Neoadjuvant (Primary) Systemic Therapy

Transcription

1 Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer Version Neoadjuvant (Primary) Systemic Therapy

2 Neoadjuvant Systemic Therapy Version Version 2002: Costa Versions : Bauerfeind / Blohmer / Dall / Fersis / Göhring / Harbeck / Heinrich / Huober / Jackisch / Kaufmann / Loibl / Lux / von Minckwitz / Müller / Nitz / Schneeweiss / Schütz / Solomayer / Untch Version 2015: Friedrich / Schneeweiss

3 Neoadjuvant Systemic Chemotherapy Indications Version Oxford / AGO LoE / GR 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 +

4 Subtype-specific General Systemic Strategies Version In case of indication for chemotherapy, AGO consider neoadjuvant approach ++ HR+/HER2- and low risk : Endocrine therapy without chemotherapy ++ HR+/HER2- and high risk Conventionally dosed AT-based chemotherapy ++ Dose dense & escalated in case of high tumor burden + Followed by endocrine therapy ++ HER2+ 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 + TNBC Conventionally dosed AT-based chemotherapy ++ Dose dense & escalated + Plus Carboplatin in case of family history for BC/OC or gbrca alteration +

5 Anteil Patienten mit pcr (%) ypt0/is ypn0 ypt0/is ypn0 ypt0/is ypn0 ypt0/is ypn0 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 ypt0/is ypn0 ypt0 ypn0 ypt0 ypn0 ypt0 ypn0 ypt0 ypn0 Verbesserung der pcr-raten durch Platin beim TNBC 70 p=0, p=0, p=0, P<0, TNBC HR (N=992)

6 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?

7 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

8 Neoadjuvant Systemic Chemotherapy Recommended Regimens and Schedules Version Oxford / AGO LoE / GR 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 +/- in case of family history of BC/OC or BRCA alteration 2b B + *Study participation recommended

9 Superior Carboplatin Containing Regimens in the Neoadjuvant Setting Version Author Study Regimen pcr rate Sikov WM, et al. (JCO 2015) von Minckwitz G, et al. (Lancet Oncol 2014) Ando M, et al. (BCRT 2014) CALGB Phase II Gepar Sixto Phase II Paclitaxel 80mg/m² qw x12 + Carboplatin AUC 6 q3w x4 dd AC q2w x4 NPLD 20mg/m² qw x18 + Paclitaxel 80mg/m² qw x18 + Carboplatin AUC 1.5 qw x18 + Bev 15mg/kg q3w x6 Phase II Paclitaxel 80mg/m² qw x12 + Carboplatin AUC 5 q3w x4 FEC q3w x4 TNBC ± Cb: 54% vs 41% (ypt0/is ypn0) TNBC ± Cb: 53% vs. 37% (ypt0 ypn0) TNBC ± Cb: 61% vs. 26%

10 Neoadjuvant Systemic Chemotherapy Recommended Regimens and Schedules Version Oxford / AGO LoE / GR 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 +/- in case of family history of BC/OC or BRCA alteration 2b B + *Study participation recommended

11 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 Overall Survival Earl HM, et al. Lancet Oncol 15: , 2014

12 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: , 2014

13 Neoadjuvant Systemic Therapy Response Prediction II Version Factor LoE 2009 CTS GR AGO Multigene signature III C B +/- Ki-67 I B A + Tumour infiltrating lymphocytes I B B +/- PIK3CA mutation II B B +/-

14 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]

15 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

16 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

17 Neoadjuvant Systemic Therapy Response Prediction II Version Factor LoE 2009 CTS GR AGO Multigene signature III C B +/- Ki-67 I B A + Tumour infiltrating lymphocytes I B B +/- PIK3CA mutation II B B +/-

18 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

19 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: , 2013

20 Neoadjuvant Targeted Therapy in HER2 Positive Tumors Version Oxford / AGO LoE / GR Trastuzumab in combination with chemotherapy 1b A ++ Lapatinib in combination with chemotherapy 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

21 Anteil Patienten mit pcr (%) Verbesserung der pcr-raten (ypt0/is ypn0) durch duale Anti-HER2 Therapie beim HER2+ EBC pcr pcr HR+ pcr HR Cortazar. Lancet 2014; 2 Carey. ASCO 2013; 3 Baselga. Lancet 2012; 4 Robidoux. Lancet Oncol 2013; 5 Von Minckwitz. Lancet Oncol 2014; 6 Gianni. Lancet Oncol 2012; 7 Schneeweiss. Ann Oncol 2013

22 Anteil Patienten mit pcr (%) pcr-raten (ypt0/is ypn0) beim HER2+ EBC Getrennt nach HR-Status % pcr pcr HR+ pcr HR HER2+ HR- HR Cortazar. Lancet 2014; 2 Carey. ASCO 2013; 3 Baselga. Lancet 2012; 4 Robidoux. Lancet Oncol 2013; 5 Von Minckwitz. Lancet Oncol 2014; 6 Gianni. Lancet Oncol 2012; 7 Schneeweiss. Ann Oncol 2013

23 Neoadjuvant Targeted Therapy in HER2 Positive Tumors Version Oxford / AGO LoE / GR Trastuzumab in combination with chemotherapy 1b A ++ Lapatinib in combination with chemotherapy 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

24 Neoadjuvant Targeted Therapy in HER2 Negative Tumors Version Bevacizumab in combination with chemotherapy Oxford / AGO LoE / GR In hormone receptor positive BC 1b B - In TNBC 1b B +/-

25 GeparQuinto (Phase III): Neoadj. EC Doc vs. ECB DocBev beim HER2- EBC 2cm (N=1.925) Überleben Disease-free Survival Overall Survival Gerber B et al. SABCS 2014 (P ), poster discussion

26 Keine Verbesserung des invasiven DFS durch Bevacizumab adjuvant beim TNBC Studie N (TNBC) Therapie Primärer Endpunkt HR p BEATRICE x CT± B B (1y) E AC-P ± B B (1y) IDFS 0,87 0,18 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

27 Neoadjuvant Systemic Chemotherapy Clinical Benefit Version 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 +/-* * Study participation recommended

28 Adjuvant Systemic Therapy after Neoadjuvant Systemic Treatment Version Endocrine treatment in endocrine responsive disease 1a A ++ Complete trastuzumab treatment for 1 year in HER2-positive disease 2b B ++ In case of insufficient response Oxford / AGO LoE / GR Further chemotherapy 3 C - Experimental therapies in clinical trials 5 D +

29 KATHERINE (Phase III): Studiendesign und Endpunkte Operation ct1-4, cn0-3, M0 HER2+ Neoadjuvante Therapie: Anti-HER2/ Taxan ± Anthrazyklin Residualer invasiver Tumor 14 x Trastuzumab 6mg/kg i.v. q3w 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

30 PENELOPE B (Phase III): Studiendesign und primärer Endpunkt Operation ct1-4, cn0-3, M0 HR+ HER2- Neoadjuvante Chemotherapie inklusive Taxan Residualer invasiver Tumor mit CPS-EG 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

31 Neoadjuvant Systemic Therapy Version Vielen Dank für Ihre Aufmerksamkeit

32 Neoadjuvant Systemic Chemotherapy Response Prediction I Version Factor CTS LoE Ox2001 GR AGO 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 +

33 Neoadjuvant Systemic Chemotherapy Recommended Methods of Monitoring of Response Version Oxford / AGO LoE / GR Breast ultrasound 2b B ++ Palpation 2b B ++ Mammography 2b B ++ MRI 2b B + PET(-CT) 2b B +/- Clip tumour region 5 D ++

34 Neoadjuvant Systemic Therapy Procedures in Case of Early Response Version In case of early response following 6 to 12 weeks of neoadjuvant chemotherapy: Oxford / AGO LoE / GR 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 +

35 Neoadjuvant Systemic Therapy Procedures in Case of No Early Response Version In case of no change: Completion of NST, followed by surgery 2b C ++ Continuation of NST with non cross-resistant regimen 2b B + AC or EC x 4 D x 4 or Pw x 12 2b B + DAC x 2 NX x 4 1b B + In case of progressive disease: Oxford / AGO LoE / GR Stop of NST and immediate surgery or radiotherapy 4 D ++* Additional adjuvant chemotherapy with non cross-resistant regimen 4 D +/-* * Study participation recommended

36 Local/Regional Procedure after Neoadjuvant Therapy Version Oxford / AGO LoE / GR Mark previous tumor region 5 D ++ Surgery 2b C ++ Microscopically clear margins 5 D ++ Tumor resection in the new margins 3b C + Sentinel node biopsy (see chapter Surgery )

37 Surgical Procedure of the Axilla Before or After NACT Version SLNB before or after NACT in cn0 SLNB before NACT SLNB after NACT Oxford / AGO LoE / GR 2b 2a B B + +/- Further surgical procedures depending on SLNB cn-status (before NST) pn-status (before NST) cn-status (after NST) Surgical procedure cn0 pn0(sn) - nihil 1a A + cn0 cn0 pn+(sn) analogue ACOZOG pn+(sn) not analogue ACOZOG cn+ cn+ (CNB/FNA) ycn0 ycn0 ALND 3 B +/- ycn0 ALND 2b B + SNB ALND 2a 2b B B +/- + ycn+ (CNB/FNA) ALND 2b B ++

38 Neoadjuvant Systemic Therapy Indications for Mastectomy Version Oxford / AGO LoE / GR Positive margins after repeated excisions 3b C ++ Radiotherapy not feasible 5 D ++ In case of clinical complete response Inflammatory breast cancer 2b C + In case of pcr +/- Multicentric lesions 2b C +/- ct4a-c breast cancer 2b B +/-

39 Neoadjuvant Systemic Therapy Timing of Surgery and Radiotherapy Version Oxford / AGO LoE / GR Surgery 4 C ++ After the nadir of the leucocyte count (2 to 4 weeks after last course of chemotherapy) Radiotherapy after surgery 2b B weeks after surgery BCS

40 Neoadjuvant Endocrine Therapy in patients with endocrine-responsive breast cancer Version Postmenopausal patients: Oxford / AGO LoE / GR 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) 1a a B + Aromatase inhibitor + lapatinib (HER2+ BC) 2b B +/- Premenopausal patients 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 + Optimal duration of neoadjuvant endocrine therapy is unknown No long term results for neoadjuvant endocrine therapy (vs. adjuvant endocrine therapy)