes No A St Gallen 2011 50 50
Von Minckwitz G, SABCS 2010
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OBJECTIVES Von Minckwitz G, SABCS 2010
Von Minckwitz G, SABCS 2010
CHARACTERISTICS OF PATIENTS
Von Minckwitz G, SABCS 2010
Neoadjuvant Bevacizumab and Anthracycline-Taxane Based Chemotherapy in 684 Triple Negative Primary Breast Cancers: Secondary Endpoint Analysis of the GEPARQUINTO Study (GBG 44) Gerber B et al. Proc ASCO 2011;Abstract 1006. Gerber B et al. Proc ASCO 2011;Abstract 1006. Gerber B et al. Proc ASCO 2011;Abstract 1006.
Benefit of bev limited to TNBC subgroup GEPARQUINTO: Benefit of Bevacizumab Added to Neoadjuvant Chemotherapy in TNBC Subgroup Benefit of bev limited to TNBC subgroup pCRbreast (with bev vs without bev)* TNBC patients: 36.4 vs 27.8% (p = 0.021) All patients: 15.0 vs 17.5% (p = NS) * pCRbreast = no inv/non-inv in breast and nodes Gerber B et al. Proc ASCO 2011;Abstract 1006. Gerber B et al. Proc ASCO 2011;Abstract 1006. 59 59 59 59
The Effect of pCR of Bevacizumab and/or Antimetabolites Added to Standard Neoadjuvant Chemotherapy: NSABP Protocol B-40 Bear HD et al. Proc ASCO 2011;Abstract LBA1005. Bear HD et al. Proc ASCO 2011;Abstract LBA1005.
Operable Breast Cancer NSABP B-40: Chemotherapy ± Bevacizumab in Patients with Operable HER2-Negative Breast Cancer Tissue for Biomarkers Tissue for Biomarkers SURGERY Operable Breast Cancer R +/- X10 T docetaxel X capecitabine G gemcitabine B bevacizumab +/-
NSABP B-40: Benefit of Adding Bevacizumab to Standard Chemotherapy Benefit of bev predominant in HR+ and not TNBC patient subgroup pCRbreast (with bev vs without bev): HR+ patients: 23.3 vs 15.2% (p = 0.008) TNBC patients: 51.3 vs 47.3% (p = 0.44) Bear HD et al. Proc ASCO 2011;Abstract LBA1005. 62 62 62 62
Neo Adjuvant Systemic Therapy Is neodjuvant endocrine therapy alone a reasonable option for postmenopausal pts with highly endocrine-responsive disease? 97.8% 2.2% 0% Yes No A If YES, for which duration (choose one)? 15.2% 3-4 months 4-8 months Maximal response 39.1% 45.7% St Gallen 2011 63
Grazie! 64