Verdringen de Aromatase-I de SERM’s? Prof. dr. Rudy Van den Broecke Coördinator Multidisciplinair Borstcentrum UZ Gent VVOG Postuniversitaire Studiedag 15 november 2007

Anastrozole Letrozole Exemestane Tamoxifen NMe2 O CH3 H3C NC CN N NC

Introduction Evidence-based Medicine Aromatase-I in adjuvant setting Special issues

Evidence-based Medicine "Evidence-based medicine is the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients.“ Full paper in peer review journal Long-term follow-up Patients numbers Double blind controlled trial(s) ….. ? Subgroup analyses !!! ? Indirect comparison !!!

All postmenopausal women with receptor positive disease should receive an AI during the course of their treatment WHEN?

Trial strategies in adjuvant setting with AI’s 1. Treatment strategies: Upfront Prospective sequential 2. Treatment opportunities: Switch Extended

Trial strategies in adjuvant setting with AI’s 0y 2y 5y ATAC BIG 1-98 Upfront ABCSG 8 BIG 1-98 Sequential Third-generation AIs are currently being tested in the adjuvant setting. The main adjuvant trials include Two trials with the nonsteroidal AI anastrozole. Two trials with the nonsteroidal AI letrozole. Four trials with the steroidal AI exemestane. The shortest trial is EXEM 027, which will take 2 years to complete. It is also the only trial that will compare AI treatment with placebo in treatment naïve patients. The trial of the longest adjuvant therapy is MA-17, which addresses 10 years of treatment. This trial will compare letrozole to placebo in the second phase of the trial, after 5 years of tamoxifen. All the other trials will examine 5 to 7 years of adjuvant treatment. The ATAC trial has already reported intermediate data at 33 months and at 47 months of follow-up.1,2 In this trial, patients in combination arm did not fare any better than those in the tamoxifen alone arm. As a result, the combination arm was discontinued. 1. The ATAC Trialists’ Group. Lancet. 2002;359:2131. 2. Buzdar. Breast Cancer Res Treat. 2003;77:295 [Abstract 28]. Randomisation TAMOXIFEN ANASTROZOLE LETROZOLE EXEMESTANE Placebo/Control

Treatment opportunities in adjuvant setting with AI’s 0y 2y 5y IES ITA ARNO 95 Switch Third-generation AIs are currently being tested in the adjuvant setting. The main adjuvant trials include Two trials with the nonsteroidal AI anastrozole. Two trials with the nonsteroidal AI letrozole. Four trials with the steroidal AI exemestane. The shortest trial is EXEM 027, which will take 2 years to complete. It is also the only trial that will compare AI treatment with placebo in treatment naïve patients. The trial of the longest adjuvant therapy is MA-17, which addresses 10 years of treatment. This trial will compare letrozole to placebo in the second phase of the trial, after 5 years of tamoxifen. All the other trials will examine 5 to 7 years of adjuvant treatment. The ATAC trial has already reported intermediate data at 33 months and at 47 months of follow-up.1,2 In this trial, patients in combination arm did not fare any better than those in the tamoxifen alone arm. As a result, the combination arm was discontinued. 1. The ATAC Trialists’ Group. Lancet. 2002;359:2131. 2. Buzdar. Breast Cancer Res Treat. 2003;77:295 [Abstract 28]. MA-17 ABCSG 6a Ext Randomisation TAMOXIFEN ANASTROZOLE LETROZOLE EXEMESTANE Placebo/Control

Aromatase Inhibitors: Upfront FU DFS (HR+ patients) TTR TTDR (ITT population) OS ATAC Anastrozole vs Tamoxifen 68 mths HR=0.83 SS HR=0.74 HR=0.80 CI: 0.70-0.99 P=0.04 SS HR=0.97 NS BIG 1-98 Letrozole vs Tamoxifen 51 mths HR=0.82 HR=0.78 HR=0.81 CI: 0.67-0.98 P=0.03 SS HR=0.91 ATAC: Lancet 2005; 365: 60-62 BIG 1-98: Coates AS et al. J Clin Oncol 2007; 25(5)

Aromatase Inhibitors after 2-3 y Tamoxifen: Switch FU DFS OS ARNO Anastrozole vs Tamoxifen 30.1 mths HR=0.66 SS HR=0.53 ARNO/ABCSG8/ ITA 30 mths HR=0.59 HR=0.71 Meta-analyse? IES Exemestane vs 55.7 mths HR=0.76 HR=0.85 for ITT pts NS HR=0.83 for ER+/unknown pts ARNO: Kaufmann M et al. J Clin Oncol 2007; 25(19) - ARNO/ABCSG 8:Jakesz R et al. Lancet Oncology 2005; 366: 455-62 - ARNO/ABCSG 8/ITA: Jonat W et al. Lancet Oncology 2006; 7: 991-996 - IES: Coombes RC et al. Lancet Feb 2007

Aromatase Inhibitors: Prospective Sequential FU DFS ABCSG 8 2y Tamoxifen + 3y Anastrozole vs 5y Tamoxifen 54.6 mths HR=0.76 NS BIG 1-98 2y Tamoxifen + 3y Letrozole vs 5y Tamoxifen or 5y Letrozole vs 2y Letrozole + 3 y tamoxifen Currently no available data TEAM 2y Tamoxifen + 3y Exemestane vs 5y Exemestane ABCSG 8: Jakesz R SABCS 2005 presentation BIG 1-98: Coates AS ESMO 2006 presentation TEAM: van de Velde CJ et al. SABCS 2005 Abstr 3057

AI’s after 5y Tam: Extended FU DFS OS MA 17* Letrozole vs placebo 30 mths HR=0.58 SS HR=0.82 NS HR=0.61 for Node + ABCSG 6a Anastrozole vs no treatment 60.4 mths HR=0.64 ND NSABP 33** Exemestane vs placebo HR=0.68 MA 17: Goss PE SABCS 2005 presentation ABCSG 6a: Jakesz R ASCO 2005 Poster 526 NSABP 33: Mamounas E SABCS 2006 Abstr 48 *Early unblinded trial **Trial closed prematurely

Conclusions (1) For each adjuvant strategy of treatment, Aromatase inhibitors are more efficient than former standard treatments In upfront 5 y, Anastrozole or Letrozole are more efficient than 5 y Tamoxifen After 2-3 y of Tamoxifen, Anastrozole or Exemestane are more efficient than continuing on Tamoxifen After 5 y of Tamoxifen, Anastrozole or Letrozole are more efficient than placebo/no treatment In all these trials, the use of Aromatase Inhibitors is beneficial for the whole populations

Conclusions (2) The best treatment available should be offered at the earliest opportunity in order to reduce the risk of recurrence and minimise life-threatening side effects Patients currently receiving adjuvant Tamoxifen should consider switching to an Aromatase Inhibitor at the earliest opportunity

All postmenopausal women with receptor positive disease should receive an AI during the course of their treatment who ?

Early peak of recurrences in presence or absence of adjuvant therapy 5 10 15 20 25 0.5 1.5 2.5 3.5 4.5 5.5 6.5 7.5 8.5 9.5 10.5 Time (years) Hazard of recurrence by yearly interval Total Node 0 Node 1-3 Node (4+) Tumour size (<1 cm) Tumour size (1.1-3 cm) Tumour size (>3 cm) ER +ve ER -ve Premenopausal Postmenopausal ER, oestrogen receptor Saphner T et al. J Clin Oncol 1996 Baum M. ASCO 2005, poster 612

Follow-up time (years) ATAC smoothed hazard-rates for recurrence HR+ve population, 68 months’ median follow-up Annual hazard rates (%) 3.0 2.5 2.0 1.5 1.0 Tamoxifen 0.5 Anastrozole 0.0 1 2 3 4 5 6 Follow-up time (years) HR+ve, hormone receptor-positive Houghton J et al. ESMO 2006, poster 243

ATAC: time to recurrence by subgroup* (68 months’ follow-up) All patients Nodal status +ve Tumour size ≤2 cm >2 cm HR (A:T) and 95% CI Anastrozole (A) better Tamoxifen (T) better 0.40 1.50 1.75 0.60 0.80 1.00 1.25 Previous chemotherapy yes no -ve * ITT population Howell T. SABCS 2005 presentation Coates AS et al. J Clin Oncol 2007; 25(5)

BIG 1-98: disease-free survival by subgroup (51 months’ follow-up) HR (L:T) and 95% CI 0.40 1.50 1.75 0.60 0.80 1.00 1.25 All patients Nodal status Tumour size ≤2 cm >2 cm Previous chemotherapy yes no Letrozole (L) better +ve -ve Tamoxifen (T) better Coates AS et al. J Clin Oncol 2007; 25(5)

ATAC vs. BIG 1-98 by subgroup Nodal status +ve -ve Previous chemotherapy yes no Tumour size ≤2 cm >2 cm All patients 0.40 0.60 0.80 1.00 1.25 1.50 1.75 HR (L:T) and 95% CI Letrozole (L) better Tamoxifen (T) better Anastrozole (A) better ATAC Trialists’ Group. Lancet 2005; 365: 60-62 Coates AS et al. J Clin Oncol 2007; 25(5)

Predictors of early relapse in postmenopausal women: BIG 1-98 trial Mauriac L. et al: Ann of Oncology 14 Feb 2007

Forest plots: Interpretation of subgroups It is inappropriate to evaluate the effects of treatment on a single subgroup by examination of the 95% CI for that subgroup. This can lead to 2 types of error Attributing an effect to a subgroup when there is no overall effect and no evidence of heterogeneity Claiming a lack of effect in a subgroup when the overall effect is significant Cuzick J. Lancet 2005; 365:1308

Definition of risk categories LOW RISK: NODE NEGATIVE pT </= 2cm, AND Grade 1 AND Absence of extensive peritumoral vascular invasion (pvi) AND HER2/neu gene neither overexpressed nor amplified AND Age >/= 35 years INTERMEDIATE RISK: NODE NEGATIVE AND AT LEAST ONE pT > 2cm OR Grade 2 – 3 OR Presence of extensive pvi OR ER and PgR absent OR HER2/neu gene overexpressed or amplified OR Age <35 years Sankt Gallen 2007 Definition of risk categories NODE POSITIVE ( 1 – 3 involved nodes) AND ER and /or PgR expressed AND HER2/neu gene neither overexpressed nor amplified HIGH RISK: NODE POSITIVE (1- 3 involved nodes) AND ER and PgR absent OR HER2/neu gene overexpressed or amplified NODE POSITIVE ( 4 or more involved nodes)

Treatment allocation by therapeutic target and risk categories: Sankt Gallen 2007 Treatment options in each cell of the table are listed in the order of preference ° ° HER2 neg HER2 pos Endocrine responsiveness highly incompletely non highly incompletely non E Low * E C→E C C→E +Tr C+Tr N- Intermediate E C→E 1-3 N+ High 1-3 N+ >4 N+ C→E C +Tr C+Tr * *Look for risk definitions ° Pre en Postmenopausal Annals of Oncology: Vol 18 No.7 July 2007

Endocrine therapy in postmenopausal patients Sankt Gallen Guidelines 2007 5 years of tamoxifen alone is still a viable option for certain patient categories Patients now on Tamoxifen should be switched to an AI after 2-3 years Initial AI is more acceptable in patients at higher risk or with HER2-positive disease After 5 years of Tamoxifen a further period of time on an AI in node+ disease Optimal duration of therapy between 5-10 years Annals of Oncology: Vol 18 No.7 July 2007

© 2006 Adjuvant! Inc.

Special Issues Contra-indications for Tamoxifen Inoperable ER+ breast carcinoma Neo-adjuvant hormonal treatment Selective Serotonine Re-uptake Inhibitors: ISSR CYP2 D6 Prevention: IBIS II –trial?

Take home messages (1) Subgroup analyses, especially when retrospective, must be interpreted with caution, and should not be used as a basis for making clinical decisions The best treatment available should be offered at the earliest opportunity in order to reduce the risk of recurrence and minimise life-threatening side effects Patients currently receiving adjuvant Tamoxifen should consider switching to an Aromatase Inhibitor at the earliest opportunity

Take home messages (2) Inderect comparisons do not seem to demonstrate reasons for prefer one or other of the available agents There are more life-threatening side effects with Tam QOL between both classes is comparable Reimbursement criteria in Belgium for AI’s are based on the risk profile of the patient For each adjuvant strategy of treatment, Aromatase inhibitors are more efficient than former standard treatments

Are AI’s replacing SERM’s as the most effective adjuvant hormonal treatment in postmenopausal women with receptor-positive disease? YES!

In which patients? IN ALL!

When? All patients schould start with an AI upfront (at least we schould be offered the possibility to choose) Patients on tamoxifen schould be switched as soon as possible