Hormonothérapie adjuvante Dr Anne-Claire HARDY-BESSARD Clinique Armoricaine, Saint-Brieuc SFCP, Metz 19 Sept 2008

Patientes ménopausées

Essais d’anti-aromatases en adjuvant Tamoxifene ATAC Anastrozole Letrozole BOCCARDO Exemestane ARNO/ABCSG Placebo ICCG Study 96 NSABP B33 TEAM EXE Le bénéfice de ces anti-aromatases a été largement démontré dans les cancers du sein avancés. plus récemment 9 études randomisées ont testé l’efficacité de ces molécules en situation adjuvante. EXEM 027 5 ans 10 ans MA-17 BIG 1,98 (BIG FEMINA)

Essais randomisés et survie globale ATAC HR 0,97 (0,85-1,12), 68 mois HR 0,86 (0,7-1,06), 25,8 mois BIG 1.98 HR 0,91 (0,75-1,11), 51 mois

Percent Alive and Disease-Free BIG 1-98 DFS à 51 mois 97.6 97.4 Yearly DFS % 95.0 93.0 91.2 88.9 87.5 84.6 84.0 81.1 No. at Risk 2393 2388 2315 2266 1828 1788 1215 1164 2463 2459 829 800 N HR (95% CI) P 4922 0.82 (.71-.95) 0.007 Events 770 100 LET 80 TAM Percent Alive and Disease-Free 60 40 BIG 1-98 Monotherapy Comparison: DFS—Primary End Point, at 51 Months This graph shows the primary end point of DFS for the monotherapy arm comparison, with yearly estimates of DFS through the first 5 years. Overall, DFS was significantly higher for patients treated with letrozole (Femara®) compared with those who received tamoxifen. Estimated DFS 5 years after randomization was 84.0% in the letrozole group and 81.1% in the tamoxifen group, an absolute difference of 2.9%. Overall, there was a hazard ratio of 0.82, or an 18% reduction in the risk of recurrence, for patients treated with letrozole, which was significant (P=0.007). According to this graph, the differences in DFS in favor of letrozole emerged early after about 1 year following randomization. 20 1 2 3 4 5 Years from Randomization Coates. Oral presentation at ESMO 2006. At: http://www.ibcsg.org/public/documents/pdf/trial_18-98_big1-98/BIG1-98_ESMO_2006.pdf. Accessed October 5, 2006.

ATAC : Evènements Patients (%) Suivi (ans) 25 20 15 10 5 1 2 3 4 5 6 A 424 575 T 497 651 HR 0.83 0.87 95% CI (0.73–0.94) (0.78-0.97) p-value 0.005 0.01 HR+ 20 ITT 15 Anastrozole (A) Tamoxifen (T) Patients (%) 10 5 As expected, differences in disease-free survival are more pronounced in the hormone receptor-positive population than the intent-to-treat population. 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. Difference Absoluee : 1.6% 2.6% 2.5% 3.3% 1 2 3 4 5 6 Suivi (ans) A risque: A 2618 2540 2448 2355 2268 2014 830 T 2598 2516 2398 2304 2189 1932 774 DFS includes all deaths as a first event

Follow-up time (years) DFS HR+ HR+ patients HR 95% CI P-value HR+ 0.76 (0.67, 0.87) 0.0001 30 25 21.8% Tamoxifen (T) 20 12.5% Patients (%) 15 17% 10 Anastrozole (A) 9.7% 5 Absolute Difference 2.8% Absolute Difference 4.8% 1 2 3 4 5 6 7 8 9 Follow-up time (years) At Risk A 2618 2541 2453 2361 2278 2159 1995 1801 1492 608 T 2598 2516 2400 2306 2196 2075 1896 1711 1396 547 Forbes JF. et al, SABCS 2007, abstract 41

Plus de 2/3 des récidives sont métastatiques A partir des études ATAC et BIG 1-98: Récidives dans les bras TAM Controlatérales (9%-11%) Locoregionales (16%-28%) Métastatiques (61%-75%)

Risque de décès en fonction des évènements P<0.001 Risque relatif de décès (HR)* P<0.001 P=0.01 Méta Locoregional Controlateral Hazard ratio par rapport aux patients sans récidive Lamerato et al. J Clin Oncol. 2005;23(16S):62s. Abstract 738.

Essais randomisés et métastases ? HR 0,73 (0,6-0,88) HR 0,81 à 51 mois BIG 1.98 HR 0,86 (0,74-0,99) HR 0,84 (0,72-0,97) à 9 ans HR+ ATAC

Anti-aromatases pour toutes les patientes ménopausées?

ATAC :Evènements par sous-groupe All patients Tumour size Grade Age Hysterectomy HRT Definitive surgery Axillary surgery Radiotherapy ≤2 2–5 >5 well-differentiated moderate poor or undifferentiated <65 years ≥65 years yes no mastectomy conservation sampling clearance 0.30 0.40 0.60 0.80 1.00 1.25 1.50 2.00 In favour of Anastrozole In favour of Tamoxifen Hazard ratio (AN/TAM)

ATAC :Evènements par sous-groupe +ve Receptor status –ve Nodal status 4+ 1–3 Previous chemo TRT No yes 0.30 0.40 0.60 0.80 1.00 1.25 1.50 2.00 In favour of Anastrozole In favour of Tamoxifen Hazard ratio (AN/TAM)

BIG 1-98 Analyse par sous-groupe /DFS à 51 mois BIG 1-98 Monotherapy Comparison: Subgroup Analysis for DFS at 51 Months Forest plot of HRs for DFS according to various patient subgroups, relative to overall DFS results (top), for monotherapy arm comparison at 51-month median follow-up. In similar subset analysis in the primary core analysis at 26 median follow up, there seemed to be much greater benefit with letrozole (Femara®) in patients who received prior adjuvant chemotherapy (vs chemotherapy-naive patients) or were node-positive (N+) (vs node-negative [N-]). These subgroup results at a longer follow-up, demonstrate continuing benefit of initial adjuvant letrozole versus tamoxifen in patient populations at increased risk: node-positive; and those who received prior chemotherapy. There is also now an emerging benefit in lower-risk node-negative patients (a 12% reduction in risk of recurrence), which was not seen in the primary core analysis (a 4% reduction in risk of recurrence). Comparison of subgroup results from the two analyses confirms the firmness and consistency of the data, with benefits seen earlier in the higher-risk patient populations (median 26-month follow-up) and also in the later analysis, whereas benefits in lower-risk patients are only seen later (as expected, since events tend to occur later in those patients). The consistency of these BIG 1-98 subgroup analysis results is in contrast to results in the ATAC trial of initial adjuvant anastrozole versus tamoxifen. In that trial, a greater benefit with anastrozole in node-negative patients than in node-positive patients was seen early, at a median follow-up of 33 months (despite node-negative patients accounting for a relatively low number of events).* Coates. Oral presentation at ESMO 2006. At: http://www.ibcsg.org/public/documents/pdf/trial_18-98_big1-98/BIG1-98_ESMO_2006.pdf. Accessed October 5, 2006. * Baum et al. Lancet. 2002;359:2131.

Et le switch, pour quelles patientes?

Essais d’anti-aromatases en adjuvant Tamoxifene Anastrozole ATAC Letrozole BOCCARDO Exemestane ARNO/ABCSG Placebo SWITCH ICCG Study 96 NSABP B33 TEAM EXE Le bénéfice de ces anti-aromatases a été largement démontré dans les cancers du sein avancés. plus récemment 9 études randomisées ont testé l’efficacité de ces molécules en situation adjuvante. EXEM 027 5 ans 10 ans MA-17 BIG 1,98 (BIG FEMINA)

ABCSG 8 – ARNO 95: Randomisation 3224 patientes Total n=3,224 ABCSG 8 + ARNO 95 n=962 TAM 3 years n=1,606 Chirurgie première +/- RTx The results were generated from a combined analysis of 3,224 patients who received - either 3 years of TAM - or 3 years of ANA after primary surgery and exposure to 2 years of TAM. + TAM 2 ans ANA 3 years n=1,618 Randomisation

Etude IES Randomisation Diagnostic du cancer du sein et traitement pour maladie primaire Tamoxifène durant 2 à 3 ans Randomisation Randomisation Dans cette étude les patientes ont été traitées par tamoxifène ou exemestane après 2 à 3 ans de tamoxifène. Tamoxifène 2 à 3 ans Exemestane 2 à 3 ans Suivi des patientes SABCS 2004 – D’après Coombes et al., Londres, Grande-Bretagne, abstr. 3 actualisé

ATAC :Taux de récidive Randomisation 2 3 Annual hazard rates (%) 3.0 2.5 2.0 Annual hazard rates (%) 1.5 1.0 Anastrozole 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. 0.5 Tamoxifen 1 2 3 4 5 6 Suivi (ans)

Essais randomisés et survie globale ATAC HR 0,97 (0,85-1,12), 68 mois HR 0,86 (0,7-1,06), 25,8 mois BIG 1.98 IES HR 0,85 (0,71-1,02) 56 mois ABCSG-8 ARNO 95 HR 0,71 (0,52-0,98) ITA

Essais randomisés et métastases HR 0,81 à 51 mois BIG 1.98 TAM AI ATAC HR 0,86 (0,74-0,99) HR 0,86 (0,87-1,00) ITT IES HR 0,83 (0,70-0,98) HR 0,82 (0,69-0,98) RE+ ABCSG-8 ARNO 95 ITA HR 0,61 (0,45-0,85)

Et le switch, pour quelles patientes? Pour celles qui ont déjà eu 2 ans de tamoxifène car péri-ménopause

Et le séquentiel alors?

Essais d’anti-aromatases en adjuvant Tamoxifene Anastrozole ATAC Letrozole BOCCARDO Exemestane ARNO/ABCSG Placebo ICCG Study 96 NSABP B33 TEAM EXE Le bénéfice de ces anti-aromatases a été largement démontré dans les cancers du sein avancés. plus récemment 9 études randomisées ont testé l’efficacité de ces molécules en situation adjuvante. EXEM 027 SEQUENTIEL BIG 1,98 (BIG FEMINA)

Résultats du séquentiel à SAN ANTONIO 2008

Questions qui restent posées ? Tamoxifène ? Bilan lipidique ? Bilan osseux ?

Upfront Adjuvant Treatment by AI 761,1,2,1,0,1,1,1,1,1,1,1,1,0 Item 1 Item 2 Item 3 Item 4 Item 5 Item 6 Item 7 Item 8 Item 9 Upfront Adjuvant Treatment by AI No treatment by bisphosphonates Already treated by bisphosphonates for postmenopausal ostéoporosis Look for risk factors Risk factors No risk factors Continue treatment with bisphosphonates • No BMD BMD BMD within 1 year T-score T > -1 -1 > T > -2,5 T < -2,5 Treatment with bisphosphonates • No BMD Repeat BMD at 5 years Repeat BMD within 1 to 2 years

Questions qui restent posées ? Quand switcher les patientes en péri-ménopause ? Faut-il prolonger les AA au-delà de 5 ans ?

Patientes non ménopausées

ABCSG-12 – Schéma de l’étude Accrual 1999-2006 1.801 premenopausal endocrine-responsive breast cancer patients Stage I & II, < 10 pos nodes, ER+ and/or PR+ Treatment duration: 3 years No chemotherapy except neoadjuvant Bone substudy (n=404) Tamoxifen 20 mg/d Tamoxifen 20 mg/d + Zoledronic Acid 4 mg q6m Surgery (+RT) Goserelin 3.6mg q28d 1:1:1:1 Anastrozol 1 mg/d Anastrozol 1 mg/d + Zoledronic Acid 4 mg q6m Gnant M. et al, ASCO 2008

ABCSG-12 : Zoledronate empêche la diminution de la DMO No Zoledronic Acid Zoledronic Acid Tamoxifen Anastrozole Tamoxifen Anastrozole 10 p=0.04 5 ns +1.0 +5.2 -0.1 ns +3.1 Baseline 36 60 Baseline 36 60 ns % change BMD (g/cm2) Baseline 36 60 Baseline 36 60 -4.5 -5 ns -7.8 -9.0 p=0.003 -10 p<0.0001 -13.6 -15 p<0.0001 Gnant M. et al, ASCO 2008

ABCSG-12 – Résultats 1801 patientes, FU 60 mois Objectif primaire : DFS 137 évènements ( 7,6 %) 42 décès ( 2,3 %) Pas de différence entre Tam et Ana HR 1,10 ( 0,79-1,54) p=0,59 Gnant M. et al, ASCO 2008

ABCSG-12 – Résultats Baisse du risque d’évènements de 36 % dans le bras Zolédronate ( osseux et non osseux) HR 0,64 ( 0,46-0,92) p=0,015 SG en faveur du bras Zolédronate mais NS HR 0,60 ( 0,32-1,11) p=0,1 Gnant M. et al, ASCO 2008