VIEL TAM TAM UM DIE NEUEN

Präsentation zum Thema: "VIEL TAM TAM UM DIE NEUEN"—  Präsentation transkript:

1 VIEL TAM TAM UM DIE NEUEN
AROMATASEHEMMER C. Jackisch

2 Relative und absolute Reduktion von Todesfällen durch adjuvante systemische Therapien
relativ (%) absolut (%) Therapieoption n <50 J. >50 J. gesamt nach 10 J. Ovarektomie   7 Tam 5 J. (ER+)  7 24  6 24  4 Chemotherapie  3 11  2 15  2 8.3 7.4 4.4 EBCTCG 2000 C. Jackisch

3 Therapeutischer Nutzen
Endokrine Therapie Therapeutischer Nutzen Albain K. St. Gallen 2005 C. Jackisch

4 Endocrine Adjuvant Treatment in Breast Cancer
EBCTCG 15-Years Follow Up: 5 yrs. Tamoxifen vs. Nil in ER positive ± ER unknown breast cancer n=10.386 ER?: 20% N+: 30% EBCTCG Lancet 2005;365: C. Jackisch

5 Polychemotherapy vs not, by entry age <50 or years:15-year probabilities of recurrence and of breast cancer mortality Entry age years: breast cancer mortality 10 20 30 40 50 60 Control 50.4% Polychemotherapy 47.4% 38.3 35.4 Breast cancer mortality (%) 21.3 18.7 The relative risk of fracture remains steady, stabilising after 2 years and shows no evidence of worsening over time. [Locker & Eastell, 2003]. Locker GY, Eastell R. The time course of bone fractures observed in the ATAC ('Arimidex', Tamoxifen, Alone or in Combination) trial. Proc Am Soc Clin Oncol 2003; 22: 25, abs 98. The ATAC Trialists’ Group. Results of the ATAC (‘Arimidex’, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Manuscript submitted 2004 15-year gain 3.0% (SE 1.3) Logrank 2p< 5 10 15 Years EBCTCG 2005 Lancet 2005;365: Younger women, 35% node-positive; older women, 70% node-positive.

6 5 Years Adjuvant Tamoxifen
Advantages Disadvantages Reduces rate of recurrence and death Reduces contralateral breast cancer risk Bone and lipid benefits EFFICACY De novo and acquired resistance Limited duration of benefit TOXICITIES Endometrial cancer Thromboembolism Hot flushes Genitourinary symptoms Arterial-vascular side effects C. Jackisch

7 Development of Aromatase Inhibitors
Toxicity Selectivity Potency First generation Aminoglutethimide Rash, etc. No adrenal insufficiency, etc. 1,000 to 10,000 100 1 Second generation Fadrozole 4-OHA, Formestane Third generation Anastrozole Exemestane Letrozole

8 Aromatase inhibitors in breast cancer: an exploding domain!
Lancet 2002 Lancet 2005

9 STEROIDREZEPTOREN SOLD OUT
St. Gallen 2005: Risikokategorien Mammakarzinom Nodal negativ – Nodal positiv (1-3 LK+) Niedriges Risiko Mittleres Risiko p T  2 cm (invasive Komponente) + Grading 1 Alter  35 Jahre V 0 Keine Her2neu Überexpression oder Amplifikation p T > 2 cm (invasive Komponente) oder Grading 2-3 Alter < 35 Jahre V 1 Her2neu Überexpression oder Amplifikation STEROIDREZEPTOREN SOLD OUT N1-3+ (+ Her2neu negativ) Goldhirsch A. et al Ann Oncol epub Sept 7, 2005 * <1% Verbesserung des Jahre

10 St. Gallen 2005: Choice of treatment modalities
Risk categorya Endocrine responsiveb Endocrine responsive Uncertainb,c Endocrine non-responsiveb Low risk ET Nild ET Nild Not applicable Inter- mediate risk ET alone,or CT  ET (CT + ET)e CT  ET (CT + ET)e CT High risk CTET (CT + ET)e CTET (CT + ET)e CT Goldhirsch A. et al Ann Oncol epub Sept 7, 2005 C. Jackisch

11 Is It Really Better To Give An Effective Therapy First ?
A Major Underlying Principle Of Adjuvant Therapy Treatment Or I am going to discuss the use of prognostic models for predicting DFS of Breast Cancer patients. Treatment Relapse C. Jackisch

12 Womit fange ich an: ECOG: Annual risk of recurrence
Total Positive nodes (0) Positive nodes (>4) Postmenopausal Premenopausal ER +ve ER -ve Tumour size (>3 cm) Tumour size (<1 cm) Hazard of recurrence by yearly interval (%) The risk of recurrence in patients diagnosed with early breast cancer is highest during the first 5 years post-diagnosis, peaking at ~2 years, irrespective of baseline prognostic factors (Saphner et al 1996). Reference Saphner T et al. Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 1996;14: Time (years) ECOG = Eastern Cooperative Oncology Group Saphner T et al. J Clin Oncol 1996;14:

13 SYSTEMTHERAPIE NODAL NEGATIV POSITIV REZEPTOR NEGATIV POSITIV C H T
Endokrine Therapie

14 SYSTEMTHERAPIE POST- MENOPAUSE (C H T*) 5 Jahre Tamoxifen
5 Jahre ARH** 2-3 Jahre Tam  3 Jahre ARH 5 Jahre Tam  5 Jahre ARH * CHT: In Abhängigkeit vom Risikoprofil, ** ARH: Aromatasehemmer C. Jackisch

15 Viel TAM TAM um die neuen Aromatasehemmer
Die Evidenzfalle…. C. Jackisch

16 Datenlage Postmenopause
Recurrence rate/year (%) 16 Node +ve 12 8 Node -ve 4 2 4 6 8 10 Time (years) Randomisation ‘Arimidex’, Tamoxifen Alone or in Combination (ATAC) Tamoxifen Anastrozole (‘Arimidex’) Initial adjuvant Tamoxifen Breast International Group (BIG) 1-98 Letrozole Tamoxifen Adapted from EBCTCG. Lancet 1998;352: Letrozole

17 ATAC: disease-free survival (HR+ population) Median follow up 68 months
Patients (%) 25 HR+ ITT HR 0.83 0.87 95% CI (0.73–0.94) (0.78–0.97) p-value 0.005 0.01 20 15 Tamoxifen 10 Anastrozole 5 Disease-free survival was significantly greater in the anastrozole group compared with the tamoxifen group, with a 17% lesser risk of recurrence and an absolute difference of 3.3% between treatment arms. The divergence in curves which begins at 1 year continues and increases out to 6 years, i.e. after treatment completion. This ‘carry-over’ effect appears greater in the anastrozole group than in the tamoxifen group. Absolute difference: 1.6% 2.6% 2.5% 3.3% 1 2 3 4 5 6 Follow-up time (years) Includes non breast cancer deaths; HR+=hormone receptor positive ATAC Trialists’ Group. Lancet 2005;365:60-62 C. Jackisch

18 Hazard-Ratio – Recurrence in HR positive Patients
Was sollte bedacht werden... Hazard-Ratio – Recurrence in HR positive Patients 3.0 2.5 2.0 Jährliche Hazard-Raten (%) 1.5 1.0 Anastrozol 0.5 Tamoxifen The benefits with anastrozole were seen throughout the follow-up period including years 1–3, when the well-described peak of recurrence with tamoxifen was not seen with anastrozole. 1 2 3 4 5 6 Follow-up Dauer (Jahre) *Hazard-Ereigniskurven geglättet nach Howell, SA2004 C. Jackisch

19 ATAC – Time to Recurrence Nodalstatus: N0
Patients (%) p<0.0009 210 (10.9%) 146 (7.8%) ATAC final analysis 68 months, AstraZeneca, Data on file Anastrozole Tamoxifen

20 BIG 1-98 Design A B C D Compares Letrozole versus Tamoxifen
2 5 YEARS Compares Letrozole versus Tamoxifen Letrozole: Arms B and D Tamoxifen: Arms A and C Excludes events and FU beyond switch for C & D ASCO 2005

21 Percent Alive and Disease-Free
Disease-Free Survival 97.7 97.6 Yearly DFS % 95.1 93.4 90.5 89.0 86.8 84.6 84.0 81.4 No. at Risk 3892 3896 2964 2926 1261 1238 892 866 4003 4007 567 544 N HR (95% CI) p 8010 0.81 ( ) 0.003 Events 779 100 L 80 T 60 Percent Alive and Disease-Free 40 20 1 2 3 4 5 Years from Randomization ASCO 2005

22 Subgruppen — DFS BIG 1-98 and ATAC
N - (n=4174) BIG m. ATAC 68m. N - (n=3791) N + (n=3311) N + (n=2137) no CT (n=5986) no CT (n=6241) CT given (n=2024) CT given (n=1345) 1.0 0.5 0.75 1.33 2.0 Hazard Ratio (L:T) Favors AI Favors T

23 Postmenopausale Patientinnen (nach 2-3 Jahren Tamoxifen)
Rezidiv Rate / Jahr (%) 16 Node +ve 12 8 4 Node -ve 2 4 6 8 10 Three switching trials have evaluated the benefit of switching patients at 2 to 3 years of tamoxifen treatment to an AI compared with maintaining tamoxifen therapy for the full five years. Two trials, the Italian Tamoxifen Anastrozole (ITA) study and the Austrian Breast & Colorectal Cancer Study group (ABCSG) 8/Arimidex-Nolvadex (ARNO) 95 study switch patients to anastrozole. The International Exemestane Study (IES) switches patients to exemestane. Taking into account the superiority anastrozole has already demonstrated over tamoxifen as initial adjuvant therapy, the concern with adopting a switching strategy is that the switch occurs in the time period after the peak recurrence rate. Reference Early Breast Cancer Trialists’ Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998;352: Time (years) Randomisation Anastrozole Exemestane Italian Tamoxifen Anastrozole (ITA); Austrian Breast & Colorectal Cancer Study Group (ABCSG) 8 / Arimidex-Nolvadex (ARNO) 95 Intergroup Exemestane Study (IES) Tamoxifen Switching Tamoxifen Adapted from EBCTCG. Lancet 1998;352:

24 IES trial design Diagnosis of breast cancer and
treatment for primary disease Time since start of tamoxifen (years) 2-3 years’ tamoxifen Time since randomisation (years) 2 RANDOMISED (n=4742) 3 2-3 years’ tamoxifen (n=2380) 2-3 years’ exemestane (n=2362) The International Exemestane Study (IES) is the largest study to date to investigate switching from tamoxifen to an AI compared with completing adjuvant therapy with tamoxifen. Here, patients were randomised to switch to exemestane after 2-3 years’ tamoxifen. Patients followed-up 2-3 5 Coombes RC et al. N Engl J Med 2004;350:

25 IES: disease-free survival
Patients disease- free (%) 100 Exemestane (E) Tamoxifen (T) 75 50 25 n HR (95% CI) p-value 4742 0.68 (0.56, 0.82) <0.001 1 2 3 4 In 2004, the IES (n=4742) reported details of a second planned interim analysis. Switching adjuvant therapy from tamoxifen to exemestane after 2-3 years significantly improved disease-free survival compared with the standard 5 years’ tamoxifen (HR 0.68; p= ). Time since randomisation (years) No. events / at risk: E 0/2362 52/2168 60/1696 44/757 20+6*/201 T 0/2380 78/2173 90/1682 76/730 18+4*/185 *Events occurring >4 years after randomisation Coombes RC et al. N Engl J Med 2004;350:

26 IES: safety and adverse events
Compared with tamoxifen, exemestane was associated with a higher incidence of: arthralgia (3.6% vs 5.4%; p=0.01) visual disturbances (5.7% vs 7.4%; p=0.04) osteoporosis (5.7% vs 7.4%; p=0.05) diarrhoea (2.3% vs 4.3%; p<0.001) Exemestane was associated with less thromboembolic disease, gynaecological symptoms, vaginal bleeding and cramps Due to early release of the efficacy data the published adverse event data are provisional. However, data suggest that exemestane increases the risk of osteoporosis, arthralgia, visual disturbances and diarrhoea compared with tamoxifen but is associated with a lower incidence of thromboembolic disease, gynaecologial symptoms, vaginal bleeding and cramps. Coombes RC et al. N Engl J Med 2004;350:

27 Switching: ...auf dem Boden der Evidence
Anastrozol und Exemestan sind nach 2-3 Jahren Tamoxifen Vorbehandlung effektiv Für beide Aromatasehemmer besteht eine Zulassung in Deutschland Beide Aromatasehemmer haben ein unterschiedliches Nebenwirkungsprofil Both trials demonstrated that switching to an AI after 2-3 years of tamoxifen therapy is superior to continuing with tamoxifen, for a completed 5-year course of hormonal therapy. The ITA trial, although underpowered, produced supplementary evidence to support switching to anastrozole, particularly in patients with positive nodal status. The AIs are different, particularly with respect to safety, and results cannot be used interchangeably. In the ABCSG 8/ARNO 95 trial, anastrozole was associated with an expected decrease in bone density and subsequent risk of fractures. In the IES, exemestane was not only associated with osteoporosis but also increased incidences of arthralgia, diarrhoea and visual disturbances. Anastrozole has a more complete safety profile as published adverse event data from the IES are provisional due to early release of efficacy data. Patients in the ABCSG 8/ARNO 95 trial had a better prognosis at the outset, with a higher proportion of patients with node -ve disease (74%) compared with the IES (50%). No conclusions can be drawn about the suitability of switching to letrozole, as no data are currently available in this setting. Switching von Tamoxifen zu einem AI nach 2-3 Jahren ist der der Fortsetzung von Tamoxifen eindeutig überlegen C. Jackisch

28 5 Jahre Tamoxifen Was nun……

29 Was kommt nach 5 Jahren Tamoxifen
Rezidivrate / Jahr (%) 16 Node +ve 12 8 Node -ve 4 2 4 6 8 10 Zeit (Jahre) Extending tamoxifen therapy beyond 5 years confers no additional survival benefit and may impose additional risks in terms of strategy. The final AI scenario being investigated, therefore, is whether using an AI as extended adjuvant therapy after a full 5 year course of therapy can improve treatment outcomes. Administration of an AI occurs at a period where the risk of recurrence is relatively low, particularly in node-negative patients. Reference Early Breast Cancer Trialists’ Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998;352: Randomisation Extended adjuvant Tamoxifen MA 17 Placebo Letrozole Adapted from EBCTCG. Lancet 1998;352: C. Jackisch

30 Time from randomization (months) Time from randomization (months)
Overall Survival: Mortalitätsreduktion um 39% bei nodal-positiven Patientinnen Nodal-Positiv Nodal-Negativ 100 100 80 80 60 60 Percent P=0.04 P=0.24 Percent 40 40 20 20 Femara Placebo Femara Placebo 10 20 30 40 50 60 10 20 30 40 50 60 Time from randomization (months) Time from randomization (months) No. at Risk Während das OS bei nodal-negativen Patientinnen nicht reduzuiert wurde, wurde eine ähnliche Reduktion für local recurrences, new primaries, und distant recurrences bei den nodal-positiven Patientinnen beobachtet Femara 1171 1144 875 508 255 81 3 1292 1265 972 572 275 93 3 Placebo 1189 1157 877 500 243 75 3 1276 1250 964 571 283 93 5 Adapted from Goss. ASCO, 2004. C. Jackisch

31 Tamoxifen ± Aminoglutethimid gefolgt Anastrozol vs. Kontrolle ABCSG 6a
RANDOM ANA 3 a (N=387) 5a TAM + Aminoglutethimid (N= 856) Kontrolle 3 a (N=469) Primärer Endpunkt: RFS Sekundäre Endpunkte: OS, ZweitCa

32 Tamoxifen ± Aminoglutethimid gefolgt Anastrozol vs
Tamoxifen ± Aminoglutethimid gefolgt Anastrozol vs. Kontrolle ABCSG 6a – RFS* HR 0.64; 95% CI ; p=0.047 Medianes FUp 5 a - 36% * Inzidenz lokaler, kontralateraler und distanter Erkrankung Jakesz, ASCO 2005

33 ST. GALLEN 2005: ENDOCRINE RESPONSIVENESS
From a biological continuum to "practical" subgroups Endocrine- responsiveness Absent Uncertain Sure ER and PR absent ER and PR low and/or any of the following: Both receptors moderate /high PgR absent UPA/PAI-1 high HER-2 overexpressed Increased proliferation markers No

34 SELECTION OF ADJUVANT ENDOCRINE THERAPY
IN 2005: MY OWN BIAS Endocrine- responsiveness Absent Uncertain Sure TAM alone Switch TAMAI AI Upfront R I S K AI upfront ADD CHEMOTHERAPY C. Jackisch

35 Einsatz von Aromatasehemmern Take home message
Tamoxifen 5 Jahre Keine Standardtherapie mehr Optional bei low risk Patientinnen, aber die Definition ist noch unklar (T< 1 cm etc.) Aromatasehmmer 5 Jahre Bessere Option als „upfront treatment“ gegen Tamoxifen Subgruppen für Tamoxifen ungeeignet : Her2 neu Überexpression ER+ / PR- ( Datenlage inkonsistent?) G III In postmenopausal women with breast cancer the NCCN recommends: Five years of anastrozole as initial therapy Switching to anastrozole or exemestane following initial 2-3 years of tamoxifen, for a completed course of 5 years of hormonal therapy Giving 5 years of letrozole after years of tamoxifen Five years of tamoxifen only in women where AI treatment is inappropriate. Tamoxifen 2-3 Jahre Aromatasehmmer3 Jahre Überlebensvorteil gegen 5 Jahre Tamoxifen Perfekte Option für Tamoxifen-Patientinnen Eindeutige Subgruppen noch unklar C. Jackisch

36 Warum all diese Daten……

37 Definition of DFS in various adjuvant trials
BIG 1-98 MA ATAC IES ARNO* Locoregional recurrence DCIS LCIS + ? Distant metastasis Contralateral breast cancer Contralateral DCIS Contralateral LCIS + ? Second primary cancer + Death from any cause * Event-free survival DCIS = ductal carcinoma in situ; LCIS = lobular cancer in situ. C. Jackisch

38 Das geht doch nur auf die Knochen !!

39 Frakturraten - Indirekter Vergleich Arimidex vs. Tam / HRT vs. Placebo
Nur Beobachtung Frakturen /100 /Jahr Prävention HRT % Gelb Placebo oder keine Therapie, Rot der Einfluß von Tamoxifen oder HRT, blau der Östrogenentzug von Arimidex Was man deutlich sieht ist, dass die Frakturraten in diesen Studien unter Placebo bei 1,8-1,9 % pro jahr liegen, Tamoxifen oder HRT einen erkennbaren Schutz auf den Knaochen ausüben und Arimidex um 0,3-0,5% pro Jahr höher liegt. Das ist nicht sehr viel, kein großer Unterschied. . Wichtig wäre es demnach , da die Frakturen nach den letzten ATAC auswertungen in den ersten 2 Jahren auftreten, die Frauen mit hohem Risiko oder schon bekannter Osteoporose zu detektieren und vorbeugend zu behandeln. . Entsprechende Fragebogen können dabei helfen. n=6.185 n=14.075 n=16.607 n=6.963 Ca. 0,3% - 0,4% Jahr erhöhte Frakturrate /Jahr im Vergleich zu Placebo Lüftner et al., DKK2004

40 Die neuen Aromatasehemmer Nebenwirkungen & Empfehlungen
Vasomotorische, klimakterische Beschwerden Muskel- und Gelenkbeschwerden Osteopenie, Osteoporose Kardiovaskuläre Erkrankungen Empfehlungen - Knochengesundheit BMD vor Therapiebeginn (danach jährlich) Ca++ Substitution (1200 mg/d) + Vit. D IE/d Bei Osteopenie/Osteoporose (T-Score ≤ -2,5):  Bisphosphonattherapie* Hiller BE et al. ASCO Bisphosphates J Clin Oncol 2003,21: C. Jackisch

41 Tamoxifen / Aromatase inhibitors (AI)
Oxford AGO LOE / GR Tamoxifen 20 mg/d for 5 yrs 1a A ++ Aromatase inhibitors 1b A + in patients with contraindications or intolerance to tamoxifen 5 D ++ Tamoxifen in combination with AIs 1b B - - Tamoxifen 20mg/d given for 5y improves survival in hormone receptor-positive primary breast cancer (EBCTCG 2005). Optimal adjuvant endocrine therapy, however, should include an aromatase inhibitor either as intial therapy or after treatment with tamoxifen, which seems to be more effective than tamoxifen alone (Winer 2005). The advantage is most relevant for improved DFS. So far, improved OS has only been shown in one single study (Goss 2004) and a small meta-analysis (Jonat 2005). In addition, follow-up of the adjuvant AI studies is still too short for definite conclusions regarding survival benefit and potential long-term side effects. In receptor-positive patients with tamoxifen contraindications or intolerance (e.g. venous thrombosis, endometrium carcinoma, etc.), adjuvant aromatase inhibitor therapy is recommended. Combination therapy of tamoxifen with aromatase inhibitors is not more effective than tamoxifen therapy alone (Baum 2002) and should therefore not be administered. References: Baum M, Budzar AU, Cuzick J, et al.. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet Jun 22;359: Erratum in: Lancet 2002;360:1520. Early Breast Cancer Trialists' Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of randomised trials. Lancet 2005;365: Goss PE, Ingle JN, Martino S, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 2005;97: Jonat W, Gnant M, Boccardo F, et al. Postmenopausal women with hormone-responsive early breast cancer: a meta-analysis of the ARNO 95 Trial, ABCSG Trial 8, and the ITA Trial. Breast Cancer Res Treat 2005;94(Suppl 1):S11, Abs 18. Winer EP, Hudis C, Burstein HJ, et al. American Society of Clinical Oncology technology assessment an the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report J Clin Oncol 2005;23: Jackisch 2006

42 Therapy duration and sequencing
Tam / AI: Therapy duration and sequencing Oxford AGO LOE / GR Tam 5 (instead of 2 or 1) yrs 1a A ++ Tam > 5 yrs 1b B - - Re-initiation Tam* (if therapy < 5 yrs) 2b B + Anastrozole or Letrozole 5 yrs 1b B + Exemestane or Anastrozole after 2-3 yrs Tam* 1b B + *up to a total of 5 yrs of endocrine therapy Tamoxifen given as 20 mg / d for 5 years is considered standard. A shorter therapy duration is less effective (EBCTCG 1998); longer duration of tamoxifen therapy does not seem to be beneficial (Fisher 2001). If tamoxifen therapy was stopped early, re-newed therapy up to a total of 5 years may be beneficial (Gradishar 2002). At present, optimal sequencing of tamoxifen and aromatase inhibitors cannot be definitely decided. According to the recently published data, three scenarios for use of aromatase inhibitors are therefore possible: Up-front use, switch after 2-3 years, and extended adjuvant therapy after 5 years of tamoxifen therapy. Due to the short follow-up in the adjuvant aromatase inhibitor trials, patients need to be counselled carefully about the lack of an overal survival benefit and potential long-term side effects. In view of follow-up data published so far, total duration of adjuvant endocrine therapy in case of up-front or switch therapy, should not extend beyond a total of 5 years. As up-front therapy, anastrozole and letrozole are more effective than tamoxifen regarding DFS. An OS advantage has not been shown so far (ATAC Trialists´Group 2005, BIG 1-98 Collaborative Group 2005). In a retrospective, hypothesis-generating study greatest DFS improvement with anastrozole was shown for patients with ER+PgR- tumors (Dowsett 2005). The Benefit of letrozole versus tamoxifen was irrespective of PgR status in ER+ tumors (Viale 2005). As a switch after 2-3 years of tamoxifen therapy, three studies (IES, ITA, ABSCG 8) and a pooled analysis of 2 studies (ARNO 95+ABCSG 8) show a benefit for aromatase inhibitors regarding DFS (Coombes 2004, Boccardo 2005, Jakesz 2005), a meta-analysis of thre studies (ITA+ABSCG 8+ARNO 95) although a better OS(Jonat 2005). The ITA, ARNO 95 and ABSCG 8 trials tested anastrozole, whereas exemestane was used in the IES trial. In the ARNO 95 and ABCSG 8 trials patients did only receive adjuvant endocrine therapy and no adjuvant chemotherapy. As extended adjuvant therapy after 5 years of tamoxifen therapy letrozole (vs. placebo) and anastrozole (vs. nil) are superior to no additional endocrine therapy with regard to DFS (Goss 2005, Jakesz 2005). In node-positive patients, additional letrozole therapy is associated with a significant OS advantage (Goss 2005). Letrozole could be started up to 30 months after cessation of tamoxifen (Goss 2005). References (in addition to references of slide 5): Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351: Fisher B, Dignam J, Bryant J, Wolmark N. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst 2001;93: Goss PE, Ingle JN, Palmer MJ, et al. Updated analysis of NCIC CTG MA.17 (letrozole vs. placebo to letrozole vs. placebo) post unblinding. Breast Cancer Res Treat 2005;94(Suppl 1):S11, Abs 16. Gradishar WJ, Hellmund R. A rationale for the reinitiation of adjuvant tamoxifen therapy in women receiving fewer than 5 years of therapy. Clin Breast Cancer 2002;2:282-6. Viale G, Regan M, Dell'Orto P, et al. Central review of ER, PgR and HER-2 in BIG 1-98 evaluating letrozole vs. tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. Breast Cancer Res Treat 2005;94(Suppl 1): Abstr. 44. Jackisch 2006

43 Aromataseinhibitors after 5 years of Tamoxifen
Oxford AGO LOE / GR Letrozole 5 yrs 1b B + node-positive disease 1b B ++ long tamoxifen-free interval (up to 30 months) 4 D + Anastrozole 3 yrs 2b B + Tamoxifen given as 20 mg / d for 5 years is considered standard. A shorter therapy duration is less effective (EBCTCG 1998); longer duration of tamoxifen therapy does not seem to be beneficial (Fisher 2001). If tamoxifen therapy was stopped early, re-newed therapy up to a total of 5 years may be beneficial (Gradishar 2002). At present, optimal sequencing of tamoxifen and aromatase inhibitors cannot be definitely decided. According to the recently published data, three scenarios for use of aromatase inhibitors are therefore possible: Up-front use, switch after 2-3 years, and extended adjuvant therapy after 5 years of tamoxifen therapy. Due to the short follow-up in the adjuvant aromatase inhibitor trials, patients need to be counselled carefully about the lack of an overal survival benefit and potential long-term side effects. In view of follow-up data published so far, total duration of adjuvant endocrine therapy in case of up-front or switch therapy, should not extend beyond a total of 5 years. As up-front therapy, anastrozole and letrozole are more effective than tamoxifen regarding DFS. An OS advantage has not been shown so far (ATAC Trialists´Group 2005, BIG 1-98 Collaborative Group 2005). In a retrospective, hypothesis-generating study greatest DFS improvement with anastrozole was shown for patients with ER+PgR- tumors (Dowsett 2005). The Benefit of letrozole versus tamoxifen was irrespective of PgR status in ER+ tumors (Viale 2005). As a switch after 2-3 years of tamoxifen therapy, three studies (IES, ITA, ABSCG 8) and a pooled analysis of 2 studies (ARNO 95+ABCSG 8) show a benefit for aromatase inhibitors regarding DFS (Coombes 2004, Boccardo 2005, Jakesz 2005), a meta-analysis of thre studies (ITA+ABSCG 8+ARNO 95) although a better OS(Jonat 2005). The ITA, ARNO 95 and ABSCG 8 trials tested anastrozole, whereas exemestane was used in the IES trial. In the ARNO 95 and ABCSG 8 trials patients did only receive adjuvant endocrine therapy and no adjuvant chemotherapy. As extended adjuvant therapy after 5 years of tamoxifen therapy letrozole (vs. placebo) and anastrozole (vs. nil) are superior to no additional endocrine therapy with regard to DFS (Goss 2005, Jakesz 2005). In node-positive patients, additional letrozole therapy is associated with a significant OS advantage (Goss 2005). Letrozole could be started up to 30 months after cessation of tamoxifen (Goss 2005). References (in addition to references of slide 5): Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351: Fisher B, Dignam J, Bryant J, Wolmark N. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst 2001;93: Goss PE, Ingle JN, Palmer MJ, et al. Updated analysis of NCIC CTG MA.17 (letrozole vs. placebo to letrozole vs. placebo) post unblinding. Breast Cancer Res Treat 2005;94(Suppl 1):S11, Abs 16. Gradishar WJ, Hellmund R. A rationale for the reinitiation of adjuvant tamoxifen therapy in women receiving fewer than 5 years of therapy. Clin Breast Cancer 2002;2:282-6. Viale G, Regan M, Dell'Orto P, et al. Central review of ER, PgR and HER-2 in BIG 1-98 evaluating letrozole vs. tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. Breast Cancer Res Treat 2005;94(Suppl 1): Abstr. 44. Jackisch 2006