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HER2-neu status en adjuvante chemotherapie bij het mammacarcinoom M. Bontenbal Erasmus MC - Daniel den Hoed Kliniek 19 november 2004.

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Presentation on theme: "HER2-neu status en adjuvante chemotherapie bij het mammacarcinoom M. Bontenbal Erasmus MC - Daniel den Hoed Kliniek 19 november 2004."— Presentation transcript:

1 HER2-neu status en adjuvante chemotherapie bij het mammacarcinoom M. Bontenbal Erasmus MC - Daniel den Hoed Kliniek 19 november 2004

2 Chemotherapy in breast cancer  Emperical, based on conclusions of studies  Extrapolated for the individual patiënt  Leads to inefficient and potentially toxic treatment for many to benefit a few Cardoso, Int J Oncol 2004, 24, 201

3 Challenge Select the best drug(s) for a particular patiënt with a biologically specific tumor Cardoso, Int J Oncol 2004, 24, 201

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5 HER2 in breast cancer Slamon D et al. Science 1987 HER2 oncoprotein overexpression HER2 oncogene amplification Shortened median survival HER2 overexpressing3 years HER2 normal6–7 years

6 MethodTargetFDA-approvedSilde-based IHCProteinYes a Yes FISHGeneYes a Yes CISHGeneNoYes Southern blotGeneNoNo RT-PCRmRNANoNo Microarray TP b mRNANoNo Tumor ELISAProteinNoNo Serum ELISAProteinYes c No a For prognosis and prediction of response and eligibility to receive trastuzumab therapy. b TP, transcriptional profiling. c For monitoring response of breast cancer to treatment. Ross, Molecular and Cellular Proteomics 2004, 3, 379 Methods of detection of HER-2/neu status in breast cancer

7 HER2-neu gene and protein and the prognosis in breast cancer Correlation status Number of Number of studies (%)cases (%) All cases None 8 (10%)1995 (8%) Univariate or 73 (90%)25.166 (92%) multivariate significance Independent on 52 (71%)NA multivariate analysis Totals 81 (%)27.161 (100%) Ross, The Oncologist 2003, 8, 307

8 HER2-neu gene and protein and the prognosis in breast cancer Cases with no correlation:Number of Number of studies (%)cases (%) Immunohistochemistry5 (63%) Southern blot2 (25%) RT-PCR1 (12%) Totals8 (100%)1995 (100%) Ross, The Oncologist 2003, 8, 307

9 HER2 positivity correlates with:  a poor prognosis

10 HER2 as a predictor of response to chemotherapy in MBC AuthorPt.HER2+TestTherapy Outcome (n)(%)HER2+ HER2- Stender ‘9731923EIAA+P;Pequal Gianni ‘97(49)35FISHA+P CR: 50% vs17% Niskanen ‘9717331IHCFEC q 1 equal or 4 wk Sjöström ‘0228342IHCMF vs D equal Poznak ‘0218825/15IHCPhase II equal P or D P, paclitaxel; D, docetaxel

11 HER2 as a predictor of response to chemotherapy in MBC AuthorPt.HER2+TestTherapyOutcome (RR) (n)(%) HER2+ HER2- Kònecny ‘0427535FISHEP 76%* 50% vs EC46% 33% Di Leo ‘0417620FISHA 27%35% vs D67%40% D, docetaxel; P, paclitaxel; *difference significant

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14 HER2 as a predictor of response to neo-adjuvant chemotherapy AuthorPt.HER2+TestTherapyOutcome (n)(%) Rozan ‘9832919IHCFAC cCR 20% HER- 31% HER+ S (5yr) : equal Colleoni ‘997310IHCFUFAvRR56% HER- 86% HER+ Zhang ‘037928IHC/FACRR, DFS (3yr): equal FISH Gonzalez ‘047128FISHP/D pCR10% HER- 16% HER+ OS (5yr): equal

15 HER2 as a predictor of response to adjuvant CMF AuthorPtHER2+TherapyConclusions (n)(%)DFS and OS Allred ‘9261314CMFpAdv. better in HER2- - Gusterson ‘93150616-19CMF (1)Adv. better in HER2- CMFp (6) Miles ‘9927430CMFAdv. better in HER2- - Menard ‘0138616CMFAdv. “equal” - Adv.: advantage

16 HER2 positivity correlates with:  a poor prognosis  relative resistance to alkylating agents

17 HER2 as a predictor of response to adjuvant anthracyclines AuthorPtHER2+TherapyConclusions (n)(%)Anthra in HER2+ Paik ‘9863838PFDFS, RFS, OS better* PAF Ravdin ‘9859516CAFTDFS better* T Paik ‘00203429ACDFS, RFS, OS better CMF Pritchard ‘0260220 (IHC)CMFDFS, OS better 24 (FISH)CEF Di Leo ‘0235421 (FISH)CMFEFS better EC hEC Moliterni ‘0350619CMF+A DFS, OS* better CMF * significant

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20 Dose-response effect of (neo-)adjuvant anthracyclines in HER2 positive tumors AuthorPt.HER2+TherapyConclusion (n)(%)HER2+ Thor ‘9899227 FISHCAFPFS, OS related (3 dose levels)to dose Petit ‘017926/30 FEC 50 orOR HER2-: equal FEC 100OR HER2+: FEC 50: 12% FEC 100: 100%

21 HER2 positivity correlates with:  a poor prognosis  relative resistance to alkylating agents  slightly higher anthracycline sensitivity

22 BCIRG 001 - Design Docetaxel 75 mg/m 2 Doxorubicin 50 mg/m 2 Cyclophosphamide500 mg/m 2 5-FU 500 mg/m 2 Doxorubicin 50 mg/m 2 Cyclophosphamide500 mg/m 2 F A C T A C R Dexamethasone premedication, 8 mg bid, 3 days Prophylactic Cipro 500 mg bid, day 5-14 Every 3 weeks x 6 cycles Stratification: Nodes: 1-3 4+ Center N= 1491

23 BCIRG 001 - Disease-Free Survival (ITT) 75% NEventsHR P-value Stratified Log Rank TAC7451720.72.0010 FAC746 227 1.0 0.8 0.6 0.4 0.2 0.0 0612182430364248546066 FAC TAC Cumulative probability 68% DFS Time(months)

24 BCIRG 001 - Overall Survival (ITT) 1.0 0.8 0.6 0.4 0.2 0.0 0 6 12 18 24 30 36 42 48 54 60 66 FAC TAC Cumulative Probability 87% 81% N EventsHR P-value Stratified Log-Rank TAC745 910.70.0080 FAC746 130 Survival Time (months)

25 HR = 0.60 P = 0.0088 Positive 0612182430364248546066 90 80 70 60 50 FAC TAC Time to First Event 100 BCIRG 001 - DFS by HER2 Status 0612182430364248546066 100 90 80 70 60 50 FAC TAC HR = 0.76 P = 0.046 Negative Time to First Event % Alive and Disease-Free (FISH performed centrally) Ratio of HRs 0.85 P = 0.4122

26 HER2 positivity correlates with:  a poor prognosis  relative resistance to alkylating agents  slightly higher anthracycline sensitivity  probably slightly higher taxane sensitivity

27 Author N Scheme RR TTPOS (%) (mo) (mo) Lück ‘00 541 EP 60/175 46 9.4NS EC 60/600 40 7.4 Carmichel ‘01 705 EP 75/200 406.5 NS EC 75/600 376.8 Jassem ‘01 267 AP 50/220 68 8.3 23.3 FAC 500/50/500 55 6.218.3 Biganzoli ‘02 271 AP 60/175 585.920.6 AC 60/600 546.020.5 First-line Anthracycline + Paclitaxel in MBC Phase III studies

28 First-line Anthracycline + Docetaxel in MBC Phase III studies 22.6 16.1 8.1 6.6 64 41 AT 50/75 FAC 500/50/500 216Bontenbal ‘03 34 28 7.8 5.9 63 34 ET 75/75 FEC 500/75/500 142Tubiana ‘03 21 22 7.1 6.7 55 44 TAC 75/50/500 FAC 500/50/500 484Mackey ‘02 22.5 21.7 8.6 7.3 59 47 AT 50/75 AC 60/600 429Nabholtz ‘03 OS (mo) TTP (mo) RR (%) SchemeNAuthor

29 Taxane-based adjuvant therapy Phase III studies Med. Trial Design Nodes Pt FU Outcome (n) (mo) (of taxane) CALGB 4AC  4P N+3170 69 DFS and OS 93444AC better NSABP4AC  4P N+3060 64 DFS better, B28 4AC OS equal BCIRG6TAC N+1491 55 DFS and OS 0016FAC better

30 Hormoon Receptoren ER+ en/of PgR+ ER- en PgR- Leeftijd / Menopauzale status / Aantal positieve klieren (N) PostmenopauzaalPremenopauzaal 50-59 jaar60-69 jaar> 70 jaar N> 1: 6 TAC + 5 jr tam. of LHRH of tam. + LHRH N> 1: 6 TAC N> 1: 5 FEC + 5 jr aromataseremmer N> 1: 5 FEC N1-3: 5 jr aromatase- remmer N 4: 5 FEC + 5 jr aromataseremmer N> 1: 5 FEC N > 1: 5 jr aromataseremmer N> 1: Geen advies mogelijk Tabel II: Richtlijn adjuvante systemische therapie bij een N+ mammacarcinoom met HER2-neu overexpressie

31 Incidence of neutropenic complications Geicam-9805 study (adjuvant TAC for N0) No. of patients % TAC FAC pre- post- pre- post- amendm. amendm. amendm. amendm. (n=109) (n=115) (n=111) (n=113) Neutropenia (all grades) 105 (96.3) 86 (74.8) 86 (86.5) 88(77.9) Neutropenia (grade 3-4) 102 (93.6) 47 (40.9) 47 (42.3) 44(38.9) Febrile neutropenia* 26 (23.9) 4 (3.5) 1 (0.9) 2 (1.8) Fever during 39 (35.8) 12 (10.4) 3 (2.7) 4 (3.5) * grade 2 fever (>38.5ºC) with grade 4 neutropenia and requiering I.V. antibiotics and/or hospitalisation in the some cycle


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