Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer © AGO e. V. in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2015.1 Neoadjuvant (Primary) Systemic Therapy Neoadjuvant Systemic Therapy © AGO e. V. in der DGGG e.V. sowie in der DKG e.V. Version 2002: Costa Versions 2003–2014: Bauerfeind / Blohmer / Dall / Fersis / Göhring / Harbeck / Heinrich / Huober / Jackisch / Kaufmann / Loibl / Lux / von Minckwitz / Müller / Nitz / Schneeweiss / Schütz / Solomayer / Untch Version 2015: Friedrich / Schneeweiss Guidelines Breast Version 2015.1 www.ago-online.de Neoadjuvant Systemic Chemotherapy Indications © AGO Oxford / AGO LoE / GR e. V. in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2015.1 www.ago-online.de Inflammatory breast cancer 2b B ++ Inoperable breast cancer 1c A ++ Large operable breast cancer primarily requiring mastectomy and adjuvant chemotherapy with the goal of breast conservation 1b B + If similar postoperative adjuvant chemotherapy is indicated 1b A + Subtype-specific General Systemic Strategies © AGO e. V. in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2015.1 In case of indication for chemotherapy, consider neoadjuvant approach Conventionally dosed AT-based chemotherapy Dose dense & escalated in case of high tumor burden Followed by endocrine therapy Trastuzumab plus • Sequential A/T-based regimen with concurrent T + H Anthracycline-free, carboplatin-cont. regimen • Dose dense & escalated in case of high tumor burden • ++ ++ + ++ HER2+ www.ago-online.de Endocrine therapy without chemotherapy HR+/HER2- and “high risk” ++ HR+/HER2- and “low risk”: AGO ++ ++ + + TNBC Conventionally dosed AT-based chemotherapy Dose dense & escalated Plus Carboplatin in case of family history for BC/OC or gBRCA alteration ++ + + Verbesserung der pCR-Raten durch Platin beim TNBC p=0,003 p=0,0029 60 p=0,005 61 P<0,0001 54 50 TNBC 53 48 40 41 37 ypT0 ypN0 ypT0 ypN0 ypT0 ypN0 ypT0 ypN0 ypT0/is ypN0 0 26 ypT0/is ypN0 10 32 ypT0/is ypN0 20 34 ypT0/is ypN0 30 ypT0/is ypN0 Anteil Patienten mit pCR (%) 70 (N=992) 1. Cortazar P, et al. Lancet 2014; 2. Ando M, et al. BCRT 2014; 3. Sikov WM, et al. J Clin Oncol 2015; 4. von Minckwitz G, et al. Lancet Oncol 2014; 5. Petrelli F, et al. BCRT 2014 HR 0.24 pCR als Surrogat für Überleben? Überträgt sich die höhere pCR-Rate in ein besseres Überleben? Wenn ja, welches Δ pCR brauchen wir für eine signifikante Verbesserung des Überlebens? Gibt es Subgruppen mit einem größeren Δ pCR? GeparSixto (Phase II): pCR abhängig von genetischer Belastung nach PMB + Carbo vs. PMB beim TNBC (N=294) Von Minckwitz G, et al. ASCO 2014 (abs 1005), oral abstract session Neoadjuvant Systemic Chemotherapy Recommended Regimens and Schedules © AGO Oxford / AGO LoE / GR e. V. in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2015.1 Standard regimens used in the adjuvant setting with a duration of at least 18 weeks 1a A ++ AC or EC D q3w or P q1w 2b A ++ DAC 2b B ++ AP CMF 1b A + Taxane followed by anthracycline sequence 1a A + Dose-dense regimen (e.g. E -P-CMF, E-P-C) 1b B +* Platinum in TNBC 1a A +/- 2b B + www.ago-online.de in case of family history of BC/OC or BRCA alteration *Study participation recommended Superior Carboplatin Containing Regimens in the Neoadjuvant Setting © AGO e. V. in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2014.1 www.ago-online.de Author Study Regimen pCR rate Sikov WM, et al. (JCO 2015) CALGB 40603 Phase II Paclitaxel 80mg/m² qw x12 + Carboplatin AUC 6 q3w x4 – dd AC q2w x4 TNBC ± Cb: 54% vs 41% (ypT0/is ypN0) von Gepar Minckwitz G, Sixto et al. (Lancet Phase II Oncol 2014) NPLD 20mg/m² qw x18 + TNBC ± Cb: Paclitaxel 80mg/m² qw x18 53% vs. 37% + Carboplatin AUC 1.5 qw x18 (ypT0 ypN0) + Bev 15mg/kg q3w x6 Ando M, et al. (BCRT 2014) Paclitaxel 80mg/m² qw x12 + Carboplatin AUC 5 q3w x4 – FEC q3w x4 Phase II TNBC ± Cb: 61% vs. 26% Neoadjuvant Systemic Chemotherapy Recommended Regimens and Schedules © AGO Oxford / AGO LoE / GR e. V. in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2015.1 Standard regimens used in the adjuvant setting with a duration of at least 18 weeks 1a A ++ AC or EC D q3w or P q1w 2b A ++ DAC 2b B ++ AP CMF 1b A + Taxane followed by anthracycline sequence 1a A + Dose-dense regimen (e.g. E -P-CMF, E-P-C) 1b B +* Platinum in TNBC 1a A +/- 2b B + www.ago-online.de in case of family history of BC/OC or BRCA alteration *Study participation recommended Neo-tAnGo (Phase III): Neoadj. Pac ± Gem EC vs. EC Pac ± Gem beim HER2- EBC > 2cm (N=831) – pCR, Überleben pCR (ypT0/is ypN0): 20% vs. 15%, p=0.03 Disease-free Survival Earl HM, et al. Lancet Oncol 15: 201–12, 2014 Overall Survival Review: (Neo)adj. Taxan Anthrazyklin vs. Anthrazyklin Taxan beim EBC • Seven studies in the adjuvant setting and eight in the neoadjuvant setting (10 randomized trials) • Nearly 5000 patients • None of the clinical trials has shown disadvantages in terms of efficacy or toxicity for…taxane…first. • Similar or increased pathological complete response rates for sequences in which the taxane…first. Conclusion: There seems to be sufficient evidence to suggest that a taxane followed by an anthracycline is a sequence option that can be incorporated into daily clinical practice. Bines J, et al. Ann Oncol 25: 1079-85, 2014 Neoadjuvant Systemic Therapy Response Prediction II © AGO e. V. in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2015.1 Factor Multigene signature III C B +/- Ki-67 I B A + Tumour infiltrating lymphocytes I B B +/- PIK3CA mutation II B B +/- www.ago-online.de LoE2009 CTS GR AGO Standards für die Evaluation von Tumor-infiltrierenden Lymphozyten (TILs) • Nur stromale TILs • Als % des Tumorstroma-Areals • Innerhalb der Tumorgrenzen • Semiquantitativ • Bei heterogener Verteilung gilt der Durchschnitt Salgado R, Denkert C, Demaria S, et al. Ann Oncol 2014 [Epub ahead of print] Stromale TILs scheinen prädiktiv für das Erreichen einer pCR nach neoadjuvanter CT + Trastuzumab Retrospektive Analyse der GeparQuattro-Studie (N=156) Loi S, et al. SABCS 2013 (S1-05), oral presentation Stromale TILs scheinen prädiktiv für eine Sensitivität gegenüber der adjuvanten CT aber nicht gegenüber Trastuzumab Retrospektive Analyse der N9831-Studie (N=945; 9,9% ≥ 60% sTILs = LPBC): TILs scheinen nicht prädiktiv für eine adjuvante Trastuzumabwirkung Perez EA, et al. SABCS 2014 (S1-06), oral pesentation Neoadjuvant Systemic Therapy Response Prediction II © AGO e. V. in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2015.1 Factor Multigene signature III C B +/- Ki-67 I B A + Tumour infiltrating lymphocytes I B B +/- PIK3CA mutation II B B +/- www.ago-online.de LoE2009 CTS GR AGO PIK3CA-Mutation und PTEN-Verlust scheinen prädiktiv für eine Resistenz auf CT + Anti-HER2-Therapie neoadjuvant Loibl S, et al. J Clin Oncol 2014; Baselga J, et al. ECC 2013; Guarneri V, et al. ESMO 2014 PIK3CA-Mutation scheinen nicht prädiktiv für eine Resistenz auf Trastuzumab adjuvant (retrospektive Analyse der FinHER-Studie, N=157) Loi S, et al. J Natl Cancer Inst 105:960–967, 2013 Neoadjuvant Targeted Therapy in HER2 Positive Tumors © AGO Oxford / AGO LoE / GR e. V. in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2015.1 www.ago-online.de Trastuzumab in combination with chemotherapy Lapatinib in combination with chemotherapy 1b A ++ 1a B - Lapatinib + Trastuzumab in combination with chemotherapy 1a B +/- Pertuzumab + Trastuzumab in combination with chemotherapy 1a B +* Two anti-HER2 agents without chemotherapy 2b B +/- Anti-HER2 agent in combination with endocrine treatment 2b C +/- * Study participation recommended Verbesserung der pCR-Raten (ypT0/is ypN0) durch duale Anti-HER2 Therapie beim HER2+ EBC Anteil Patienten mit pCR (%) 80 70 60 50 40 30 pCR pCR HR+ pCR HR- 20 10 0 1Cortazar. 5Von Lancet 2014; 2Carey. ASCO 2013; 3Baselga. Lancet 2012; 4Robidoux. Lancet Oncol 2013; Minckwitz. Lancet Oncol 2014; 6Gianni. Lancet Oncol 2012; 7Schneeweiss. Ann Oncol 2013 pCR-Raten (ypT0/is ypN0) beim HER2+ EBC Getrennt nach HR-Status Anteil Patienten mit pCR (%) 80 70 60 50 40 30 + 40% pCR pCR HR+ pCR HR- 20 10 0 HER2+ HRHR 0.25 1Cortazar. 5Von Lancet 2014; 2Carey. ASCO 2013; 3Baselga. Lancet 2012; 4Robidoux. Lancet Oncol 2013; Minckwitz. Lancet Oncol 2014; 6Gianni. Lancet Oncol 2012; 7Schneeweiss. Ann Oncol 2013 Neoadjuvant Targeted Therapy in HER2 Positive Tumors © AGO Oxford / AGO LoE / GR e. V. in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2015.1 www.ago-online.de Trastuzumab in combination with chemotherapy Lapatinib in combination with chemotherapy 1b A ++ 1a B - Lapatinib + Trastuzumab in combination with chemotherapy 1a B +/- Pertuzumab + Trastuzumab in combination with chemotherapy 1a B +* Two anti-HER2 agents without chemotherapy 2b B +/- Anti-HER2 agent in combination with endocrine treatment 2b C +/- * Study participation recommended Neoadjuvant Targeted Therapy in HER2 Negative Tumors © AGO Oxford / AGO LoE / GR e. V. in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2015.1 Bevacizumab in combination with chemotherapy In hormone receptor positive BC 1b B - In TNBC 1b B +/- www.ago-online.de GeparQuinto (Phase III): Neoadj. ECDoc vs. ECB DocBev beim HER2- EBC ≥ 2cm (N=1.925) – Überleben Disease-free Survival Gerber B et al. SABCS 2014 (P3-11-01), poster discussion Overall Survival Keine Verbesserung des invasiven DFS durch Bevacizumab adjuvant beim TNBC Studie N (TNBC) Therapie Primärer Endpunkt HR p BEATRICE 2591 ≥ 4 x CT± B B (1y) IDFS 0,87 0,18 E5103 1079 AC-P ± B B (1y) IDFS 0,77 0,08 AC, Doxorubicin/Cyclophosphamid; B, Bevacizumab; CT, Chemotherapie; HR, hazard ratio; IDFS, invasive disease-free survival; P, Paclitaxel 38% TNBC Cameron D, et al. Lancet Oncol 2013; Miller K, et al. ASCO 2014 (abs 500), oral abstract session Neoadjuvant Systemic Chemotherapy Clinical Benefit © AGO e. V. in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2015.1 Oxford / AGO LoE / GR Survival is similar after neoadjuvant (preoperative, primary) and adjuvant systemic therapy 1a A Pathological complete response is associated with improved survival in particular subgroups 1b A Can achieve operability in primary inoperable tumors 1b A ++ Improved options for breast conserving surgery 1b A ++ Allows individualization of therapy according to mid-course treatment effect 1b B +* Allows individualization of post-neoadjuvant management according to refined risk assessment after neoadjuvant treatment and surgery 2b B +/-* www.ago-online.de * Study participation recommended Adjuvant Systemic Therapy after Neoadjuvant Systemic Treatment © AGO e. V. Oxford / AGO LoE / GR in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2015.1 www.ago-online.de Endocrine treatment in endocrine responsive disease Complete trastuzumab treatment for 1 year in HER2-positive disease In case of insufficient response 1a A 2b B ++ 3 Experimental therapies in clinical trials 5 Further chemotherapy ++ C D + KATHERINE (Phase III): Studiendesign und Endpunkte Operation cT1-4, cN0-3, M0 HER2+ Neoadjuvante Therapie: Anti-HER2/ Taxan ± Anthrazyklin 14 x Trastuzumab 6mg/kg i.v. q3w Residualer invasiver Tumor 14 x T-DM1 3,6mg/kg i.v. q3w Bestrahlung gemäß Leitlinien; endokrine Therapie falls ER/PgR pos Primärer Endpunkt: Invasives Disease-free Survival (IDFS); 3y-IDFS 70%76,5% (HR 0,75) Sekundäre Endpunkte: IDFS, inklusive Zweitkarzinome; DFS; OS; distantes Rezidiv-freies Interval (DRFI) PI: G. von Minckwitz PENELOPEB (Phase III): Studiendesign und primärer Endpunkt Operation Residualer cT1-4, cN0-3, M0 HR+ HER2- invasiver Tumor mit Neoadjuvante CPS-EG Chemotherapie inklusive Taxan Score ≥3 13 x Placebo p.o. d1-21 q4w 13 x Palbociclib 125mg p.o. d1-21 q4w Bestrahlung und endokrine Therapie gemäß Leitlinien Primärer Endpunkt: Invasives Disease-free Survival (IDFS) PI: G. von Minckwitz Neoadjuvant Systemic Therapy © AGO e. V. in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2015.1 Vielen Dank für Ihre Aufmerksamkeit www.ago-online.de Neoadjuvant Systemic Chemotherapy Response Prediction I © AGO e. V. in der DGGG e.V. sowie in der DKG e.V. Factor CTS LoEOx2001 GR AGO Guidelines Breast Version 2015.1 Young age B 1a A + cT1 / cT2 tumors o. N0 o. G3 B 1a A ++ Negative ER and PgR status B 1a A ++ Triple negative breast cancer (TNBC) B 1a A ++ Positive HER2 status B 1a A ++ Non-lobular tumor type B 1a A + Early clinical response B 1b A + www.ago-online.de Neoadjuvant Systemic Chemotherapy Recommended Methods of Monitoring of Response © AGO e. V. Oxford / AGO LoE / GR in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2014.1 www.ago-online.de Breast ultrasound 2b B ++ Palpation 2b B ++ Mammography 2b B ++ MRI 2b B + PET(-CT) 2b B +/- Clip tumour region 5 D ++ Neoadjuvant Systemic Therapy Procedures in Case of Early Response © AGO e. V. Oxford / AGO LoE / GR in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2014.1 In case of early response following 6 to 12 weeks of neoadjuvant chemotherapy: Complete all chemotherapy before surgery i.e. ≥ 18 weeks of treatment 1b A ++ In case of response after 2 cycles of DAC in HR positive breast cancer consider 8 instead of 6 cycles of DAC 2b C www.ago-online.de + Neoadjuvant Systemic Therapy Procedures in Case of No Early Response © AGO Oxford / AGO LoE / GR e. V. in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2014.1 www.ago-online.de In case of no change: Completion of NST, followed by surgery Continuation of NST with non cross-resistant regimen AC or EC x 4 D x 4 or Pw x 12 DAC x 2 NX x 4 In case of progressive disease: Stop of NST and immediate surgery or radiotherapy Additional adjuvant chemotherapy with non cross-resistant regimen 2b C ++ 2b B + 2b B + 1b B + 4 D ++* 4 D +/-* * Study participation recommended Local/Regional Procedure after Neoadjuvant Therapy © AGO e. V. Oxford / AGO LoE / GR in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2014.1 www.ago-online.de Mark previous tumor region 5 Surgery 2b C ++ Microscopically clear margins 5 Tumor resection in the new margins Sentinel node biopsy (see chapter “Surgery”) D ++ D ++ 3b C + Surgical Procedure of the Axilla Before or After NACT © AGO Oxford / AGO LoE / GR e. V. in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2014.1 SLNB before or after NACT in cN0 SLNB before NACT SLNB after NACT 2b 2a B B + +/- Further surgical procedures depending on SLNB www.ago-online.de cN-Status (before NST) pN-Status (before NST) cN-Status (after NST) Surgical procedure cN0 pN0(sn) - nihil 1a A + cN0 pN+(sn) analogue ACOZOG ycN0 ALND 3 B +/- cN0 pN+(sn) not analogue ACOZOG ycN0 ALND 2b B + ycN0 SNB ALND 2a 2b B B +/+ ycN+ (CNB/FNA) ALND 2b B ++ cN+ cN+ (CNB/FNA) Neoadjuvant Systemic Therapy Indications for Mastectomy © AGO Oxford / AGO LoE / GR e. V. in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2014.1 Positive margins after repeated excisions 3b C ++ Radiotherapy not feasible 5 ++ In case of clinical complete response Inflammatory breast cancer www.ago-online.de D 2b C + +/- In case of pCR Multicentric lesions 2b C +/- cT4a-c breast cancer 2b B +/- Neoadjuvant Systemic Therapy Timing of Surgery and Radiotherapy © AGO e. V. in der DGGG e.V. sowie in der DKG e.V. Oxford / AGO LoE / GR Guidelines Breast Version 2014.1 Surgery 4 C ++ 2b B ++ After the nadir of the leucocyte count (2 to 4 weeks after last course of chemotherapy) www.ago-online.de Radiotherapy after surgery 2–3 weeks after surgery BCS Neoadjuvant Endocrine Therapy in patients with endocrine-responsive breast cancer © AGO Oxford / AGO LoE / GR e. V. in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2014.1 Postmenopausal patients: who are inoperable and can / will not receive chemotherapy 2a B + Optimizes the option for breast conserving therapy 1b A + Aromatase inhibitors (for > 3 months) 1aa B + Aromatase inhibitor + lapatinib (HER2+ BC) 2b B +/- who are inoperable and can / will not receive chemotherapy 5 C + Tamoxifen 2b C + Aromatase inhibitors + LHRH 1b C +/- Concurrent chemo-endocrine therapy 1b A - Prognostic factors during/after NST: quantitative ERexpression, level of Ki-67, N status, T status 1b B + Premenopausal patients www.ago-online.de Optimal duration of neoadjuvant endocrine therapy is unknown No long term results for neoadjuvant endocrine therapy (vs. adjuvant endocrine therapy)