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Post San Antonio & Post EBCC Chemotherapie Aafke H. Honkoop.

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Presentatie over: "Post San Antonio & Post EBCC Chemotherapie Aafke H. Honkoop."— Transcript van de presentatie:

1 Post San Antonio & Post EBCC Chemotherapie Aafke H. Honkoop

2 San Antonio BCS & EBCC Presentaties Neoadjuvante chemotherapie (2) Adjuvante chemotherapie (4) Gemetastaseerde ziekte (2) Posters Neoadjuvante chemotherapie Adjuvante chemotherapie Nieuwe middelen Gemetastaseerde ziekte

3 Neoadjuvante chemotherapie Comparison of TAC versus NX in patients non- responding to 2 cycles of neoadjuvant TAC- first results of the phase III GEPARTRIO study by the German Breast Group Primary endocrine therapy versus chemotherapy in postmenopausal ER-positive patients Semiglazov, et al

4 Comparison of Dox/Doce/Cyclo (TAC) versus Vino/Cape ) (NX) in patients non-responding to 2 cycles of neoadjuvant TAC GEPARTRIO

5 GEPARTRIO Doseringen: TAC: 75/50/500 mg/m2 NX : 25 d1,8/2500 d1-14 Eindpunten studie Echografische response Pathologische response

6 GEPARTRIO N=620TACNX Klin R72%67% Echo R59%63% BCS58%60% Path CR5.3%5.9%

7 GEPARTRIO, conclusies 2/3 heeft uiteindelijk nog response op TAC TAC meer toxiciteit (hematologisch als ook niet-hematologisch) NX goed alternatief voor TAC

8 Neoadjuvante endocriene therapie versus chemotherapie T2N1, T3N1-0, T4NOMO (geen IBC) ER+, postmenopausale patienten AI versus Doxorubicine/Paclitaxel 60/200, q 3wkn Eindpunten: Klinische response Echografische response Pathologische response mammasparende operatie Semiglazov, et al

9 Neoadjuvante endocriene therapie versus chemotherapie N=239EndocrienChemotherapie Klin R62.2%63.5% Tijd tot R57 dgn51 dgn Path R5.2%8.5% Progressie9%8.5% Sparende OK60%59%

10 Neoadjuvante endocriene therapie versus chemotherapie CONCLUSIES Effectiviteit endocriene therapie gelijk aan chemotherapie Endocriene therapie minder toxisch

11 Adjuvante chemotherapie GEICAM 9906; 6xFEC versus 4xFEC -8xP q1wk 4xTC versus 4xAC, Jones et al. Houston INT C9741 Dose Dense INT E1199, 4xAC- P1, P3, D1 of D3

12 Doce/Cyclo (TC) versus Dox/Cyclo (AC) in early breast cancer N=1016, N0 en N+ 4 x AC versus 4 x TC Chemotherapie voor Radiotherapie Tam na chemotherapie, indien ER+ Eindpunten: DFS (primair) OS en Toxiciteit (secundair) Jones et al, Texas

13 TC versus AC

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16 TC versus AC conclusies TC betere DFS TC minder toxiciteit TC nieuwe standaard

17 Five year follow-up of INT C9741: dose-dense is safe and effective

18 INT C9741

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24 INT C9741 conclusies Dose Dense is superior Geen verschil sequentieel versus gelijktijdig Data stabiel t.o.v. 3 jaar geleden Toxiciteit van DD acceptabel Groter voordeel van DD bij ER-

25 Phase III study of AC followed by P or D Q 1wk or Q 3wk in N+ and N0 high risk Patients: INT E1199

26 INT E1199 Eindpunten : DFS en OS Vergelijking : P versus D Q1 versus Q3 P3 als standaard versus andere armen (subset ER- P3 versus andere armen) Median follow-up: 46.5 mnd N=4988

27 INT E1199

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31 INT E1199 conclusies Docetaxel en Paclitaxel even effectief Q1 wk gelijk aan Q3 wk Trend voor een betere DFS P1 tov P3 (meer uitgesproken bij ER-) D1 meer gr3/4 tox; 39% versus 24%

32 GEICAM xFEC versus 4xFEC- 8xP in N+ BC

33 GEICAM 9906 Eindpunten: DFS en OS Vergelijking: 6xFEC90 4xFEC90 - 8xP 100 q1wk Median follow-up: 47 mnd N=1248

34 GEICAM 9906

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36 Geicam 9906

37 Geicam 9906 conclusies Toxiciteit van beide schema’s acceptabel FEC - P meer myalgie FEC meer neutropenie Adjuvant FEC - P effectiever in alle subgroepen tav DFS Geen verschil in OS

38 Gemetastaseerd mammacarcinoom Meta-analyse eerste lijn Taxanen (Piccart) Hoge dosis chemotherapie (Rodenhuis)

39 INCORPORATION OF TAXANES IN FIRST LINE CHEMOTHERAPY FOR ADVANCED BREAST CANCER : A META-ANALYSIS Presenter : Martine J. Piccart-Gebhart, MD, PhD Statisticians : Tomasz Burzykowski, PhD, Marc Buyse, ScD Clinical Fellows : Gul Atalay, Daniela Rosa Financial support : EORTC Breast Cancer Group

40 In2002 In2002 N = 12 trials with inconsistent results N = 12 trials with inconsistent results – Doxorubicin (8), Epirubicin (4) – Docetaxel (6), Paclitaxel (6) Survival gain in only one trial (Jassem et al) Survival gain in only one trial (Jassem et al) Greater toxicity and cost with the anthracycline + taxane regimens Greater toxicity and cost with the anthracycline + taxane regimens – Febrile neutropenia 8 – 21% (paclitaxel + A) 23 – 33% (docetaxel + A) 23 – 33% (docetaxel + A) – Cross-over rates 24 – 57%

41 TrialAuthor Control arm and taxane N Combination trials : Paclitaxel (P) CCEI Paclitaxel BCSG Jassem FAC / ET 267 EORTC Biganzoli AC / AT 275 UKCCCR AB01 Carmichael EC / ET 705 AGOLuck 516 Combination trials : Docetaxel (D) TAX 306 Study Group Nabholtz AC / AD 429 TAX 307 study Group Mackey FAC / DAC 484 CCC Netherlands Bontenbal FAC / AD 216 French trial Bonneterre FEC / ED 142 Single agent trials : Paclitaxel (P) or Docetaxel (D) ECOG E1193 Sledge A / P 490 EORTC Paridaens A / D 331 Tax 303 Study Group Chan A / D 98 Total3953

42 Individual patient data were collected (not merely summary statistics from the literature): All relevant trials were included, whether published or not All relevant trials were included, whether published or not Reporting biases were avoided Reporting biases were avoided Data were extensively checked (and resulted in the exclusion of one trial) Data were extensively checked (and resulted in the exclusion of one trial) The power of the analyses was maximized The power of the analyses was maximized Subgroup analyses (by visceral disease / ER status) could be performed Subgroup analyses (by visceral disease / ER status) could be performed

43 Progression-free survival hazard ratios

44 Overall survival hazard ratios

45 Single agent doxorubicine (at 75 mg/m2) was better than single agent taxane in terms of response rate and PFS in one of 3 trials Single agent doxorubicine (at 75 mg/m2) was better than single agent taxane in terms of response rate and PFS in one of 3 trials Taxanes in combination with anthracyclines provide greater chances of "response" remain the treatment of choice when a "response" is desirable Taxanes in combination with anthracyclines provide greater chances of "response" remain the treatment of choice when a "response" is desirable The impact of taxanes on progression-free survival appears to be marginal and their impact on survival has not been shown by this meta-analysis of trials conducted in the "empirical" era of oncology The impact of taxanes on progression-free survival appears to be marginal and their impact on survival has not been shown by this meta-analysis of trials conducted in the "empirical" era of oncology More attention needs to be paid to cross-over More attention needs to be paid to cross-over Strong considerations should be given to trials run in better defined “molecular” sub-populations Strong considerations should be given to trials run in better defined “molecular” sub-populations

46 High-Dose Chemotherapy in Breast Cancer A ‘Critical Review’, or: Is it dead ? Rodenhuis

47 High-dose Therapy in Breast Cancer: in stage IV patients (phase II) Strong rationale derived from model systems High objective response rates Excellent DFS rate in high-risk primary breast cancer (phase II)

48 861 Stage IV Patients Randomized 6 studies, 6 different HD regimens

49 High-Dose Chemotherapy with PBPC-Tx in Advanced Breast Cancer High-dose chemotherapy cannot eradicate macroscopic disease It may (sometimes) eradicate micrometastases (when any macrometastatic disease is either resected or irradiated ( ? but could this also be achieved by conventionally dosed chemotherapy ? )

50 High-Dose Chemotherapy with PBPC-Tx in High-Risk Breast Cancer Over 5500 patients treated in 14 (reported) randomized studies Many studies (all underpowered, most too early for OS analysis) show trend for RFS benefit for dose-intensive arm

51 5627 Patients with High-Risk Breast Cancer in 14 Randomized Studies of HD

52 Dutch National Study of High-Dose Chemotherapy in the Adjuvant Treatment of High-Risk Breast Cancer (‘N4+ trial’) Largest Randomized Study of HD Chemotherapy (N=885) No excessive Therapy-Related Mortality (1%) Study with best patient compliance (e.g. no cross- over conventional to high-dose arm) Symmetrical design (HD chemo only difference between arms) Cyclophosphamide and ThioTepa not as continuous and simultaneous infusions Only study with Pathology Review

53 Dutch National Study of HD-CT in High-Risk Breast Cancer Recurrence-Free Survival – All 885 Patients 58.9% 64.3% HR = 0.84, p=0.076 March 2005

54 Dutch National Study of HD-CT in High-Risk Breast Cancer Recurrence-Free Survival – 181 HER2/neu-positives HR = 1.26, p= % 43.9%

55 Dutch National Study of HD-CT in High-Risk Breast Cancer Recurrence-Free Survival – 621 HER2/neu-negatives HR = 0.68, p= % 70.7% March 2005

56 Dutch National Study of HD-CT in High-Risk Breast Cancer Overall Survival – 621 HER2/neu-negatives 78.2% 71.0% HR = 0.72, p=0.02 March 2005

57 Predictive Markers for the Optimal Selection of Chemotherapy HER2/neu overexpression – decreased sensitivity to alkylator regimens, e.g. CMF –Several retrospective studies: IBCSG and American Intergroup Study publ. In 1989 HER2/neu overexpression – sensitivity to anthracyclines –CALBG study –NSABP studies B11 and B15 –European consortium –EORTC –NCIC MA.9 Trial –And several others

58 HER2/neu Subgroup Analysis Unplanned subgroup analysis: suspect BUT: 1.The subgroup is very large (621 patients) 2.Not a multiple-testing result nPrecisely one cut-off value defines subgroups nTest for interaction: p < Makes sense with respect to biology nHER2-positives not associated with BRCA/Fanconi pathway defects nHER2/neu-positives resistant to alkylating agents (in the absence of Trastuzumab) 4.Makes sense clinically: subgroup analyses of other (non- randomized) high-dose trials

59 Subgroup Analysis: Triple Negative Tumors (“basal –like”) Basal subtype Luminal subtype HER+ subtype

60 Patients with ‘Triple-negative’ (= basal-like) Tumors HR=0.67, p= % 49.5% March 2005

61 Conclusion Dutch Study 1.HER2-amplified tumors do not respond to HD-alkylators (confirmed) 2.HD-sensitive subgroup present in set of HER2-negative tumors –Luminal-like tumors: part castration effect ? –Basal-like tumors: CTC is effective (HR=0.70) 3.Formal proof to be delivered (prospective study)

62 High-Dose Alkylating Therapy in Breast Cancer A Testable Hypothesis All data from clinical studies are compatible with the existence of a subgroup of breast cancers (+/- 20%) which is exquisitely sensitive to alkylating chemotherapy This subgroup is HER2/neu-negative It may well be characterized by a DNA repair- deficit (no Homologous Recombination), as caused by –Loss of BRCA 1 or –2 –A defect in the Fanconi anemia pathway –Amplification of the EMSY gene HR-deficiency causes x sensitivity to Cyclophosphamide and Cisplatin/Carboplatin in vitro

63 Pacitaxel 175 mg/m 2 q 2 wk x 2 Pacitaxel 175 mg/m 2 q 2 wk x 2 Cycloph: 3 g/m 2 ThioTepa: 250 mg/ m 2 Carbopl: AUC = 10 G-CSFPBPC Cycloph: 3 g/m 2 ThioTepa: 250 mg/ m 2 Carbopl: AUC = 10 Endocrine Adj. Therapy Follow-Up Out-patient Tandem PBPC-Tx High-risk patients following anthracycline- based chemotherapy. Tumors with HR-defect (IHC & microarray)

64 HD Alkylating Chemotherapy in Breast Cancer: not to be Abandoned Strong biological and clinical evidence (short of proof) that HD alkylating chemotherapy is very active in a subgroup of breast cancers (20-30%) Adequate studies that include these subgroups are desirable, despite the absence of industry funding A 30% decrease in mortality due to HD therapy remains very important, even in the era of Trastuzumab and Aromatase Inhibitors (e.g. in triple-negative tumors)

65 POSTERS

66 Neoadjuvant chemotherapie Veel kleine fase II studies Verschillende schema’s, conventioneel of dose-dense Path CR 10-35%

67 Neoadjuvant chemotherapie Chemotherapie schemaNK RpCR 4xFEC100 q3wk – 4xD 100, q3wk10065 %25% 3xG1000 +D 75 d1,8 – V25+E100 d21,29, q6wk6290%27% 6xA50+D30 d1,8,15 + X1500, d1-14, q4wk3480%12% 4xAC60/600 q3wk – 12xD35, q1wk6389%16% 4xEC90/600, q2wk – 4xD75, q2wk8160%25% 4xEC90/600, q2wk – 2xD35, d1,8,15+X2500, d1-14, q4wk 2496%25% 4xAC60/600, q 2wk – 4xD100 of P175,q2wk4294%35% 4xD100, q2wk – 4xAC 60/600, q 2wk5480%12% 80%544xD100, q2wk – 4xAC 60/600, q 2wk 35%94%424xAC60/600, q 2wk – 4xD100 of P175,q2wk 25%96%244xEC90/600, q2wk – 2xD35, d1,8,15+X2500, d1-14, q4wk 25%60%814xEC90/600, q2wk – 4xD75, q2wk 16%89%634xAC60/600 q3wk – 12xD35, q1wk 12%80%346xA50+D30 d1,8,15 + X1500, d1-14, q4wk 27%90%623xG1000 +D 75 d1,8 – V25+E100 d21,29, q6wk 25%65 %1004xFEC100 q3wk – 4xD 100, q3wk pCRK RNChemotherapie schema

68 Neoadjuvant chemotherapie Ago groep N=93 IBC, gerandomiseerd: 3xE150 – 3xP 250, q 2wk versus 4xEP 90/175 q 3wk Post OK 3xCMF pCR 21% versus 12% GeparDuo studie N=913 LABC, gerandomiseerd 4xAD 50/75, q2wk versus 4xAC 60/600 q 3wk – 4xD 100, q 3wk pCR 7% versus 14% EFS 5 jaar 65% versus 73%

69 Neoadjuvant chemotherapie EORTC, POCOB, Preoperatief 4xCMF versus postoperatief 4xCMF N= 689, M Follow-up 10 jaar MST versus Mastectomie 37% versus 21% Geen verschil in OS, RFS en LRR Italiaanse studie Inductie chemo 6xCis50E100V25, q2wk Vervolgens S, RT, 6xCMF en evt Tam Indien < pCR, randomisatie (n=35) : niets versus 3xE100-3xD100, q3wk M F-up 6 jr, DFS en OS in behandelgroep 100%, versus 53 en 68%

70 Adjuvant chemotherapy AGO groep Fase II, N=102, N+ (4-9) 3xE150, q 2wk – 3xP 225, q2wk – 3xC 2500, q 2wk F-Up 6,5 jr, DFS 72% en OS 78%

71 Chemotherapie, nieuwe middelen E7389, preventie van microtubuline groei Fase II bij taxaan resistentie RR 20%, TTP 2 mnd, weinig neurotoxiciteit Tocosol, Cremophor vrij taxol Fase II, 1e lijn RR 50%, TTP 7 mnd, geen premedic en weinig neurotox. XRP 6258, semisynthetisch taxaan Fase II, bij taxaan resistentie RR 14%, TTP 2 mnd KOS-802, Epothilone D Fase II bij taxaan resistentie RR 14%, TTP 2-3 mnd, neurotox max gr 2

72 Gemetastaseerd mammacarcinoom Drie studies Capecitabine + Vinorelbine oraal, Cape Vino 60, d1,8(15), q 3 wk Eerste lijn RR 45-50%, 2e lijn 35%, TTP 3-7 mnd Neutropenie 10-12%, ( 40% bij vino d1,8,15) Vino 25 d1,8 + Doce 75, q 3wk x6 – 6x Cape 2500 N=25, 1e lijn, RR 83%, TTP 28 mnd, geen gr 4 tox. Gemsar 1250 d1,8 + Doce 75, q3wk N=42, 1e lijn RR 80 %, TTP ??, Doce 50 q2wk, N=31, > 65 jr, 1e of 2e lijn RR 38%, TTP 9 mnd, 16% delay ivm neutropenie, weinig tox.

73 OPMERKINGEN & CONCLUSIES Piccart : Nieuw paradigma adjuvante therapie: “first select the target than think about the risk” Afname presentaties/posters chemotherapie alleen Echter: chemotherapie niet dood; “Triple Negative BC” target voor chemotherapie Hoge Dosis voor subgroepen Dose Dense effectief en goed verdraagbaar Nieuwe middelen nog volop in ontwikkeling Taxanen adjuvant geen OS voordeel; gevoelige patienten beter identificeren, wellicht niet de “Triple Negative BC”

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