Bir olgu sunumu eşliğinde Triple (-) meme kanserli hastaya yaklaşım / Kadrialtundağ
1. Bir Olgu Sunumu Eşliğinde Triple Negatif Meme Kanserli Hastaya Yaklaşım Dr. Kadri Altunda ğ Hacettepe Ü niversitesi Onkoloji Enstitüsü Medikal Onkoloji B ilim Dalı Ankara Meme Hastalıkları Derneği 16 Aralık 2010, Ankara
5. Meme Kanseri Gen Profili ER(-) ER(+) So r lie et al. PNAS 2001; 98:10869-10874
6. Sotiriou C and Pusztai L. N Engl J Med 2009;360:790-800 Meme Kanserinde Moleküler Sınıflama ve Klinikopatolojik Özellikler
7. Nielsen et al. Clin Cancer Res 2004 “ Basal Like” Meme Kanserlerinin Gen ve İmmünhistokimyasal Profili
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9. “ Tripl Negati f ” “Basal-like” Gen Ekspresyon Profili (basal?) ER-, PR-, HER2- (cyclin D1-, CK5/6/17+, EGFR+, vimentin+, nestin+…) “ ” “ Tripl negati f ” İ mm ü nohisto kimyasal profil Tripl negatif meme kanserlerinin ~ % 10-20 si ba zal değildir …. ? Parker J, et al. JCO 2009, Rakha EA, et al. Breast Cancer Res Treat 2009
10. TR i PL NEGAT İF KANSERLER BA Z AL- HÜCRE BENZERİ KANSERİ METAPLAST İK MED ÜLLER A . B .
11. Basal-Like Breast Cancer (ER, PR, HER2-Negative) Bazal Hücre Benzeri Meme Tümörü Karsinogenezi Basal-like Tumors
12. 496 meme kanserli hasta-IHC ye göre altgruplara ayrılmış % 40 ’ı Afr o -Ameri k an, % 50 ’si premenop ozal Carolina Meme Kanser Çalışması Carey LA et al, JAMA 2006
13. P=0.0001 Carey LA et al, JAMA 2006 Irk ve Yaşa Göre Meme Kanser Altgrupları N Basal-like HER2+ (ER-) Luminal A Luminal B Premenop oz al Afr o -Ameri k an 97 % 39 % 9 % 36 % 9 Postmenop ozal Afr o -Ameri k an 99 % 14 % 7 % 59 % 16 Premenop ozal Afr o -Ameri k an olmayan 164 % 16 % 6 % 51 % 18 Postmenop ozal Afr o -Ameri k an olmayan 136 % 16 6% % 58 % 16 TOTAL 496 % 20 7% % 51 % 16
17. TN Meme Kanseri : Klinik Özellikler ve Rekürrens Özellikleri Dent R, et al. Clin Cancer Res 2007;13 : 4429-4434
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19. Tripl-Negati f Meme Kanseri : Klinik Özellikler Dent R, et al. Clin Cancer Res 2007;13 : 4429-4434 Tripl Negati f Non-Tripl Negati f p Ort. yaş 53.0 57.7 <0.0001 Grad 3 % 66 % 28 <0.0001 T < 2.0 cm % 36.5 % 62.7 <0.0001 Nod po zitif %54.6 % 45.6 0.02
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21. Triple-Negati f ve Diğer Meme Kanserlerinde Uzak Metastaz Oranları Dent R, et al. Clin Cancer Res 2007;13 ; 4429-4434
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24. Meme Kanseri Spesifik Sağkalım TN vs Non-TN Dent R, et al. Clin Cancer Res 2007;13 : 4429-4434
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26. Dana-Farber Triple-Negative Series – Recurrence Sites Lin NU et al. Cancer 2008;113(10):2638-45. Site(s) of Metastatic Disease at Diagnosis of Metastasis Patients (n = 116) N % Lung/pleura 48 41 Liver 34 29 Bone 28 24 Breast/chest wall 28 24 Soft tissue/distant lymph nodes 25 22 Regional lymph nodes 17 15 CNS 16 14
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28. Triple-negatif Meme Kanserli Hastaların Epidemiyolojik, Demografik ve Patolojik Özellikleri Sercan Aksoy, Ömer Dizdar, Hakan Harputluoğlu, Yavuz Özışık, Gülten Tekuzman, Kadri Altundağ Hacettepe Üniversitesi Onkoloji Enstitüsü, Medikal Onkoloji Bilim Dalı, Ankara, Türkiye II. Tıbbi Onkoloji Kongresi 26-30 Mart 2008, Antalya
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30. S ONUÇLAR Aksoy et al. Ann Oncol 2007 Tripl Negatif Diğerleri p n (%) 24 (%1 1.7 ) 181 (%8 8.3 ) Ortanca yaş 45.5 (aralık, 26-73) 48 (aralık, 20-78) 0.35 M. Durumu Pre Peri Post 15 (% 62.5 ) - 9 (%37.5) 7 9 (%4 4.1 ) 7 (%3.4) 95(%52.5) 0.0 7 LN Metastazı Var Yok 8 ( %33.3 ) 16 ( %66.7 ) 107 ( %62.6 ) 64 ( %37.4) 0.008 Grad I-II III 9 (% 40 . 1 ) 13 (%59.1) 55 (% 70.9 ) 48 (%29.1) 0. 0 14 OK kullanımı Evet Hayır 10 ( %41.7 ) 14 ( %58.3 ) 34 ( %19.3 ) 141 ( %80.7 ) 0.019
31. Metastatik Tripl Negatif Meme Kanserli Hastalarda CEA ve CA 15-3 Seviyelerinin Başlangıç Değerlerine Göre Değişimi UKK 2009, ASCO 2009, Dede et al, Med Oncol 2010 Tripl (-) (Ortalama ± SD) Non Tripl(-) (Ortalama ± SD) P değeri Tanı anında CEA (ng/mL) 2,5 ± 5,9 4,0 ± 16,4 0.35 Tanı anında CA 15-3 (U/mL) 23,7 ± 14,6 37,1 ± 117,0 0.021 Metastatik CEA (ng/mL) 3,2 ± 3,8 29,6 ± 106,4 0.022 Metastatik CA-15-3 (U/mL) 46,9 ± 46,3 203,2 ± 534 0.008
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34. albumin e - bağlı pa k litaxel Hücre zarı Küçük damar lümeni Caveolin-1 gp60 gp60 albumine bağlı paklitaxeli yakalar Caveola: G p60 re s ept örüyle birlikte alb ü min e bağlı pa k litaxel hücre içine alınır Albümine bağlı paklitaxel tümör hücresi içinde depo edilir T ü m ö r Interstitium Albümine bağlı Paklitakselin Farmakokinetiği
37. Brenton, J. D. et al. J Clin Oncol; 23:7350-7360 2005 Meme Kanseri Altgruplarının Sağkalım Profilleri
38. Aksoy ve ark. UTOK 2010 Meme Kanseri Altgruplarının Sağkalım Profilleri- Hacettepe Luminal A Luminal B HER-2 Overexpressing Tripl negatif
39. Meme Altgruplarında Tedavi Seçenekleri Endo krin T edavi Trastuzumab Kemoterapi Luminal A Evet Hayır Evet Luminal B Evet Evet / Hayır Evet HER2 Hayır Evet Hayır Bazal Hayır Hayır Evet
40. TNBC de Güncel Hedefler Cleator S et al. Lancet Oncology 2007;8:235-244 Hedef R asyonel Tedavi DNA DNA aberra syonları (BRCA1 muta syonu ) , DNA onarım mekanizmasındaki bozuklukluklar Kemoterapi - Çift zincir DNA kırıkları , platin analogları , topoi zomeraz I ve II inhibit örleri PARP1 BRCA1 disfonksiyonu PARP inhibit örleri EGFR Artmış ekspresyon (%50 – %70) Cetuximab, erlotinib c-kit Artmış ekspresyon (%31) İ matinib Src Artmış ekspresyon , dasatinib ’e hassasiyet Dasatinib
41. P<0.001 1 Rouzier et al, Clin Cancer Res 2005; 2 Carey LA et al, SABCS 2004 P=0.003 Altgruplar a Göre Neoadjuvan Tedavilerle Elde Edilen pCR Oranları Rejim Altgrup T-FAC 1 (N=82) AC-T 2 (n=107) Luminal A/B 2/30 (%7) 4/62 (%7) Normal 0/10 (0) NA HER2+/ER- 9/20 (%45) 4/11 (%36) Ba z al hücre benzeri 10/22 (%45) 9/34 (%26)
46. BRCA1 D isfonksiyonunda Spesifik Tedavi Rasyoneli Kennedy R et al. J Nat Cancer Inst 2004;96(22):1659-68 .
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49. Intergroup/CALGB-40603 Triple Negative Neoadjuvant Trial Breast imaging Blood MUGA Tumor biopsy SURGERY Breast imaging Blood MUGA Breast imaging Blood Dose-dense AC RT prn Bevacizumab N = 400 ER/PR/HER2- Stage II-IIIB Paclitaxel ± Carboplatin Paclitaxel ± Carboplatin www.clinicaltrials.gov, November 2010.
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52. TNBC de Potansiyel Hedefe Yönelik Tedaviler Hücre siklüsü Tran skripsiyonel kontrol MAP kinaz yolağı Akt yolağı EGFR tirozin kinaz c -KIT t irozin kinaz Hücre ölümü DNA Onarım yollları An j iogen ez Cleator S et al. Lancet Oncology 2007;8:235 Mi krotübül stabiliz asyonu Bevacizumab Abraxane-Ixabepilon Cetuximab Erlotinib-Gefitinib Sunitinib Dasatinib MAPK inhibitörleri PARP inhibitörleri, Trabectedin
53. Kemoterapötik Ajanlar : Çift Zincir DNA Kırıkları Kennedy R et al. JNCI 2004; 96:1659-1668 Alk illeyiciler DNA interstrand cross-links double strand (DS) DNA breaks Siklofosfamid Platin analogları DNA adductları oluşturur Cisplatin Carboplatin Oxaliplatin Topoi zomeraz I inhibitörleri DNA repli kasyon fork ta arrest Etoposid İ rinotecan Topotecan Mitoxantrone Topoi zomeraz II inhibitörleri DNA interstrand cross-linking, generation of O 2 free radicals Doxorubicin Epirubicin Bleom isin Dire kt DNA hasarı DS DNA kırıkları
55. Phase II Genomics Study of Ixabepilone as Neoadjuvant Treatment for Breast Cancer Baselga J et al. J Clin Oncol 2009;27(4):526-34.
56. Hormon ve HER2 Re septör Durumuna göre Neoadjuvant Ixabepilon sağlanan pC R (Meme) Oranları Baselga J et al. J Clin Oncol 2009;27(4):526-34 . Neoadjuvant ixabepilone bütün altgruplarda olduğu gibi TNMK de de aktif bir tedavi Hasta Altgrupları To plam Hasta Cevap veren hastalar % Bütün hastalar 161 29 18 ER-negati f 72 21 29 ER/PR-negati f 61 20 33 ER/PR/HER2-negative 42 11 26
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58. Results: Pooled Analysis of Patients with Metastatic TNBC Rugo HS et al. Proc SABCS 2008;Abstract 3057. (Poster) Median PFS (months) Median PFS HR = 0.63 (95% CI, 0.52 to 0.77) p < 0.0001 Response Rate (%) ORR Median OS (months) Median OS HR = 0.87 (95% CI, 0.71 to 1.07) p = 0.1802 Ixa + Cape (N = 213 for OS) (N = 191 for ORR and PFS) Cape (N = 230 for OS) (N = 208 for ORR and PFS) 4.2 (95% CI: 3.6-4.4) 1.7 (95% CI: 1.5-2.4) 10.3 (95% CI: 9.1-11.8) 9.0 (95% CI: 6.7-10.6)
60. Birinci Basamak Metastatik TNBC Tedavisinde Cetuximab Carey L et al. J Clin Oncol 2008;26(15s):43s (abstr 1009) O’Shaughnessy J et al. Breast Cancer Res Treat 2007;106:S32 (abstr 308) Fakat her iki çalışmada da PFS de iyileşme yok: TBCRC PFS : 1.4 ay vs 2 ay, US Oncol PFS : 5.1 ay vs. 4.7 ay TBCRC Çalışma 001 US Oncology Re jim Cetuximab Carboplatin/ Cetuximab Irinotecan/ Carboplatin Irinotecan/ Carboplatin + Cetuximab N 31 71 33 39 ORR 2 (%6) 13 (%18) 10 (%30) 19 (%49)
62. Comparison of Subgroup Analyses of PFS from Three Phase III Studies of Bevacizumab in Combination with Chemotherapy in Patients with HER2-Negative Metastatic Breast Cancer O’Shaughnessy J et al. Proc SABCS 2009;Abstract 207. (Poster)
63. Improvement in PFS with Addition of Bevacizumab (B) in E2100, AVADO and RIBBON-1 O’Shaughnessy J et al. Proc SABCS 2009;Abstract 207. (Poster) * B 7.5 mg/kg, 15 mg/kg (doses were also used in the other two trials); † Capecitabine/B; Taxane/anthracycline/B Patient Subgroup Improvement in PFS, months (HR) E2100 (n = 722) AVADO* (n = 736) RIBBON-1 † (n = 1,237) Overall (Hazard Ratio, HR) 5.5 (0.48) 0.8 (0.70); 0.9 (0.61) 2.9 (0.69); 1.2 (0.64) Triple-negative (HR) 5.3 (0.49) 0.8 (0.69); 2.8 (0.53) 1.9 (0.72); 0.3 (0.78) Neoadjuvant/adjuvant taxane (HR) 7.3 (0.33) 4.2 (0.62); 1.9 (0.43) 4.5 (0.62); 2.4 (0.65) Age ≥ 65 (HR) 4.3 (0.67) 0.8 (0.76); 0.8 (0.68) 2.9 (0.69); 1.6 (0.83)
64. BEATRICE: TN MK de Adjuvan Bevacizumab Faz III Çalışması Operabl meme kanseri ER-neg, PR-neg, HER2-neg N = 2530 Standard adjuvant kemoterapi * * ant rasiklin ta ksan veya tek başına taksan Primer sonlanım noktası : DFS Standard adjuvant kemoterapi * + Bevacizumab x 1 yıl 15 mg/kg q 3 hfta
65. SUN 1077: Phase II Trial of Sunitinib Malate vs Standard of Care In Pre-treated Triple-Negative Advanced Breast Cancer Patients with ER-negative, PR-negative, and HER2- negative advanced breast cancer N=200 1:1 SUNITINIB 37.5 mg oral 1 x daily Standard-of-Care Chemotherapy Regimens PER CYCLE (3 WEEKS) Capecitabine 1000*-1250 mg/m 2 oral 2 x daily on days 1-14 OR Vinorelbine 25-30 mg/m 2 IV 1 x weekly OR Vinorelbine 60-80 mg/m 2 oral 1 x wkly OR Paclitaxel 175-200 mg/m 2 IV day 1 OR Paclitaxel 80-90 mg/m 2 IV 1 x weekly OR Gemcitabine 800-1250 mg/m 2 IV days 1 and 8 * Patients >65 years of age http://clinicaltrials.gov Trial design Endpoints Study sites Treatment FPFV Multinational, multi-center, randomized, open label Primary: PFS Secondary: safety, ORR, OS, QoL, PK, biomarker US, EU 2 nd line or 3 rd line Enrolling
66. Poly (ADP-Ribose) Pol imeraz (PARP) İnhibitörleri
67. PARP İnhibitörlerinin Etki Mekanizması O’Shaughnessy J, et al. ASCO 2009. Platin DNA adduct ve çapraz bağlanma ile DNA hasarı yapar . PARP1 Upregülasyonu (Base-excision repair) 3. PARP1 İnhibisyonu : Çift Zincir Kırığı Hücrenin sağkalımı Hücre ölümü BRCA1 BRCA2 P t Pt Pt Pt P t CG CG CG GC TA AT T A CG CG TA AT T A CG CG A T T TA GC A G C C G G PARP1 PARP1 BSI-201 PARP1 C
68. PARP1 Upregulation in Breast Cancer IDC Subtypes * Defined by percentage of samples exceeding the 95% UCL of normal tissue distribution. O’Shaughnessy J. TNBC 101 Research To Practice Webinar, 2010. % PARP1 Upregulation* IDC subtype Normal
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70. TNBC de Faz II BSI-201 Çalışması BSI-201 + Gem/Carbo (n = 57) Median PFS = 6.9 months Gem/Carbo (n = 59) Median PFS = 3.3 months P < 0.0001 HR = 0.342 (95% CI, 0.200-0.584) O'Shaughnessy J, et al. SABCS 2009. Abstract 3122.
71. Final Efficacy Results of the Phase II Trial of Iniparib (BSI-201) in Combination with Gemcitabine/Carboplatin for Patients with mTNBC * Not adjusted for multiple interim analyses. CBR, clinical benefit rate; ORR, objective response rate; OS, overall survival; PFS, progression-free survival O’Shaughnessy J et al. Proc ESMO 2010;Abstract LBA11. Clinical Variable Gem/Carbo (n = 62) Iniparib/Gem/Carbo (n = 61) p -value* ORR 32.3% 52.5% 0.023 CBR 33.9% 55.7% 0.015 Median PFS 3.6 mos 5.9 mos 0.012 Median OS 7.7 mos 12.3 mos 0.014
74. Oral Poly(ADP-ribose) Polymerase Inhibitor Olaparib in Patients with BRCA1 or BRCA2 Mutations and Advanced Breast Cancer: A Proof-of-Concept Trial Tutt A et al. Lancet 2010;376(9737):235-44.
75. BRCA- Mutasyonu Gösteren Metastatik Meme Kanserinde Olaparib Tutt A et al. Lancet 2010;376(9737):235-44 . Cevap 400 mg BID* (n = 27) 100 mg BID* (n = 27) ORR, n (%) 11 (41) 6 (22) CR, n (%) 1 (4) 0 (0) PR, n (%) 10 (37) 6 (22) Median PFS, mos (range) 5.7 (4.6-7.4) 3.8 (1.9-5.6)
77. Diğer “Drugable” Hedefler PTEN, phosphatase and tensin homolog mTOR, mammalian target of rapamycin TGF- , transforming growth factor-beta TRAIL, tumor necrosis factor-related apoptosis-inducing ligand Hedef / Yolak İlaç Andro j en re s ept örü Bicalutamide PTEN kaybı mTOR inhibit örü TGF- TGF- antagonist leri TRAIL TRAIL re s ept ö r agonist leri
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Editor's Notes
Figure 1. Correspondence between Molecular Class and Clinicopathological Features of Breast Cancer. Data are from Sorlie et al.,3 Hu et al.,5 Rouzier et al.,28 and van de Vijver et al.29 HER2 status, as determined by immunohistochemical (IHC) analysis, was available for only 82 of 535 patients in the combined studies. ER denotes estrogen receptor, and Ki-67 nuclear antigen Ki-67.
BRCA1 is a substrate for DNA damage response kinases e.g. ATM, CHK2 and regulates G2/M checkpoint – prevents replication of damaged DNA. Also involved in Spindle poisons like taxanes bind to and stabilize beta-tubulin preventing depolymerization; vincas bind to and destabilize beta-tubulin, promoting depolymerization act to cause mitotic arrest and apoptosis. BRCA1 acts in that mitotic arrest. Thus BRCA1 modulates an apoptotic pathway in response to spindle damage; this role is in direct contrast to its role in promoting DNA repair and cell survival after treatment with DNA-damaging drugs.
Delete first line of “investigation of PARP…” Add in
Study Design: This trial was a Randomized, Open-label, Phase III Trial of ixa + cape vs capecitabine alone in women with metastatic or locally advanced breast cancer that was considered incurable. The doses are shown on the right hand side of the slide. Ixabepilone at 40 mg/m2 was administered as a 3 hour intravenous infusion once every 3 weeks. Capeciiabine was administered at 2000 mg/m2/day divided BID for days 1 to 14 on a 21 day cycle. These doses were chosen based on a Phase I/II study that established efficacy and reasonable side effect profile. The capecitabine arm was the US FDA approved dose of 2500 mg/m2/day given on days 1 to 14 of a standard 21 cycle. At randomization, pts were stratified for the presence or absence of visceral metastases, anthracycline resistance, prior chemotherapy for MBC and study site References
CR, complete response; ORR, overall response rate; PFS, progression-free survival; PR, partial response. However, there was also evidence of a dose-dependent response to olaparib. The table on the left side of this slide demonstrates that patients receiving the higher olaparib dose experienced a 2-fold higher response rate relative to patients receiving the lower dose. Most of those responses were partial responses. There was also an incremental improvement in progression-free survival. Regardless of the presence of BRCA1 or BRCA2 mutations, a significant fraction of patients had some degree of tumor shrinkage even if they did not meet the criteria for a partial response. For more information, go online to: http://clinicaloptions.com/Oncology/Conference%20Coverage/Clin%20Onc%20June%202009/Tracks/Breast_Cancer/Capsules/CRA501.aspx
CI, confidence interval; PFS, progression-free survival. Median progression-free survival for individuals receiving olaparib 400 mg twice daily was 5.7 months vs 3.8 months for patients receiving olaparib 100 mg twice daily. For more information, go online to: http://clinicaloptions.com/Oncology/Conference%20Coverage/Clin%20Onc%20June%202009/Tracks/Breast_Cancer/Capsules/CRA501.aspx