Verlängerte endokrine Therapie KONTRA Oleg Gluz Westdeutsche Studiengruppe/Brustzentrum Niederrhein Uniklinik Köln

primum non nocere, secundum cavere, tertium sanare… Hippocrates Ein paar Grundsätze… primum non nocere, secundum cavere, tertium sanare… Hippocrates Erstens nicht schaden, zweitens vorsichtig sein, drittens heilen… Das Ziel im kurativen Setting bleibt das Überleben Im Rahmen dieses Vortrages werden teilweise Positionen vertreten, die vom Autor nicht geteilt werden;)))) 09.05.2018

Pooled analysis ATLAS + aTTom: Breast Cancer Mortality 10 vs 5 yrs BC mortality RR by period in ER+ve (or unknown) patients ATLAS1 Er+ve n=10543* HR (95% CI) aTTom2 ER+ve n=6934 in UK Combined ER+ve n=17477 Years 5-9 0.92 (0.77-1.09) 1.08 (0.85-1.38) 0.97 (0.84-1.15) Years 10+ 0.75 (0.63-0.90) p=.002 (0.63-0.90) p=.007 (0.65-0.86) p=.00004 All years 0.83 (0.73-0.94) p=.004 0.88 (0.74-1.03) p=.1 0.85 (0.77-0.94) p=.001 Smith IE. How Long Is Long Enough? Defining Optimal Duration and Selection of Adjuvant Endocrine Therapy for Breast Cancer. ASCO 2014, Breast Cancer Track - Navigating a Changing Sea: Optimizing Treatment of Hormone Receptor-Positive Breast Cancer Also significant improvements in Overall Survival 5-9 yrs 10-14 yrs All yrs HR 0.99 HR 0.84 HR 0.91 (0.89-1.10) (0.77-0.93) (0.84-0.97) (p=0.0007) (p=0.008) * IPCW (Inverse probability of censoring weighted) estimate of effect in ER+ Gray RG et al. ASCO 2013 (Abstract 5); 1ATLAS: Smith ASCO 2014; 2aTTom: Gray ASCO 2013 Mod. Smith IE. ASCO 2014, Breast Cancer Track - Navigating a Changing Sea: Optimizing Treatment of Hormone Receptor-Positive Breast Cancer

Risiko Endomterium-Ca RR 2,06 Risiko Lungenembolie RR 1,9 Meta-Analyse Risiko Endomterium-Ca RR 2,06 Risiko Lungenembolie RR 1,9

Effect of additive „T+N score“ (range 1-6) Score: 1/2 for T1/T2, plus 0/1/4 for N0/N1-3/N4-9 47% T2N4-9 (score=6) 41% T1N4-9 29% T2N1-3 22% T1N1-3 or T2N0 14% T1N0 (score=1) 36% 12,5% Mod. Hongchao P et al. J Clin Oncol 34, 2016 (suppl; abstr 505)

Number to treat: Wieviel Patientinnen müssen behandelt werden? Mubarak et al. 2014

95% vs. 91%, p=0.01 93% vs. 94%, n.s.

Trotz 56% Bisphosphonate Toxizität MA 17 R Studie Signifikant schlechtere Lebensqualität unter AI vs. Placebo Trotz 56% Bisphosphonate 90% C/Vit D3 Prophylaxe

Auch bei N+ kein höherer Effekt zu erwarten….

NSABP B-42 Schema Stratification: Pathological nodal status (Negative, Positive) Prior adjuvant TAM (Yes, No) Lowest BMD T score: spine, hip, femur (>-2.0 ≤ -2.0 SD) Postmenopausal Pts with ER+ or PR+ Breast Cancer Stage I, II, or IIIa invasive BC at diagnosis Disease-free After 5 Years of Endocrine Therapy TAM X ≤ 3 yrs  AI to Complete 5 yrs AI X 5 yrs or Letrozole X 5 yrs R Mamounas EP, Bandos H, Lembersky BC, Geyer CE, Fehrenbacher L, Graham ML, Chia SL, Brufsky AM, Hennessy BT, Soori GS, Dakil SR, Seay TE, Wade JL, McCarron EC, Paik S, Swain SM, Wickerham DL, Wolmark N. NRG Oncology/NSABP (NSABP Legacy trials are now part of the NRG Oncology portfolio). A randomized, double-blinded, placebo-controlled clinical trial to evaluate extended adjuvant endocrine therapy (5 years of letrozole) in postmenopausal women with hormone-receptor positive breast cancer who have completed previous adjuvant endocrine therapy: Initial results of NRG oncology/NSABP B-42. SABCS 2016, General Session 1, Abstract No. S1-05 Placebo X 5 yrs Mod. Mamounas EP et al. SABCS 2016, General Session 1, Abstract No. S1-05

Disease-Free Survival NSABP B-42 Disease-Free Survival 84.7% Disease-Free Survival 81.3% Letrozole Placebo # Events 292 339 Mod. Gnant M. SABCS 2016, General Session 1, Abstract No. S1-06. Discussant HR=0.85 (0.73 - 0.999) p= 0.048* Years after Randomization Letrozole Placebo 1959 1964 1813 1814 1644 1639 1225 1208 216 210 Mamounas E et al. SDABCS 2016; *p- value did not reach statistical significance level of 0.0418

Mamounas E et al. SABCS 2016

Nach 2- 3 Jahren Tamoxifen… DATA Study Design 80% power to detect an increase in 3-year adapted Disease-Free Survival (aDFS) from 90% to 94%, i.e., a hazard ration (HR) of 0.60 and a significance level of 0.05 Accounting for 10% drop-out: 950 patients per group to be included (n=1912 patients actually included) Minimum follow-up: ≥6 years after randomization, i.e., ≥3 years of adapted follow-up (last patient included in August 2009) Postmenopausal at randomization ER+ and/or PR+ No sign of disease recurrence M0 breast cancer After 2-3 years adjuvant Tamoxifen 6 years anastrozole 1 mg daily 3 years anastrozole Stratification Nodal status ER/PR HER2 status Tamoxifen duration Tjan-Heijnen VC, Van Hellemond IE, Peer PG, Swinkels AC, Smorenburg CH, Van der Sangen M, Kroep JR, De Graaf H, Honkoop AH, Erdkamp F, Van den Berkmortel FW, Kitzen JJ, De Boer M, De Roos WK, Linn SC, Imholz AL, Seynaeve C. First results from the multicenter phase III DATA study comparing 3 versus 6 years of anastrozole after 2-3 years of tamoxifen in postmenopausal women with hormone receptor-positive early breast cancer. SABCS 2016, General Session 1, Abstract No. S1-03 Mod. Tjan-Heijnen VC et al. SABCS 2016, General Session 1, Abstract No. S1-03

Aromatase Inhibitor (AI) IDEAL trial Trial design Investigation on the Duration of Extended Adjuvant Letrozole treatment Tamoxifen Aromatase Inhibitor (AI) (AI) R Letrozole 5 years adjuvant therapy 0-2 years 2.5 or 5 years extended therapy Blok EJ, van de Velde CJH, Meershoek-Klein Kranenbarg EM, Putter H, van den Bosch J, Maartense E, van Leeuwen-Stok AE, Liefers G-J, Nortier JWR, Rutgers EJT, Kroep JR. Optimal duration of extended letrozole treatment after 5 years of adjuvant endocrine therapy; results of the randomized phase III IDEAL trial (BOOG 2006-05). SABCS 2016, General Session 1, Abstract No. S1-04 Mod. Blok EJ et al. SABCS 2016, General Session 1, Abstract No. S1-04

Zusammenfassung Kein unselektierter Einsatz der verlängerten endokrinen Therapie Anwendung nur bei Frauen mit einem sehr hohen Risiko-Profil, stark hormonempfindlichen Tumoren und guter Verträglichkeit Aufklärung über Risiken/Nebenwirkungen!!!! Bisher nur eine eindeutige Studie zum Vorteil von 5 Jahre AI nach 5 Jahre Tamoxifen bei perimenopausalen Frauen oder N+, sonst 4 (mehr oder weniger) negative Studien, falls AI in ersten 5 Jahren der Therapie