Post San Antonio & Post EBCC Chemotherapie Aafke H. Honkoop

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

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

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

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

GEPARTRIO N=620 TAC NX Klin R 72% 67% Echo R 59% 63% BCS 58% 60% Path CR 5.3% 5.9%

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

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

Neoadjuvante endocriene therapie versus chemotherapie Klin R 62.2% 63.5% Tijd tot R 57 dgn 51 dgn Path R 5.2% 8.5% Progressie 9% Sparende OK 60% 59%

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

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

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

TC versus AC

TC versus AC

TC versus AC

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

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

INT C9741

INT C9741

INT C9741

INT C9741

INT C9741

INT C9741

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-

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

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

INT E1199

INT E1199

INT E1199

INT E1199

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%

GEICAM 9906 6xFEC versus 4xFEC- 8xP in N+ BC

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

GEICAM 9906

GEICAM 9906

Geicam 9906

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

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

INCORPORATION OF TAXANES IN FIRST LINE CHEMOTHERAPY FOR ADVANCED BREAST CANCER : A META-ANALYSIS Statisticians : Tomasz Burzykowski, PhD, Marc Buyse, ScD 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

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%

Combination trials : Paclitaxel (P) CCEI Paclitaxel BCSG Jassem Author Control arm and taxane N Combination trials : Paclitaxel (P) CCEI Paclitaxel BCSG Jassem FAC / ET 267 EORTC 10961 Biganzoli AC / AT 275 UKCCCR AB01 Carmichael EC / ET 705 AGO Luck 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 10923 Paridaens A / D 331 Tax 303 Study Group Chan 98 Total 3953 Bontenbal

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

Progression-free survival hazard ratios

Overall survival hazard ratios

More attention needs to be paid to cross-over 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 CLINICAL PRACTICE

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

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)

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

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 ? )

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

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

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

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

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, p=0.22

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, p=0.002 March 2005

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

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

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 < 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

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

Patients with ‘Triple-negative’ (= basal-like) Tumors 61.8% 49.5% HR=0.67, p=0.087 March 2005

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 (HR=0.70) Formal proof to be delivered (prospective study)

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

Out-patient Tandem PBPC-Tx Pacitaxel 175 mg/m2 q 2 wk x 2 Pacitaxel 175 mg/m2 q 2 wk x 2 Cycloph: 3 g/m2 ThioTepa: 250 mg/ m2 Carbopl: AUC = 10 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

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)

POSTERS

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

Neoadjuvant chemotherapie 12% 80% 54 4xD100, q2wk – 4xAC 60/600, q 2wk 35% 94% 42 4xAC60/600, q 2wk – 4xD100 of P175,q2wk 25% 96% 24 4xEC90/600, q2wk – 2xD35, d1,8,15+X2500, d1-14, q4wk 60% 81 4xEC90/600, q2wk – 4xD75, q2wk 16% 89% 63 4xAC60/600 q3wk – 12xD35, q1wk 34 6xA50+D30 d1,8,15 + X1500, d1-14, q4wk 27% 90% 62 3xG1000 +D 75 d1,8 – V25+E100 d21,29, q6wk 65 % 100 4xFEC100 q3wk – 4xD 100, q3wk pCR K R N Chemotherapie schema Chemotherapie schema N K R pCR 4xFEC100 q3wk – 4xD 100, q3wk 100 65 % 25% 3xG1000 +D 75 d1,8 – V25+E100 d21,29, q6wk 62 90% 27% 6xA50+D30 d1,8,15 + X1500, d1-14, q4wk 34 80% 12% 4xAC60/600 q3wk – 12xD35, q1wk 63 89% 16% 4xEC90/600, q2wk – 4xD75, q2wk 81 60% 4xEC90/600, q2wk – 2xD35, d1,8,15+X2500, d1-14, q4wk 24 96% 4xAC60/600, q 2wk – 4xD100 of P175,q2wk 42 94% 35% 4xD100, q2wk – 4xAC 60/600, q 2wk 54

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%

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%

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%

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 RR 14%, TTP 2-3 mnd, neurotox max gr 2

Gemetastaseerd mammacarcinoom Drie studies Capecitabine + Vinorelbine oraal, Cape 2000-2500+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.

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”