Primär systemische Therapie beim

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1 Primär systemische Therapie beim Mammakarzinom W.Eiermann Claus Hanusch A.Albert M.Kern H.Schuhmacher B.Ataseven ROTKREUZKLINIKUM München, Frauenklinik Akad. Lehrkrankenhaus der TU München EUSOMA Brustzentrum Cancer Internat. Research Group (CIRG) Translational Research In Oncology (TRIO) Michelangelo Foundation GABG - GBG

2 Primär systemische stemische Therapie Chemotherapie +/- Herceptin oder endokrine Therapie

3 NSABP B-27: Survival pcr vs. non-pcr Pat % Surv viving TRT N Deaths Non pcr pcr HR=0.33 p< Years after Surgery

4 ECTO: Main Efficacy Outcome at 7 years Arm A Arm B Arm C S A CMF S AT CMF AT CMF S RFS 69% 76% 72% DRFS 77% 84% 80% OS 82% 85% 84% LBR Cons. 6.9% 5.2% 5.3% Mast. 2.3% 3.5% 2.7% Eiermann,ASCO breast 2008

5 Primär systemische Therapie Zusammenhang: Rezeptorstatus und pcr Autor Patientenzahl Regime % HR negativ % pcr in HR negativ % pcr in HR positiv Houston 1018 Pooled data NA 20,6 5,6 Geparduo 913 dd AD/ACdoc 26,3 22,8 6,2 ECTO 438 AP-CMF 38,2 42,2 11,6 NSABP-B AC vs AC-doc 32 16,7 83 8,3 Gepartrio 286 DAC/DAC-NX 31,9 36,6 10,1 Gepardo 250 dd AD +/Tam 43,9 15,4 1,1

6 ECTO: Rate of breast conserving surgery 80 p < % 40 63% % ADJ PST (arms A+B) (arm C)

7 ECTO: Cumulative risk of LBR Patients LBR Treatment Adjuvant CT Primary CT 4.6% 4.1% years

8 ECTO: Cumulative risk of LBR Conservative surgery Mastectomy Patients LBR Treatment Patients LBR Treatment Adjuvant CT Adjuvant CT Primary CT Primary CT 5.3% 6.0% 2.7% 29% 2.9% years years

9 Faktoren die eine hohe LRR nach PST mit BET vorhersagen Klinisch N 2 3 Verbliebener Tumor über 2 cm Multifokaler Resttumor nach PST Lymphangiosis Vaskuläre Invasion Eiermann etal ASCObreast 2008

10 Integrated meta-analysis on 6634 patients with early breast cancer receiving neoadjuvant anthracycline-taxane +/- trastuzumab containing i chemotherapy von Minckwitz G, Kaufmann M, Kümmel S, Fasching P, Eiermann W, Blohmer JU, Costa SD, Loibl S, Mehta K, Untch A G O

11 Predictive Factors 35% 30% 25% Hormone Receptor Status P<0.001 yptis No ypt0 No 6.5% pcr20% 15% 10% 5% 3.2% 7.8% 54% 5.4% 31% 3.1% 11.4% 13.1% 1% 24.3% 0% ER + / PgR + ER + / PgR - ER - / PgR + ER - / PgR - N=3019 N=708 N=350 N=2179

12 25% 20% 15% Treatment Group Effects* Planned Duration of Regimen P< % 4.2% yptis No ypt0 No pcr 10% 2.6% 15.4% 15.1% 5% 6.9% 0% 8-12 w eeks 18 w eeks w eeks N=1369 N=1350 N=3244 * excluding patients treated with trastuzumab

13 25% 20% Treatment Group Effects* Concomitant vs. Sequential P=0.329 yptis No ypt0 No pcr 15% 10% 5% 3.2% 42% 4.2% 13.3% 13.3% 0% Concomitant Sequential N=3393 N=2570 * excluding patients treated with trastuzumab

14 Predictive Factors Age 35% 30% 25% 6.1% P<0.001 yptis No ypt0 No pcr 20% 15% 10% 5% 24.1% 6.1% 4.6% 17.1% 15.8% 42% 4.2% 4.0% 12.6% 12.2% 0% < N=424 N=667 N=2198 N=1980 N=1365

15 35% 30% 25% Predictive Factors Clinical Nodal Stage P<0.001 yptis No ypt0 No pcr 20% 15% 10% 5% 0% 5.0% 46% 4.6% 2.5% 16.5% 2.2% 13.7% 12.3% 7.6% cn0 cn1 cn2 cn3 N=3159 N=2904 N=285 N=92

16 35% 30% Predictive Factors Histological Grade P<0.001 yptis No ypt0 No 25% 6.3% pcr 20% 15% 10% 3.3% 21.5% 5% 0% 2.5% 4.2% 9.6% grade 1 grade 2 grade 3 N=237 N=3448 N=2497

17 Hormonrezeptor pos. Mammakarzinom und PST Niedrige pcr Rate ca. 10% Falls Brusterhaltende Therapie erwünscht sinnvoll Alternative Option präoperativ Aromatasehemmer (Letrozol oder Anastrozol )

18 GEPARTRIO -frühes Ansprechen (2 Zyklen) prädiktiv für pcr -aber die frühen Non responder zeigen trotzdem noch 5% pcr

19 Invasiv lobuläres Carcinom pcr Rate bei 3% vs 20 % bei invasiv i ductalem Ca.

20 Triple neg. Mamma Ca (TNBC) - Höhere pcr Rate als non -TNBC 22 vs 11% - Bei pcr vergleichbares OS (Liedtke 2008) - Bei Resttumor nach Chemotherapie hat TNBC schlechteres OS im Vergleich zu non TNBC mit Resttumor

21 Neoadjuvant trastuzumab in patients with HER2-positive locally ll advanced d breast cancer: primary efficacy analysis of the NOAH trial L Gianni, W Eiermann, V Semiglazov, GM Manikhas, A Lluch, S Tjulandin, A Feyereislova, P Valagussa, J Baselga The study is co-sponsored by the Michelangelo Foundation and F Hoffmann-La Roche

22 NOAH study design HER2-positive LABC HER2-negative LABC (IHC 3+ or FISH+) (IHC 0/1+) (n=115) (n=113) (n=99) H + AT AT AT q3w x 3 cycles q3w x 3 cycles q3w x 3 cycles H + T T T q3w x 4 cycles q3w x 4 cycles q3w x 4 cycles H q3w x 4 cycles CMF CMF + CMF q4w x 3 cycles q4w x 3 cycles q4w x 3 cycles Surgery followed by radiotherapy a Surgery followed by radiotherapy a Surgery followed by radiotherapy a H continued q3w 19 crossed over to H to week 52 IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation; H, trastuzumab (8 mg/kg loading dose then 6 mg/kg); AT, doxorubicin (60 mg/m 2 ), paclitaxel (150 mg/m 2 ); q3w, every 3 weeks; T, paclitaxel (175 mg/m 2 ); q4w, every 4 weeks a Hormone receptor-positive patients will receive adjuvant tamoxifen

23 Baseline characteristics (1) HER2 positive HER2 negative With H (n=115) Without H (n=112 a ) (n=99) Stage group, % T4, non-inflammatory Inflammatory disease N2 or ipsilateral il l nodes Hormone receptor status, % ER and / or PgR positive Both negative Age group, % <50 years years a 1/113 did not receive ethics approval for the last protocol amendment at the moment of the analysis ER, oestrogen receptor; PgR, progesterone receptor

24 pcr of primary tumour: intent-to-to treat population Patients, % % p=0.002 p=0.29 p= % p= % 17% 20% 16% 0 With H Without H HER2 With H Without H HER2 negative negative HER2 positive HER2 positive pcr tpcr tpcr: total pathologic complete response in breast and nodes Eiermann et al 2008; Semiglazov et al 2008

25 EFS by subgroup analysis of patients with HER2-positive disease: with vs without trastuzumab HR Patients (n) Total series Non inflammatory Inflammatory ER and / or PgR positive ER and PgR negative cn0 cn 1 pcr Non pcr 159 Median follow-up is 3 years Favours H Favours no H

26 Prim. systemische endokrine Therapie Kein Standard d Ältere Pat. mit fortgeschrittenem Ca. Bei Ablehnung einer Chemotherapie Keine Daten i.d. Prämenopause Beste Datenlage mit Letrozol

27 Primär systemische endokrine Therapie Aromataseinhibitoren in der Postmenopause Autor/Studie Patientenzahl Therapie crr (%) BCS (%) Eiermann et al Letrozol vs Tam 55 vs vs 35 Smith et al 2003 IMPACT 330 Anastrozol vs Tam vs Anastrozol+Tam 37 vs 36 vs vs 22 vs 26 Gil et al Exemestan Paepke et al Letrozol (4 Mo) Vs Letrozol o (8 Mo) 57 vs Semiglazov et al 2004 Chemo Vs 121 Anastrozol Vs Exemestan 76 vs 76 vs vs 32 vs 34

28 Welchen e Pat. ist Prim.syst. Therapie e als Alternative zur Adj.Therapie zu empfehlen? 1. Primär inoperables bzw. nicht brusterhaltend operables Ca. 2. Inflammatorisches Ca. 3. Stadium IIIA-B oder T3 oder Beteiligung ipsilateraler supra oder infraclav. Lnn (N3) 4. Rezeptorneg. und / oder HER2 neu pos. Befund nach hstanzbiopsie i 5. Kontraindikation für Chirurgie

29 Behandlungsvorschläge ausserhalb klin. Studien die empfohlen werden können. Regime Dosierung (mg/m²) Zeitablauf AC/EC D (P) A75, E90, C600, D100 Jeweils 4 Zyklen 3 wöchentlich DAC/DEC D75, A50, E75, C500 6 Zyklen 3 wöch. AP-CMF A60, P200, CMF i.v. 4 Zyklen 3 wöch. 4 Zyklen Tag 1+8, q 28 A=Doxorubicin, C=Cyclophophamide, E=Epirubicin, D=Docetaxel, P=Paclitaxel, M=Methotrexate, F=5-Fluorouracil

30 Primär systemische Chemotherapie MammaCa - Vorteile In vivo Chemosensitivitäts-Test Schnelle Beurteilung der Effektivität neuer Therapieregime Beurteilung von Tumoransprechen durch Patientin Vergleich von Biomarkern mit Tumoransprechen (prädiktive Faktoren, Resistenz-Faktoren) Erhöhte BET-Rate Plattform für Phase III Studien adjuvant