Hormon Duyarlı Metastatik Meme Kanserinde Sıralama Nasıl Olmalı? Erhan Gökmen Ege Üniv. Tıp Fakültesi

Hormon Duyarlı Metastatik Meme Kanserinde Sıralama Nasıl Olmalı? Erhan Gökmen Ege Üniv. Tıp Fakültesi

Hormonal Tedavide Sıralama: Göz Önüne Alınması Gereken Faktörler Menopozal durum: Premenopozal Postmenopozal Önceki tedaviler; nükse kadar geçen süre: Adjuvan tedavi sırasında veya sonrasında 12 ay içinde nüks: 2. hat tedavi Adjuvan tedaviden >12 ay sonra nüks: 1. hat tedavi Tümor biyolojisi: HER2 negatif veya pozitif Komorbid hastalıklar (kardiak hast., osteoporoz vb)

Premenopozal Hastalarda Hormonal Tedavi Seçenekleri: Birinci hat Over ablasyonu veya supresyonu SERM (tamoksifen) Over ablasyonu/supresyonu + SERM AI kullanılmamalı

Premenopozal Hastalarda Hormonal Tedavi Seçenekleri: Birinci hat Tamoksifen vs Over Ablasyonu: 1997 meta-analizi: 4 çalışma, 220 hasta (Breast Cancer Res Treat. 1997;44(3):201) PFS ve OS benzer (OR 0.86 ve 0.94), trend tmx lehine Tamoksifen + over supresyonu vs over supresyonu 2001 meta-analizi: 4 çalışma, 550 hasta (EORTC, J Clin Oncol. 2001;19(2):343) PFS ve OS kombinasyonla daha iyi (HR 0.70 ve 0.78) Tamoksifen + over supresyonu vs tamoksifen çalışması yok

Premenopozal Hastalarda Hormonal Tedavide Sıralama Birinci hat Over supresyonu + tamoksifen veya Tamoksifen veya Over supresyonu/ablasyonu İkinci ve ileri hatlar İlk hatta kullanılmamış ise over supresyonu veya Over supresyonunun teyidi + postmenopozal algoritma

Postmenopozal Hastalarda Hormonal Tedavi Seçenekleri: Birinci hat Aromataz İnhibitörleri SERM (tamoksifen) Fulvestrant AI+fulvestrant

Proportion of Patients Alive First-line Letrozole İlk vs Hat Tamoxifen, Letrozol vs Tamoksifen Then Crossover 1.0 0.9 0.8 0.7 0.6 0.5 0.4 Median OS Letrozole: 34 mos Tamoxifen: 30 mos Time to Crossover Letrozole: 17 mos Tamoxifen: 14 mos 0.3 0.2 P =.53 (log-rank test) 0.1 0 0 6 12 18 24 30 36 42 48 54 60 Mos Letrozole 1st Tamoxifen 1st Mouridsen H, et al. J Clin Oncol. 2003;21:2101-2109.

Postmenopozal Hastalarda Birinci Hat Tedavi: AI vs Diğer Endokrin Tedaviler 2006 Meta-analizi 23 klinik çalışma; 8504 hasta OS AI vs tamoksifen (HR 0.89, 95% CI 0.80-0.99), ilk hat AI vs diğer endokrin tedaviler (HR 0.87, 95% CI 0.82-0.93), ileri hatlar Mauri D, J Natl Cancer Inst. 2006;98(18):1285

Proportion of Patients Alive and Progression Free FIRST Study: Fulvestrant vs Anastrozol FIRST Study: TTP at TTP Follow-up at Follow-up Analysis Analysis Treatment and Management Approaches in Metastatic Breast Cancer clinicaloptions.com/oncology 1.0 0.8 Fulvestrant 500 mg Anastrozole 1 mg 0.6 0.4 Patients at Risk, n Fulvestrant 500 mg Anastrozole 1 mg 0.2 0 HR: 0.66 (95% CI: 0.47-0.92; P =.01) 0 6 12 18 24 102 103 74 69 65 55 52 39 Mos 45 30 30 36 42 48 34 21 20 8 6 2 0 0 Robertson JF, et al. Breast Cancer Res Treat. 2012;136:503-511.

Treatment and Management Approaches in Metastatic Breast Cancer FACT: Phase III Study of First-line Anastrozole clinicaloptions.com/oncology ± Fulvestrant in HR+ MBC Post- or premenopausal women receiving GnRH agonist, ER- or PgR-positive, in first relapse after treatment for localized disease (N = 514) Fulvestrant 500 mg on Day 1, then 250 mg on Days 15, 29, then every 4th wk Anastrozole 1 mg/day PO (n = 258) Anastrozole 1 mg/day PO (n = 256) Treat until progression or undue toxicity Primary endpoint: TTP Secondary endpoints: ORR, TTF, DoR, clinical benefit rate, OS Bergh J, et al. J Clin Oncol. 2012;30:1919-1925.

Probability of Survival Without Progression Treatment and Management Approaches in Metastatic Breast Cancer FACT: Phase III Study of First-line Anastrozole clinicaloptions.com/oncology ± Fulvestrant in HR+ MBC: TTP 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Bergh J, et al. J Clin Oncol. 2012;30:1919-1925. Median TTP Anastrozole (n = 256): 10.2 mos Anastrozole + fulvestrant (n = 258): 10.8 mos HR: 0.99 (95% CI: 0.81-1.20; P =.91) 0 0 6 12 18 24 30 36 42 48 54 Mos

SWOG S0226: Phase III Study of First-line Anastrozole ± Fulvestrant in HR+ MBC Treatment and Management Approaches in Metastatic Breast Cancer clinicaloptions.com/oncology Stratified by previous adjuvant tamoxifen Treatment until disease progression Postmenopausal women with HR+ MBC (N = 707) Primary endpoint: PFS Anastrozole 1 mg/day PO + Fulvestrant 500 mg on Day 1, 250 mg on Days 14 and 28, 250 mg q28 days thereafter (n = 355) Anastrozole 1 mg/day PO (n = 352) Secondary endpoints: OS, clinical benefit rate, ORR Mehta RS, et al. N Engl J Med. 2012;367:435-444. Women with progression encouraged to cross over to receive fulvestrant

PFS OS S0226 Study of First-line Anastrozole ± Fulvestrant in HR+ MBC: PFS and OS Treatment and Management Approaches in Metastatic Breast Cancer clinicaloptions.com/oncology 1.00 Median PFS Combination: 15.0 mos (95% Cl: 13.2-18.4) Anastrozole: 13.5 mos (95% Cl: 12.1-15.1) 1.00 Median OS Combination: 47.7 mos (95% Cl: 43.4-55.7) Anastrozole: 41.3 mos (95% Cl: 37.2-45.0) 0.75 0.50 0.25 0 Anastrozole (297 events) HR: 0.80 (95% Cl: 0.68-0.94; P =.007 by stratified log-rank test) Anastrozole + Fulvestrant (268 events) 0 12 24 36 48 60 Mos Since Randomization 0.75 0.50 0.25 0 Anastrozole (176 deaths) HR: 0.81 (95% Cl: 0.65-1.00; P =.049 by stratified log-rank test) Anastrozole + Fulvestrant (154 deaths) 0 12 24 36 48 60 72 Mos Since Randomization Mehta RS, et al. N Engl J Med. 2012;367:435-444.

Treatment and Management Approaches in Metastatic Breast Cancer S0226: PFS and OS Overall and by Previous clinicaloptions.com/oncology Adjuvant Tamoxifen Endpoint Anastrozole + Fulvestrant Anastrozole HR (95% CI) P Value Median PFS (n = 694), mos 15.0 13.5 0.80 (0.68-0.94) No previous adjuvant tamoxifen (n = 414) Previous adjuvant tamoxifen (n = 280) 17.0 12.6 0.74 (0.59-0.92) 13.5 14.1 0.89 (0.69-1.15) Median OS (n = 694), mos 47.7 41.3 0.81 (0.65-1.00) No previous adjuvant tamoxifen (n = 414) Previous adjuvant tamoxifen (n = 280) 47.7 39.7 0.74 (0.56-0.98) 49.6 44.5 0.91 (0.65-1.28).007.0055.37.049.0362.59 Mehta RS, et al. N Engl J Med. 2012;367:435-444.

First-line Anastrozole ± Fulvestrant in HR+ MBC: FACT vs SWOG S0226 Treatment and Management Approaches in Metastatic Breast Cancer clinicaloptions.com/oncology FACT [1] SWOG S0226 [2] Patients, n 514 707 De novo metastatic disease, % 13 39 Prior adjuvant chemotherapy, % 45 33 Previous adjuvant endocrine therapy (tamoxifen), % 68 40 Mean PFS range, mos 10-11 13-15 PFS benefit No Yes 1. Bergh J, et al. J Clin Oncol. 2012;30:1919-1925. 2. Mehta RS, et al. N Engl J Med. 2012;367:435-444.

Postmenopozal Hastalarda Hormonal Tedavide Sıralama Birinci hat Aromataz inhibitörü Aİ nün uygun olmadığı veya tolere edilemediği durumlarda Tamoksifen Fulvestrant (faz II randomize çalışma) Aİ+fulvestrant kullanımı standart değil

Postmenopozal Hastalarda Hormonal Tedavide Sıralama: İkinci Hat Tedavi Çapraz direnç göstermeyen Aİ Fulvestrant Tamoksifen Exemestan+everolimus

AI sonrası İkinci Hatta Tamoksifen Efficacy of tamoxifen following anastrozole ( Arimidex ) compared with anastrozole following tamoxifen as first-line treatment for advanced breast cancer in postmenopausal women European Journal of Cancer, Volume 39, Issue 16, 2003, 2310-2317

AI sonrası İkinci Hatta Tamoksifen Objective response and clinical benefit following cross-over treatment with anastrozole and tamoxifen for patients with oestrogen and/or progesterone receptor-positive status European Journal of Cancer, Volume 39, Issue 16, 2003, 2310-2317

İkinci Hat Tedavi: EFFECT EFECT Fulvestrant similar to exemestane in postmenopausal women progressing following prior NSAI with HR+ ABC in phase lll placebo-controlled trial N = 693 PMW with HR+ ABC after failure of NSAI therapy FUL 500 mg day 1, 250 mg day 14, 28, monthly EXE 25 mg QD Primary: TTP Secondary: ORR, CBR, DOR, TTR, OS, tolerability FUL n = 351 EXE n = 342 P Value TTP, mo 3.7 3.7.653 ORR, % 7.4 6.7.736 CBR, % 32.2 31.5.853 CBR, clinical benefit rate; DOR, duration of response; EXE, exemestane; FUL, fulvestrant; OS, overall survival; PMW; postmenopausal women; TTR, time to response Chia S, et al. J Clin Oncol. 2008;26(10):1664-1670. Chia S, J Clin Oncol. 2008;26(10):1664

İkinci Hat Tedavi: SoFEA SoFEA Fulvestrant + anastrozole similar to fulvestrant alone or exemestane alone in postmenopausal women with HR+ ABC progressing following prior NSAI therapy N = 723 PMW with HR+ ABC following progression on NSAI FUL 500 mg loading day 0, then 250 mg monthly + ANA 1 mg/daily FUL 500 mg loading day 0, then 250 mg monthly EXE 25 mg/daily EXE n = 249 FUL n = 231 ANA + FUL n = 243 PFS, mo 3.4 4.8 4.4 Primary: PFS (F + A vs F; F vs E) Secondary: ORR, CBR, OS, tolerability EXE vs FUL HR 0 95, 0 79-1 14; log-rank p=0 56 HR (95% CI): 1.00 (0.83 1.21) P =.98 No differences were observed in PFS, ORR, CBR, or OS. Johnston S, et al. Eur J Cancer. 2012;48(Suppl 3):2LBA. Johnston SR, Lancet Oncol. 2013;14(10):989

BOLERO-2: Exemestane ± Everolimus in Nonsteroidal AI Refractory Advanced BC Treatment and Management Approaches in Metastatic Breast Cancer clinicaloptions.com/oncology Postmenopausal women with HR-positive, HER2-negative advanced breast cancer refractory to letrozole or anastrozole (N = 724) Refractory to therapy: Recurrence during or within 12 mos of end of adjuvant treatment Progression during or within 1 mo after end of treatment for advanced disease Baselga J, et al. N Engl J Med. 2012;366:520-529. Everolimus 10 mg/day + Exemestane 25 mg/day (n = 485) Placebo + Exemestane 25 mg/day (n = 239) Stratification: Sensitivity to previous hormonal therapy Presence of visceral disease No crossover allowed Primary endpoint: PFS Secondary endpoints: OS, ORR, CBR, safety, QoL, bone markers

Patients (%) Treatment and Management Approaches in Metastatic Breast Cancer clinicaloptions.com/oncology BOLERO-2: PFS at 18-Mo Follow-up Higher ORR (9.5 versus 0.4 percent) 100 80 60 Censoring Times EVE + EXE (n/n = 310/485) PBO + EXE (n/n = 200/239) Median PFS, Mos EVE + EXE: 7.82 PBO + EXE: 3.19 HR: 0.45 (95% CI: 0.38-0.54; Log-rank P <.0001) 40 20 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120 Week Patients at Risk, n EVE + EXE 485 436 366 304 257 221 185 158 124 91 66 50 35 24 22 13 10 8 2 1 0 PBO + EXE 239 190 132 96 67 50 39 30 21 15 10 8 5 3 1 1 1 0 0 0 0 Piccart-Gebhart M, et al. ASCO 2012. Abstract 559.

Treatment and Management Approaches in Metastatic Breast Cancer clinicaloptions.com/oncology BOLERO-2: Advers Events at 18-Mo Follow-up Adverse Event, % Everolimus + Exemestane (n = 482) Grade Placebo + Exemestane (n = 238) Grade All 3 4 All 3 4 Total 100 44 9 91 23 5 Stomatitis 59 8 0 12 < 1 0 Rash 39 1 0 7 0 0 Fatigue 37 4 < 1 27 1 0 Diarrhea 34 2 < 1 19 < 1 0 Nausea 31 < 1 < 1 29 1 0 Appetite decreased 31 1 0 13 1 0 Noninfectious pneumonitis 16 3 0 0 0 0 Hyperglycemia 14 5 < 1 2 < 1 0 Piccart-Gebhart M, et al. ASCO 2012. Abstract 559.

Treatment and Management Approaches in Metastatic Breast Cancer clinicaloptions.com/oncology Postmenopozal Hastalarda Hormonal Tedavide Sıralama: İkinci Hat Tedavi Standart tedavi yok: Exemestan+everolimus Exemestan Fulvestrant Tamoksifen

Treatment and Management Approaches in Metastatic Breast Cancer clinicaloptions.com/oncology Endokrin Duyarlı Meme Kanserinde Sıralama: Sonuçlar Premenopozal Birinci hat Over supresyonu+tamoksifen Tamoksifen İkinci hat Gonadal supresyon sonrası postmenopozal algoritma Postmenopozal Birinci hat Aromataz İnhibitörü İkinci hat Exemestan+everolimus, Exemestan, Fulvestrant, Tamoksifen