Post San Antonio

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Post San Antonio Post EBCCChemotherapie
Aafke H. Honkoop
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San Antonio BCS EBCC

• Presentaties
• Neoadjuvante chemotherapie (2)
• Adjuvante chemotherapie (4)
• Gemetastaseerde ziekte (2)
• Posters
• Neoadjuvante chemotherapie
• Adjuvante chemotherapie
• Nieuwe middelen
• Gemetastaseerde ziekte

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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

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

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

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GEPARTRIO
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GEPARTRIO, conclusies

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

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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

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Neoadjuvante endocriene therapie versus
chemotherapie
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Neoadjuvante endocriene therapie versus
chemotherapie

• CONCLUSIES
• Effectiviteit endocriene therapie gelijk aan
  chemotherapie
• Endocriene therapie minder toxisch

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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

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Doce/Cyclo (TC) versus Dox/Cyclo (AC) in early
breast cancer

• N1016, 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

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TC versus AC
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TC versus AC
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TC versus AC
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TC versus AC conclusies

• TC betere DFS
• TC minder toxiciteit
• TC nieuwe standaard

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

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Phase III study of AC followed by P or D Q 1wk or
Q 3wk in N and N0 high risk Patients INT E1199
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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
• N4988

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INT E1199
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INT E1199
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INT E1199
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INT E1199
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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

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GEICAM 99066xFEC versus 4xFEC- 8xP in N BC
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GEICAM 9906

• Eindpunten DFS en OS
• Vergelijking
• 6xFEC90
• 4xFEC90 - 8xP 100 q1wk
• Median follow-up 47 mnd
• N1248

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GEICAM 9906
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GEICAM 9906
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Geicam 9906
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Geicam 9906 conclusies

• Toxiciteit van beide schemas acceptabel
• FEC - P meer myalgie
• FEC meer neutropenie
• Adjuvant FEC - P effectiever in alle subgroepen
  tav DFS
• Geen verschil in OS

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Gemetastaseerd mammacarcinoom

• Meta-analyse eerste lijn Taxanen
• (Piccart)
• Hoge dosis chemotherapie
• (Rodenhuis)

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

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

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Progression-free survival hazard ratios
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Overall survival hazard ratios
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• 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
• 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
• Strong considerations should be given to trials
  run in better defined molecular sub-populations

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High-Dose Chemotherapyin Breast Cancer

• A Critical Review, or
• Is it dead ?
• Rodenhuis

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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)

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861 Stage IV Patients Randomized6 studies, 6
different HD regimens
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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 ? )

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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

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5627 Patients with High-Risk Breast Cancer in 14
Randomized Studies of HD
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Dutch National Study of High-Dose Chemotherapy in
the Adjuvant Treatment of High-Risk Breast Cancer
(N4 trial)

• Largest Randomized Study of HD Chemotherapy
  (N885)
• 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

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Dutch National Study of HD-CT in High-Risk Breast
Cancer Recurrence-Free Survival All 885 Patients
64.3
58.9
HR 0.84, p0.076
March 2005
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Dutch National Study of HD-CT in High-Risk Breast
Cancer Recurrence-Free Survival 181
HER2/neu-positives
55.9
43.9
HR 1.26, p0.22
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Dutch National Study of HD-CT in High-Risk Breast
Cancer Recurrence-Free Survival 621
HER2/neu-negatives
70.7
57.7
HR 0.68, p0.002
March 2005
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Dutch National Study of HD-CT in High-Risk Breast
Cancer Overall Survival 621 HER2/neu-negatives
78.2
71.0
HR 0.72, p0.02
March 2005
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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 10854
• NCIC MA.9 Trial
• And several others

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HER2/neu Subgroup Analysis

• Unplanned subgroup analysis suspect
• BUT
• The subgroup is very large (621 patients)
• Not a multiple-testing result
• Precisely one cut-off value defines subgroups
• Test for interaction p lt 0.001
• Makes sense with respect to biology
• HER2-positives not associated with BRCA/Fanconi
  pathway defects
• HER2/neu-positives resistant to alkylating agents
  (in the absence of Trastuzumab)
• Makes sense clinically subgroup analyses of
  other (non-randomized) high-dose trials

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Subgroup Analysis Triple Negative Tumors (basal
like)
Basal subtype
Luminal subtype
HER subtype
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Patients with Triple-negative ( basal-like)
Tumors
61.8
49.5
HR0.67, p0.087
March 2005
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Conclusion Dutch Study

• HER2-amplified tumors do not respond to
  HD-alkylators (confirmed)
• HD-sensitive subgroup present in set of
  HER2-negative tumors
• Luminal-like tumors part castration effect ?
• Basal-like tumors CTC is effective (HR0.70)
• Formal proof to be delivered (prospective study)

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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 10-100x sensitivity to
Cyclophosphamide and Cisplatin/Carboplatin in
vitro
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Out-patient Tandem PBPC-Tx
Pacitaxel 175 mg/m2 q 2 wk x 2
Cycloph 3 g/m2 ThioTepa 250 mg/ m2 Carbopl AUC
10
Pacitaxel 175 mg/m2 q 2 wk x 2
G-CSF
PBPC
Cycloph 3 g/m2 ThioTepa 250 mg/ m2 Carbopl AUC
10
High-risk patients following anthracycline- based
chemotherapy. Tumors with HR-defect (IHC
microarray)
Endocrine Adj. Therapy Follow-Up
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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)

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POSTERS
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Neoadjuvant chemotherapie

• Veel kleine fase II studies
• Verschillende schemas, conventioneel of
  dose-dense
• Path CR 10-35

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Neoadjuvant chemotherapie
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Neoadjuvant chemotherapie

• Ago groep
• N93 IBC, gerandomiseerd
• 3xE150 3xP 250, q 2wk versus
• 4xEP 90/175 q 3wk
• Post OK 3xCMF
• pCR 21 versus 12
• GeparDuo studie
• N913 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

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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 lt pCR, randomisatie (n35)
• niets versus 3xE100-3xD100, q3wk
• M F-up 6 jr, DFS en OS in behandelgroep 100,
  versus 53 en 68

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Adjuvant chemotherapy

• AGO groep
• Fase II, N102, N (4-9)
• 3xE150, q 2wk 3xP 225, q2wk 3xC 2500, q 2wk
• F-Up 6,5 jr, DFS 72 en OS 78

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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

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Gemetastaseerd mammacarcinoom

• Drie studies Capecitabine Vinorelbine oraal,
• Cape 2000-2500Vino 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
• N25, 1e lijn, RR 83, TTP 28 mnd, geen gr 4
  tox.
• Gemsar 1250 d1,8 Doce 75, q3wk
• N42, 1e lijn
• RR 80 , TTP ??,
• Doce 50 q2wk,
• N31, gt 65 jr, 1e of 2e lijn
• RR 38, TTP 9 mnd, 16 delay ivm neutropenie,
  weinig tox.

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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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