Neues aus San Antonio 2013

Transkript

1 Campus Innenstadt Campus Großhadern Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe Neues aus San Antonio 2013 Prof. Dr. Nadia Harbeck Leitung Brustzentrum der Universität München Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe Ludwig-Maximilians-Universität München Direktor: Prof. Dr. Klaus Friese

2 San Antonio 2013 Prof. Harbeck NEUES AUS SAN ANTONIO 2013: PRIMÄRES MAMMAKARZINOM Lokaltherapie Adjuvante Therapie Bisphosphonate HER2-positiv KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

3

4

5

6

7

8

9

10

11

12

13

14

15 KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

16 San Antonio Breast Cancer Symposium December 10-14, 2013 Cancer Therapy and Research Center at UT Health Science Center Effects Of Bisphosphonate Treatment On Recurrence And Cause-specific Mortality In Women With Early Breast Cancer: A Meta-analysis Of Individual Patient Data From Randomised Trials R Coleman, M Gnant, A Paterson, T Powles, G von Minckwitz, K Pritchard, J Bergh, J Bliss, J Gralow, S Anderson, D Cameron, V Evans, H Pan, R Bradley, C Davies, R Gray. Early Breast Cancer Trialists Collaborative Group (EBCTCG) s Bisphosphonate Working Group. KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe This presentation is the intellectual property of the EBCTCG.Contact r.e.coleman@sheffield.ac.uk for permission to reprint and/or distribute.

17 San Antonio Breast Cancer Symposium December 10-14, 2013 Cancer Therapy and Research Center at UT Health Science Center 15 Years of Adjuvant Bisphosphonate Trial Data Clodronate Diel et al (GABG; n=302) NEJM 1998 Saarto et al (Finnish; n=299) JCO 2001 Powles et al (RMH; n=1089) JCO 2002 Paterson et al (NSABP B34; n=3323) Lancet Oncol 2012 Zoledronic acid Gnant et al (ABCSG 12; n=1803) NEJM 2009 Coleman et al (AZURE; n=3360) NEJM 2011 Coleman et (ZO FAST; n=1065) Ann Oncol 2013 KLINIKUM DER UNIVERSITÄT MÜNCHEN Improved outcomes on ITT analysis No improved outcomes on ITT analysis Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe This presentation is the intellectual property of the EBCTCG.Contact for permission to reprint and/or distribute.

18 San Antonio Breast Cancer Symposium December 10-14, 2013 Cancer Therapy and Research Center at UT Health Science Center Bisphosphonate Analysis Outcomes Primary outcomes Time to recurrence: includes distant recurrence, local recurrence and new second primary breast cancer (ipsilateral or contralateral). Time to first distant recurrence: includes distant recurrence and ignores any prior loco-regional or contralateral recurrences. Breast cancer mortality. KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe This presentation is the intellectual property of the EBCTCG.Contact for permission to reprint and/or distribute.

19 San Antonio Breast Cancer Symposium December 10-14, 2013 Cancer Therapy and Research Center at UT Health Science Center Planned Subgroup Analyses Site of recurrence: distant metastasis, local recurrence or contralateral breast cancer Site of first distant metastasis: bone other, not bone Menopausal status: pre, peri, postmenopausal (natural/induced) Type of bisphosphonate: aminobisphosphonate, clodronate Schedule of bisphosphonate: advanced cancer, bone protection Age: <45, 45-54, 55-69, 70 ER status Nodal status: negative, N = 1-3+, N = 4+ Histological grade Duration of bisphosphonate: <1 year, 1-2 years, 2years Presence/ absence of chemotherapy KLINIKUM DER UNIVERSITÄT MÜNCHEN Recurrence rates in years 0-1, 2-4, 5-9, & 10+ after randomisation Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe This presentation is the intellectual property of the EBCTCG.Contact r.e.coleman@sheffield.ac.uk for permission to reprint and/or distribute.

20 San Antonio Breast Cancer Symposium December 10-14, 2013 Cancer Therapy and Research Center at UT Health Science Center Data Received And Included In Analyses Numbe r trials Number patients Trials received Patients received Percent received Trialsoforalclodronate % Trialsofaminobisphosphonates* % Alltrials % Aminobisphosphonates include: Zoledronic acid (65% of patient data received), Oral ibandronate (24%), Oral pamidronate (8%), Oral residronate (2%) Oral alendronate (1%) KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe This presentation is the intellectual property of the EBCTCG.Contact r.e.coleman@sheffield.ac.uk for permission to reprint and/or distribute.

21 San Antonio Breast Cancer Symposium December 10-14, 2013 Cancer Therapy and Research Center at UT Health Science Center Breast Cancer Recurrence: All Women All Recurrences Distant recurrences 3408 events 2835 events This presentation is the intellectual property of the EBCTCG.Contact for permission to reprint and/or distribute.

22 San Antonio Breast Cancer Symposium December 10-14, 2013 Cancer Therapy and Research Center at UT Health Science Center Distant Recurrence: All Patients Bone Recurrence 888 events Non-bone Recurrence 1947 events This presentation is the intellectual property of the EBCTCG.Contact for permission to reprint and/or distribute.

23 San Antonio Breast Cancer Symposium December 10-14, 2013 Cancer Therapy and Research Center at UT Health Science Center Breast Cancer Recurrence: Postmenopausal Women* Distant Recurrence Bone Recurrence Non Bone Recurrence 1564 events 508 events 1056 events Significantly Greater Effect on Bone than Other Distant Recurrence * Includes induced menopause and women aged >55 if unknown This presentation is the intellectual property of the EBCTCG.Contact r.e.coleman@sheffield.ac.uk for permission to reprint and/or distribute.

24 San Antonio Breast Cancer Symposium December 10-14, 2013 Cancer Therapy and Research Center at UT Health Science Center Bone Recurrence By Menopausal Status * includes women aged < 45 if unknown * Includes women aged if menopausal status unknown Significantly Reduced Bone Recurrence in Postmenopausal Women This presentation is the intellectual property of the EBCTCG.Contact r.e.coleman@sheffield.ac.uk for permission to reprint and/or distribute.

25 San Antonio Breast Cancer Symposium December 10-14, 2013 Cancer Therapy and Research Center at UT Health Science Center Distant Recurrence At Sites Other Than Bone By Menopausal Status * * May be an underestimate due to different competing risks No Difference in Non-bone Recurrence in Postmenopausal Women This presentation is the intellectual property of the EBCTCG.Contact r.e.coleman@sheffield.ac.uk for permission to reprint and/or distribute.

26 San Antonio Breast Cancer Symposium December 10-14, 2013 Cancer Therapy and Research Center at UT Health Science Center Bone Recurrence By Menopausal Status Aminobisphosphonates e.g. zoledronic acid Clodronate 0.79 SE p = 0.01 This presentation is the 0.74 SE p = 0.02 Bone Recurrence Irrespective Of Bisphosphonate Type

27 San Antonio Breast Cancer Symposium December 10-14, 2013 Cancer Therapy and Research Center at UT Health Science Center Bone Recurrence By Bisphosphonate Schedule: Postmenopausal Women This presentation is the intellectual property of the EBCTCG.Contact for permission to reprint and/or distribute.

28 San Antonio Breast Cancer Symposium December 10-14, 2013 Cancer Therapy and Research Center at UT Health Science Center Mortality All Women Breast cancer mortality 2097 events Non-breast cancer mortality 493 events This presentation is the intellectual property of the EBCTCG.Contact for permission to reprint and/or distribute.

29 San Antonio Breast Cancer Symposium December 10-14, 2013 Cancer Therapy and Research Center at UT Health Science Center Breast Cancer Mortality By Menopausal Status Significantly Improved Survival in Postmenopausal Women This presentation is the intellectual property of the EBCTCG.Contact for permission to reprint and/or distribute.

30 San Antonio Breast Cancer Symposium December 10-14, 2013 Cancer Therapy and Research Center at UT Health Science Center Mortality In Post-menopausal Women Breast cancer mortality 1146 events All cause mortality 1524 events This presentation is the intellectual property of the EBCTCG.Contact for permission to reprint and/or distribute.

31 San Antonio Breast Cancer Symposium December 10-14, 2013 Cancer Therapy and Research Center at UT Health Science Center Conclusions Adjuvant bisphosphonates reduce bone metastases and improve survival in post-menopausal women. 34% reduction in risk of bone recurrence (p= ). 17% reduction in risk of breast cancer death (p=0.004). No significant reduction in first distant recurrence outside bone Risk reductions similar irrespective of ER, node status, use/non use of chemotherapy. Benefits similar for aminobisphosphonates and clodronate. No effects apparent on disease outcomes in pre-menopausal women. No significant effects on non breast cancer deaths, contralateral breast cancer or loco-regional recurrence. This presentation is the intellectual property of the EBCTCG.Contact for permission to reprint and/or distribute.

32 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December 10-14, 2013 Postneoadjuvant treatment with zoledronate in patients with tumor residuals after anthracycline-taxane-based chemotherapy for primary breast cancer the phase III NATAN study (GBG 36/ABCSG 29) Gunter von Minckwitz, Mahdi Rezai, Holger Eidtmann, Hans Tesch, Jens Huober, Bernd Gerber, Dirk Michael Zahm, Jörn Hilfrich, Serban Costa, Michael Gnant, Jens Uwe Blohmer, Carsten Denkert, Claus Hanusch, Christian Jackisch, Sherko Kümmel, Peter A. Fasching, Andreas Schneeweiß, Stefan Paepke, Michael Untch, Valentina Nekljudova, Keyur Mehta, Sibylle Loibl for the GBG / AGO-B / ABCSG study groups This presentation is the intellectual property of GBG and AGO-B. Contact them at publications@germanbreastgroup.de for permission to reprint and/or distribute.

33 Study design Stratification factors Center Hormon receptor status (<10 or 10 % ER or PgR) Age (<50 / 50 years) Time since surgery (within 3 months, 1 year, 2 years, or 3 years) R A N D O M I Z A T I O N Observation Zoledronic acid 4 mg iv. Every 4 weeks for the first 6 doses (year 0-0.5) Every 3 months for 8 doses (year ) Every 6 months for 5 doses (year ) Prior and/or simultaneous endocrine/trastuzumab treatment or radiotherapy

34 Primary objective To determine disease-free survival (DFS) after zoledronic acid for 5 years vs. observation in patients with chemo-insensitive breast cancer after preoperative anthracycline/taxane containing chemotherapy Event definition: any invasive or non-invasive ipsilateral locoregional, contralateral, distant recurrence, secondary primaries or death due to any cause (corresponding to DFS-DCIS 1 ) 1 Hudis C, JCO 2007

35 Baseline Characteristics N = 693 patients Age Median 50 years Range ypt0/n+ 3 % ypn0 27 % ypt % N+ 73 % ypt4 4 % Her2 pos 17% HR pos 80% Her2 neg 83% HR neg 20% Ductal Lobular Other 71% 17% 12%

36 Event rate Observed event rate only 50% of expected rate Interim analysis was therefore supported by a non-protocolled Bayesian futility analysis Futility boundary was set to 15% for the likelihood that results would become statistically significant if follow up continued until 316 events (approximately 8 additional years)

37 Disease free survival HR=1.042 (observation to ZA) 95% CI

38 Conclusions Postneoadjuvant treatment of zoledronate does not improve outcome in patients without pcr after neoadjuvant anthracycline-taxane-based chemotherapy for early breast cancer. No subgroup effect observed No new safety signal for zoledronate observed Other options are currently investigated in this setting, e.g. Rucaparib (PARP-inh.) in TNBC (BRE09-146) Trastuzumab emtansine in HER2+ disease (Katherine) palbociclib in HR+/HER2- disease (Penelope)

39 BETH: A Randomized Phase III Study Evaluating Adjuvant Bevacizumab Added to Trastuzumab/Chemotherapy for Treatment of HER2+ Early Breast Cancer TRIO -011 / NSABP B-44-1 / BO20906 D.Slamon, S.Swain, M.Buyse, M.Martin, C.Geyer, Y-H.Im, T.Pienkowski, S-B.Kim, N.Robert, G.Steger, J.Crown, S.Verma, W.Eiermann, J.Costantino, SA.Im, E.Mamounas, L.Schwartzberg, A.Paterson, J.Mackey, L.Provencher, M.Press, M.Thirlwell, V.Bee-Munteanu, V.Henschel, A.Crepelle-Flechais, N.Wolmark

40 BETH Trial Design N=3509 Node-Positive or High Risk Node-Negative Breast Cancer HER2 Positive by Central Testing COHORT 1 Non-anthracycline regimen COHORT 2 Anthracycline regimen TCH H 6 (T 75 / C AUC 6) 1 year H ( load 8mg/kg H 6 mg/kg q3w) TH FEC H 3 T Fu 600 / E 90 / C year H (load 8mg/kg H 6 mg/kg q3w - not during FEC) N=3231 N=278 STRATIFICATION Number of positive Nodes (0, 1-3,4+) Hormone Receptor Status (+/-) Geographic Center STRATIFICATION Number of positive Nodes (0, 1-3,4+) Hormone Receptor Status (+/-) Geographic Center TCH H Arm 1A TCHB HB Arm 1B TH FEC H Arm 2A THB FEC HB Arm 2B N=1617 N=1614 N=140 N=138 Slamon et al, SABCS 2013

41 BETH Assumptions BETH: Assumptions based on results of BCIRG-006 (AC T vs AC TH vs TCH) at 3-year follow-up: 86% DFS on TCH arm 87% DFS on AC TH arm Slamon et al, SABCS 2013

42 Primary Endpoint: IDFS for overall study population % Estimated probability CTx+H (N=1757) CTx+H +BEV (N=1752) Events, n (%) 145 (8) 147 (8) Stratified HR (95% CI) Log-rank p-value Unstratified HR (95% CI) Log-rank p-value 1.00 ( ) ( ) % Median Follow-up: 38 months 0 No. at risk: Time (months) CTxHB-HB CTxH-H Slamon et al, SABCS 2013

43 AEs of Special Interest Grade 3/4 AEs, # of patients (%) All grade 3/4 AEs of special interest Chemo- Trastuzumab (n=1750) Chemo- Trastuzumab Bevacizumab (n=1722) p value 143 (8%) 463 (27%) < Hypertension 78 (4%) 329 (19%) < Thromboembolic event 42 (2%) 50 (3%) Bleeding 9 (<1%) 42 (2%) < CHF 12 (<1%) 23 (2.1%) Wound healing complication 10 (<1%) 15 (<1%) Proteinuria 1 (<1%) 21 (1%) < Gastrointestinal perforations 1 (<1%) 11 (<1%) Fistula/Abscess 3 (<1%) 3 (<1%) Slamon et al, SABCS 2013

44

45

46

47

48

49

50

51

52

53 San Antonio 2013 Prof. Harbeck KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

54 WSG-ADAPT Studie: HR+ Subprotokoll Hohes Risiko Chemotherapie Endokrine Therapie Prognose Stanzbiopsie (RS, Ki-67) Endokrine Therapie 3 weeks Ansprechen OP / Stanz- Biopsie (RS, Ki-67) Mittleres Risiko Niedriges Proliferations- Ansprechen Gutes Proliferations- Ansprechen Niedriges Risiko Endokrine Therapie Studienleitung: N. Harbeck (LKP), München; U. Nitz, Mönchengladbach

55 ADAPT Studie: Rekrutierung HR+ (HER2-) WSG GmbH 55

56 Biomarkers in early breast cancer Prof. Harbeck ADAPT run-in phase (n=400) bestätigt: Machbarkeit des Studiendesigns im klinischen Alltag Annahmen im Protokoll: > 70% Ki67 Abfall nach endokriner Induktionstherapie Harbeck et al, SABCS 2013 KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

58 San Antonio 2013 Prof. Harbeck PRIMÄRES MAMMAKARZINOM NACH SAN ANTONIO 2013: Adjuvante Strahlentherapie: Strahlentherapie verbessert lokale Kontrolle nicht aber Gesamtüberleben bei älteren Patientinnen mit low risk hormonempfindlichen Tumoren Differenzierte Aufklärung auch über Alternativen (z.b. IORT, Hypofraktionierung) erforderlich KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

59 San Antonio 2013 Prof. Harbeck PRIMÄRES MAMMAKARZINOM NACH SAN ANTONIO 2013: Adjuvante Bisphosphonat-therapie: Signifikanter Effekt auf Knochenmetastasen und Brustkrebsbedingte Mortalität nur bei POSTmenopausalen Frauen: unabhängig von ER Status oder Bisphosphonat-Regime (oral vs. i.v.) HER2-positiv: Frühes Mammakarzinom (Stadium I): Exzellentes Outcome nach Paclitaxel und Trastuzumab (3 Jahres DFS 98,7%) Studie beantwortet nicht die Frage, welche Pat. KEINE Chemotherapie mit Trastuzumab benötigt BETH-Studie: keine Rolle für Bevacizumab KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

60 EVIDENZBASIERTE BRUSTKREBS-THERAPIE Jährlich aktualisierte, evidenzbasierte Empfehlungen zur Diagnostik und Therapie AGO (DKG, DGGG) KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe