Meme Kanserinde Gelecege Bakis: Yeni alismalar

1. Meme Kanserinde Gelecege Bakis: Yeni �alismalar Dr. Yesim ERALP I.�. ONKOLOJI ENSTIT�S�

2. DCIS KORUNMA ERKEN EVRE MEME KANSERI Y�KSEK RISKLI NOD NEGATIF HASTALIK NOD POZITIF HASTALIK HORMON DUYARLI HASTALIK

3. DCIS TAMAMLANMIS RT ROLU NSABP-B06 NSABP-B17 EORTC 10853 TMX NSABP-B24 UKCCR DEVAM EDEN RT RTOG ANASTRAZOL BIG-5 (IBIS-II-DCIS) NSABP-B35

5. IBIS-II DCIS

6. NSABP-B35

7. RTOG 9804- CALGB 49801 NCI sponsorlu, a�ik �alisma Iyi riskli DCIS Unisentrik tm = 2.5 cm NG1 veya NG2 + tutulmus duktuslarin < 1/3��nde nekroz sinir = 3 mm Non-palpabl yas=26 6 yilda 1790 hasta alimi hedefleniyor Takip vs t�m meme RT (� TMX)

8. KORUNMA TAMAMLANMIS TMX NSABP-P1 ROYAL MARSDEN ITALYAN IBIS-I DEVAM EDEN ANASTRAZOL BIG-5 (IBIS-II-KORUNMA) NSABP-P2 (STAR) EXEMESTANE ApreS

9. KORUNMA

10. MEME KANSERI INSIDANSI

11. YAN ETKILER

12. NSABP-P1: 288 meme kanserli hastalarin 19�unda BRCA mutasyonu saptandi TMX BRCA-2 mutasyonu olanlarda meme kanseri insidansini azaltti (OR:0.38) BRCA-1�de etkilemedi ROYAL MARSDEN: %60 hasta muhtemel BRCA tasiyici olarak hesaplandi. TMX ile meme kanseri insidansi azalmadi HBCCSG: TMX BRCA-1(+) lerde kontrlateral meme ca insidansini azaltti (OR:0.38) BRCA-2�de etkilemedi Narod, Lancet 2000,356. TMX & BRCA TASIYICILARI

13. DEVAM EDEN �ALISMALAR

14. ERKEN EVRE MEME KANSERI:NOD NEGATIF HASTALIK TAMAMLANAN �ALISMALAR BIG 5 : postop 36. st 1 k�r CMF ? � BIG 8 : CMF = OA ? CMF+OA BIG 9 : CMF (3)+TMX ? TMX (Postmen, ER � hastada anlamli yarar) NSABP-B20 : CMF (6)+TMX ? TMX (yas =60 ve premenapozal hastada daha y�ksek yarar) NSABP-B23: CMF (6)�TMX = AC(4) �TMX (ER -) Y�KSEK RISKLI HASTALIK GEICAM : FAC(6) ? CMF q21(6) INT 0102 : CAF(6) ? klasik CMF(6)

15. ERKEN EVRE MEME KANSERI:NOD NEGATIF HASTALIK Y�R�YEN �ALISMALAR *Hedef: KT�den faydalanan y�ksek riskli alt grup belirlemek -Mikroarray teknolojisi ile desteklenen translational �alismalar TRANSBIG KONSORSIYUM ONCOTYPE-DX (NEJM Dec 10, 2004) -PACCT-1 RANDOMIZE �ALISMALAR

16. TRANSBIG

17. ONCOTYPE DX- N�KS SKORU NEJM 2004, 10 Aralik

18. PACCT-1

19. NSABP-B36

20. CALGB 40101 NCI destekli, a�ik �alisma 4646 hasta hedefleniyor Y�ksek riskli nod (-) hastalar Q14 doz yogun tedavi AC x 4 vs AC x 6 vs P x 4 vs P x 6

21. NOD POZITIF ERKEN EVRE MEME KANSERI Antrasiklinler vs CMF: EBCTCG 2000 14,000 kadin, 15 �alisma N�ks riskinde %11, �l�m riskinde % 16 azalma Nod (+) lerde yarar 10 yildan sonra da devam ediyor Ortalama net yarar (sagkalim): %4

23. YANIT BEKLEYEN SORULAR Optimal rejim : 2�li vs 3�l� kombinasyonlar 4 vs 6 k�r KT Epi vs Doxo Ardisik Doxo & CMF rejimlerinin rol� Taxanlar� Yogun- doz (dose-dense) Y�ksek-doz (dose-intense / high-dose) HERCEPTIN

24. 4 vs 6 k�r 4 AC = 6 CMF NSABP-B15 (n: 2194) NSABP-B23 (n:2008) 6 FEC-50 ? 3 FEC-50 FASG-01 6 FAC/ FEC ? 6 CMF Charing Cross (n:759) FEC-50 ? 6 CMF NCIC-MA-5 (n:710) FECoral-120 ? 6 CMF Danimarka (n:1195) FEC-60 ? 9 CMF (q21) INT-102 (n: 2691) FACoral-60 ? 6 CMF

25. ADJUVAN KT: TAXANLAR

26. NOD POZITIF HASTALIK- KT Y�r�yen �alismalar GOIM 9902 (n: 700, kapali, abstr) DOCE x 4 � EC x 4 EC x 4 ECOG 2197 (n:2958, kapali, abstr) AD x 4 AC x 4 INRC-MIG-5 (n:1000, kapali, bildirim yok) EP x 4 FEC x 6 EU-INT 23/96 (n:450, kapali, bildirim yok) AP x 4 � CMF x 4 A x 4 � CMF x 4 NCIC-MA21 (n:1500,a�ik, hasta alimi devam, T0-4, N0-2) EC x 6 / AC x 4 � P x 4 Kanada FEC x 6 PACS 04 (A�ik, hasta alimi devam) ED X 6 FEC100 x 6

27. NOD POZITIF HASTALIK- KTY�R�YEN �ALISMALAR NSABP-B30 (hasta alimi tamamlandi, �alisma kapali) TAC x 4 AC x 4 AC x 4 - DOCE x 4 BCIRG 005 (3150) AC x 4 - DOCE x 4 TAC x 6 EU-20221; (= 4 LN, 446 hasta) FEC x 6 DEC x 6 NCIC : AC x 4 - DOCE x 4 AC x 4 - DX x 4 EU 20 PEC PEC � GEM CALGB 49907 : (1800) AC x 4 /CMF x 6 CAPECITABINE x 6

28. NSABP-B30

29. BCIRG 005

30. CALGB 49907-ECOG-SWOG NCI sponsorlu a�ik �alisma Evre I-III Yas = 65 2-6 yilda 1800 hasta alimi hedefleniyor AC x 4 / CMF x 6 XELODA x 6

31. Doz Miktari (Intensity) Antrasiklin: CALGB 8541: CAF 400/40/400 x 6= CAF 600/60/600 x 4 ? CAF 300/30/300 x 4 Budman, JNCI �98 FASG-05 : FEC-100 x 6? FEC-50 x 6 Bonneterre, JCO 2001 CALGB-9344: AC-90 = AC-75 = AC-60 x 4 Henderson ,JCO, 2003 Siklofosfamid NSABP-B22 : 4 x AC-600 = 2 x AC-1200 = 4 x AC-1200 Fisher; JCO 1997 NSABP-B25 : 4 x AC-600 = 4 x AC-1200 = 2 x AC-2400 = 4 x AC-2400 Fisher, JCO 1999

32. Intansif Doz Y�R�YEN �ALISMA  BIG 15-95 ILK BILDIRIM ASCO 2003 Randomized trial comparing up-front, multi-cycle, dose-intensive CT vs standard dose CT in women with high-risk stage 2 or 3 breast cancer:First results from IBCSG Trial 15-95 R Basser, ve ark. International Breast Cancer Study Group ASCO 2003

33. Patients were stratified according to menopausal status, oestrogen receptor status and by institution. They were randomised to receive either a conventional dose, anthracycline-based regimen given over 6 months, or dose-intensive EC given over 6 weeks. In this latter treatment, women initially received filgrastim and leukapheresis, followed as soon as possible afterwards by chemotherapy. Tamoxifen was given for 5 years at completion of chemotherapy to all patients, regardless of receptor status. Patients were stratified according to menopausal status, oestrogen receptor status and by institution. They were randomised to receive either a conventional dose, anthracycline-based regimen given over 6 months, or dose-intensive EC given over 6 weeks. In this latter treatment, women initially received filgrastim and leukapheresis, followed as soon as possible afterwards by chemotherapy. Tamoxifen was given for 5 years at completion of chemotherapy to all patients, regardless of receptor status.

34. IBCSG 15-95�alisma kriterleri Y�ksek riskli, operabl meme kanseri 10+ nod, herhangi ER 5+ nod ER (-) 5+ nod, T3 18-65 yas normal kalp fonksiyonu Women were eligible for IBCSG 15-95 if they had poor prognosis breast cancer as defined by the following: 10+ involved axillary nodes 5+ involved nodes and ER negative or a T3 tumour. These pts were included because in a combined assessment of previous IBCSG and ECOG trials they were found to have a similarly poor outcome to the 10+ node group Women had to be between the ages of 18 and 65 years, have normal cardiac function, and be randomised within 6 weeks of surgery.Women were eligible for IBCSG 15-95 if they had poor prognosis breast cancer as defined by the following: 10+ involved axillary nodes 5+ involved nodes and ER negative or a T3 tumour. These pts were included because in a combined assessment of previous IBCSG and ECOG trials they were found to have a similarly poor outcome to the 10+ node group Women had to be between the ages of 18 and 65 years, have normal cardiac function, and be randomised within 6 weeks of surgery.

35. Ilk degerlendirme: 1995 � 2000: n= 344 160 olay median follow-up = 4 yil 344 women were recruited at 17 sites from 1995 to 2000. The current analysis occurred after 160 events, defined as either relapse or death, at median follow-up of 4 years.344 women were recruited at 17 sites from 1995 to 2000. The current analysis occurred after 160 events, defined as either relapse or death, at median follow-up of 4 years.

36. IBCSG 15-95hasta �zellikleri The patients were reasonably well matched between the two treatments, although there were was a slight inbalance in the number of involved nodes. This was because more women with 5+ nodes and ER negative or T3 tumours were allocated to dose-intensive treatment.The patients were reasonably well matched between the two treatments, although there were was a slight inbalance in the number of involved nodes. This was because more women with 5+ nodes and ER negative or T3 tumours were allocated to dose-intensive treatment.

37. Toksisite Treatment-related toxicity observed in both arms was of the expected nature and severity. The major side-effects of the dose-intensive treatment were myelosuppression, nausea and vomiting, mucositis and infection. There were no treatment-related deaths in the standard arm. In the dose-intensive group, 2 women died during chemotherapy from sepsis due to severe neutropenia, while two patients died from anthacyline-induced cardiomyopathy 10 and 12 months after completion of chemotherapy. Treatment-related toxicity observed in both arms was of the expected nature and severity. The major side-effects of the dose-intensive treatment were myelosuppression, nausea and vomiting, mucositis and infection. There were no treatment-related deaths in the standard arm. In the dose-intensive group, 2 women died during chemotherapy from sepsis due to severe neutropenia, while two patients died from anthacyline-induced cardiomyopathy 10 and 12 months after completion of chemotherapy.

38. IBCSG 15-95sonu� This slide shows the key data. It is an analysis of all patients, based on an intention-to-treat. One can see that the disease-free survival curves start to separate after 18 months, and the curves for overall survival separate after 40 months. This indicates a trend in favour of the dose-intensive treatment, but as one can see from the p values, this is not statistically significant. This slide shows the key data. It is an analysis of all patients, based on an intention-to-treat. One can see that the disease-free survival curves start to separate after 18 months, and the curves for overall survival separate after 40 months. This indicates a trend in favour of the dose-intensive treatment, but as one can see from the p values, this is not statistically significant.

39. IBCSG 15-95sonu� For the standard and dose-intensive arms, 4 yr disease-free survival was 46% and 57%, respectively, and the hazard ratio was 0.78 with 95% confidence intervals 0.57 to 1.07, in favour of the dose-intensive arm. Overall survival was 64% for the standard and 73% for the dose-intensive arms, with the hazard ratio 0.78 and 95% confidence intervals 0.53 to 1.15, again in favour of the dose-intensive treatment. For the standard and dose-intensive arms, 4 yr disease-free survival was 46% and 57%, respectively, and the hazard ratio was 0.78 with 95% confidence intervals 0.57 to 1.07, in favour of the dose-intensive arm. Overall survival was 64% for the standard and 73% for the dose-intensive arms, with the hazard ratio 0.78 and 95% confidence intervals 0.53 to 1.15, again in favour of the dose-intensive treatment.

40. IBCSG 15-95 ER/PgR g�re DFS Randomization was stratified according to oestrogen receptor status, and assessment of disease free survival according to hormone receptors is shown here. There were non-significant trends in favour of dose-intensive treatment in 139 women with receptor negative tumours, shown in the panel on the left, and in the 203 receptor positive patients, shown in the panel on the right. Randomization was stratified according to oestrogen receptor status, and assessment of disease free survival according to hormone receptors is shown here. There were non-significant trends in favour of dose-intensive treatment in 139 women with receptor negative tumours, shown in the panel on the left, and in the 203 receptor positive patients, shown in the panel on the right.

41. Amenore When we looked at the 193 premenopausal women, amenorrhoea, defined as cessation of menses for at least 3 consecutive months in the first 9 months of study, was more common in the group treated with dose-intensive therapy, as was permanent cessation of menses. One can see from the figures shown here that this difference was especially marked in women less than 40 years of age, where amenorrhoea occurred in 85% of women given dose-intensive treatment vs 48% for women in the standard arms, and permanent amenorrhoea in 61% and 24%, respectively. When we looked at the 193 premenopausal women, amenorrhoea, defined as cessation of menses for at least 3 consecutive months in the first 9 months of study, was more common in the group treated with dose-intensive therapy, as was permanent cessation of menses. One can see from the figures shown here that this difference was especially marked in women less than 40 years of age, where amenorrhoea occurred in 85% of women given dose-intensive treatment vs 48% for women in the standard arms, and permanent amenorrhoea in 61% and 24%, respectively.

42. ER/PgR pozitif hastalarda DFS In order to explore the possible impact of this hormonal effect, we looked at the disease free survival in women with hormone receptor positive tumours by age. The left panel represents 45 women aged less than 40 years, while the right panel represents 148 women 40 years and above. As one can see, dose-intensive therapy appeared to be of benefit to patients less than 40 years, but appeared to have less influence on outcome in the older women. This observation is, of course, hypothesis-generating and must be interpreted with caution.In order to explore the possible impact of this hormonal effect, we looked at the disease free survival in women with hormone receptor positive tumours by age. The left panel represents 45 women aged less than 40 years, while the right panel represents 148 women 40 years and above. As one can see, dose-intensive therapy appeared to be of benefit to patients less than 40 years, but appeared to have less influence on outcome in the older women. This observation is, of course, hypothesis-generating and must be interpreted with caution.

43. IBCSG 15-95 sonu� Doz-intensif EC standart tedaviye g�re sagkalim avantaji saglayabilir Yanitlanmasi beklenen sorular: Yararin devamliligi Hormon etkisinin devami? Uzun d�nem toksisite In conclusion, analysis at 4 years shows that in the adjuvant therapy of women with poor prognosis, operable breast cancer, up-front dose-intensive EC may provide disease-free and overall survival advantage compared with standard dose chemotherapy. Further follow up is required to assess for possible ongoing benefit, the potential contribution of a hormone effect of therapy, and the important issue of long-term toxicity. In conclusion, analysis at 4 years shows that in the adjuvant therapy of women with poor prognosis, operable breast cancer, up-front dose-intensive EC may provide disease-free and overall survival advantage compared with standard dose chemotherapy. Further follow up is required to assess for possible ongoing benefit, the potential contribution of a hormone effect of therapy, and the important issue of long-term toxicity.

44. Y�KSEK DOZ

45. erken kapatilmis 1000 hasta alinmis 4-9 LN + A x 3-P x 3-C x 3 AC x 4 - STAMP I / V + PSCT STAMP-I: cisplatin+CTX+carmustin STAMP-V: carbo+CTX+thiotepa CALGB 9640

46. YOGUN DOZ STRATEJILER: Tedavi direncini kirmak i�in doz araligini azaltmak �apraz diren�li olamayan ardisik ajanlarla kombinasyon

47. Doz YogunluguArdisik vs Es Zamanli 4 x DOXO � 8 x CMF ? (2 X CMF / 1 x DOXO) x 4 Bonnadonna, JAMA 1995 CALGB 9741 Doz Yogun AC-T / A-C-T ? ST AC-T / A-C-T Ardisik A-C-T = Eszamanli AC-T Citron, JCO 2003

48. CALGB 9741

49. DOZ YOGUN DEVAM EDEN:

50. CALGB 40101 NCI sponsorlu a�ik �alisma Nod-negatif hastalik En az 6 neatif LN (aksiller diseksiyon) veya SLNB (-) IHC ile nod i�inde < 0.2 mm tm infiltrasyonu 30 ayda 4650 hasta alimi hedefleniyor AC x 4 q 14 AC x 6 q 14 P x 4 q 14 P x 6 q 14

51. Ardisik vs Es Zamanli DEVAM EDEN �ALISMALAR INT 0137 Ardisik A-C = Eszamanli AC x 6 Haskell, ASCO 2002 NEAT E 100 x 4 � CMF x 4 CMF x 6 , ASCO 2003 TACT (3340): Hasta alimi devam ediyor FEC x 8 EPI x 4 � CMF x 4 FEC x 4 � DOCE x 4 BIG 02-98 (2200) : Kapali, bildirim yok DOXO x 4 � CMF x 4 AC x 4 � CMF x 4 DOXO x 3- DOCE x 3- CMF x 4 AD x 4 � CMF x 3 TAXIT-216 (1000): Kapali, bildirim yok EPI x 4 � CMF x 4 EPI x 4- DOCE x 4- CMF x 4

53. HERCEPTIN

54. CALGB 49909-ECOG-SWOG NCI sponsorlu a�ik �alisma NOD (+) veya y�ksek riskli nod (-): tm> 2.0 cm + (ER)- ve (PR)-pozitif hastalik veya tm > 1.0 cm + ER and PR negatif Her 2 (+) 6 yilda 3300 hasta alimi hedefleniyor AC x 4 �P x 4 AC x 4 ---P x 4 + Herceptin (1 yil) AC x 4 ---P x 4--- Herceptin (1 yil)

55. HORMONAL TEDAVI TMX AI OVER ABLASYONU

56. TMX S�RE Uzun s�reli kullanim ? 5 yil s�re ile tedavi

57. AROMATAZ INHIBIT�RLERI

58. ATAC 68 aylik takip %8 hasta halen tedavi altinda %84 hasta HR (+) %61 hasta nod (-) San Antonio-2004

61. ABCSG 8 � ARNO San Antonio-2004 28 aylik takip Hasta alimi sonlandirildi %18 hasta ER (+), PR (-) %27 nod (+) Adjuvan KT yok

62. Postmenapozal hastalarda y�r�t�len �alismalar

63. 5 yil TMX sonrasi idamede AI ile y�r�t�len �alismalar

64. NSABP-B38

65. MA-27-CALGB-NCIC NCI sponsorlu a�ik �alisma pT1-3; pNX, pN0-2 or pN3*; M0 Adjuvan KT tercihi helime birakilmis postmenapozal 4 yilda 6830 hasta alimi hedefleniyor Exemestan (5 yil) � Celecoxib (3 yil) Anastrazol (5 yil) � Celecoxib (3 yil)

66. OVER ABLASYONU:Tamamlanmis �alismalarKT vs OAKT + OA vs OA

67. 50 yas alti kadinlarda OA, KT ve TMX�nin indirekt karsilastirmasi The EBCTCG Overviews included randomised trials of: ovarian ablation vs. no ovarian ablation chemotherapy vs. no chemotherapy tamoxifen vs. no tamoxifen.The EBCTCG Overviews included randomised trials of: ovarian ablation vs. no ovarian ablation chemotherapy vs. no chemotherapy tamoxifen vs. no tamoxifen.

68. KT�ye alternatif olarak Zoladex ? Tamoxifen ZEBRA Trial ABCSG AC05 Trial GROCTA 02 Trial ZEBRA = �Zoladex� 3.6mg Early Breast Cancer Research Association. ABCSG = Austrian Breast & Colorectal Cancer Study Group. GROCTA = Italian Breast Cancer Adjuvant Study Group. ZEBRA = �Zoladex� 3.6mg Early Breast Cancer Research Association. ABCSG = Austrian Breast & Colorectal Cancer Study Group. GROCTA = Italian Breast Cancer Adjuvant Study Group.

69. ZEBRA

70. ZEBRAGenel Sagkalim

71. ABCSG AC05: Austrian Adjuvant Breast Cancer Trial (�Zoladex� 3.6mg + tamoxifen vs. KT

72. GROCTA 02

73. KT ile birlikte Zoladex ? Tamoxifen IBCSG VIII ZIPP Trial INT-0101 Trial Mam-1 GOCSI Trial

74. BIG 8

75. ZIPP

76. ZIPP

77. INT-0101: 5 yillik takip sonu�lari

78. Mam-I GOGSI

79. Over supresyonunun yarari Aromataz inhibit�rlerinin rol� KT ve endokrin tedavi kombinasyonunun etkinligi GnRH analoglarinin uygulama s�resi

80. Premenapozal hastalarda y�r�t�len �alismalar

83. SOFT [IBCSG 24-02, BIG 2-02]

84. TEXT [IBCSG 25-02, BIG 3-02]

85. PERCHE [IBCSG 26-02, BIG 4-02]

86. NEOADJUVAN KEMOTERAPI

87. EORTC 10994 Lokal ileri veya b�y�k operabl tm Hedef 1440 hasta, 5 yilda Hasta alimi devam ediyor Epirubisin + Docetaxel x 6 -- CERRAHI FEC x 6 � CERRAHI FEC100 FEC120 TAILORED FEC

88. UCLA-9911084AVENTIS-GIA-11156, GENENTECH-H2269s NCI destekli �alisma Lokal ileri veya b�y�k operabl tm, herhangi N Hedef 400 hasta, 4 yilda Hasta alimi devam ediyor Carboplatin + Docetaxel x 4 + Herceptin- CERRAHI Carboplatin + Docetaxel x 4--CERRAHI