Endocrinoterapia adiuvante del carcinoma nel 2008 Ritmi circadiani e qualità di vita: actigrafia e uovi orizzonti nel carcinoma della mammella Mediterranean Scholl of Oncology Endocrinoterapia adiuvante del carcinoma nel 2008 Cecilia Nisticò Dipartimento di Oncologia Medica Oncologia Medica C Direttore: Prof. E. Terzoli IRE - Istituto Nazionale Tumori Regina Elena Roma Roma, 28 Novembre 2008

Breast Cancer Treatment Final Outcomes: Adjuvant setting Treatment Goal: to Cure Advanced Disease Treatment Goal: to Care

Adjuvant Therapy - Early Breast Cancer - Chemotherapy Endocrine therapy Biologic targeted therapy Bisphosphonates Organ specific therapy

Recent decrease in UK and USA breast cancer mortality at ages 35­69 years Adj CTX Adj HT Screening Modified from Peto et al. Lancet 355:1822, 2000

13% 18% 25% 30% 12% 15% !

Benefits from Adjuvant Systemic Therapy It is estimated that Optimal chemotherapy would reduce annual odds of recurrence by about 50%-60% Optimal endocrine therapy would reduce annual odds of recurrence by about 60%-70% Trastuzumab would reduce annual odds of recurrence by 45%-55% Zoledronic acid would reduce odds of recurrence by about 36% Reductions in odds of mortality are somewhat more modest because of competing causes of death

Benefits from Adjuvant Systemic Therapy Benefits of endocrine therapy are restricted to ER +/or PgR+ tumors Can we predict response to individual endocrine agents? Optimal endocrine therapy would reduce annual odds of recurrence by about 60%-70% Sequential administration of chemotherapy followed by endocrine therapy provides optimal benefit for the overall group Can we identify patients in this group who do not benefit from the addition of chemotherapy?

Davidson N, ASCO 2007

Breast Cancer Recurrence, % Breast Cancer Mortality, % Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) 15-Year Reductions in Recurrence and Disease-Specific Mortality Meta-analysis of 194 randomized trials Meta-analysis of 144,939 women Treatment Comparison Breast Cancer Recurrence, % Log Rank 2P Breast Cancer Mortality, % Tamoxifen 5 yrs vs none, ER-positive women 11.8 < .00001 9.2 EBCTCG. Lancet. 2005;365:1687-17.

EFFICACY OF ADJUVANT TAM Relative reduction in odds of 5 YEARS, ER +/UNKNOWN Relative reduction in odds of AGE RECURRENCE DEATH < 50 34%(+6%) 24%(+7%) 50-59 35%(+6%) 20%(+7%) 60-69 50%(+5%) 27%(+5%) > 70 38%(+18%) p=.00001 26%(+15%) p=.00001 EBCTCG, Lancet 2005;365:1687-17

Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) Polychemotherapy versus tamoxifen-treated ER+ disease, for entry age <50: 5-year probabilities of recurrence (ER+ includes 12% ER unknown) Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) Lancet 2005; 365: 1687–1717 EBCTCG Overview (2005)

Davidson N, ASCO 2007

Davidson N, ASCO 2007

Davidson N, ASCO 2007

Davidson N, ASCO 2007

5 yrs

Davidson N, ASCO 2007

Breast Cancer Recurrence, % Breast Cancer Mortality, % Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) 15-Year Reductions in Recurrence and Disease-Specific Mortality Meta-analysis of 194 randomized trials Meta-analysis of 144,939 women Treatment Comparison Breast Cancer Recurrence, % Log Rank 2P Breast Cancer Mortality, % Ovarian ablation or suppression vs none 4.3 .00001 3.2 .004 EBCTCG. Lancet. 2005;365:1687-17.

Breast Cancer Recurrence, % Breast Cancer Mortality, % EBCTCG. Lancet. 2005;365:1687-1717. Treatment Comparison Breast Cancer Recurrence, % Log Rank 2P Breast Cancer Mortality, % Ovarian ablation or suppression vs none 4.3 .00001 3.2 .004 EBCTCG Overview (2005)

Ovarian function suppression (OFS) was accepted as an alternative where tamoxifen was contraindicated. Retrospective subset analysis suggests that women younger than 40 years seemed to benefit from the addition of goserelin to CMF.

Retrospective subset analysis suggests that women younger than 40 years seemed to benefit from the addition of goserelin to CAF. J Clin Oncol 2005;23:5973-82

Davidson N, ASCO 2007

TAM standard all pts TAM for 5 yrs Chemo + TAM better than whatever alone OS beneficial in youger pts continuing to menstruate after chemo or TAM Optimal LHRH duration uncertain AIs in Meno after chemo: caution! No data of AIs + LHRH vs TAM (RCTs ongoing)

AIs & TAM: mechanism of action

Hormonal Adjuvant Treatment Strategies in Early Breast Cancer “Up-Front” R Tamoxifen Aromatase Inhibitors 5 years “Extended Switch” Placebo R Tamoxifen Aromatase Inhibitors 10 years “Early Switch” Tamoxifen R Tamox. Arom. Inhibitors 2-3 years 3-2 years

RCTs – AIs Adjuvant BC DFS/EFS OS Strategy RCTs Pts Update Median FU (mo.) AI Efficacy [HR, p] DFS/EFS OS Up-Front ATAC 6186 Lancet 2006 68 ANA 0.87 (0.01) 0.85 (0.7) BIG-1-98 4922 JCO 2007 51 LET 0.82 (0.007) 0.91 (>0.05) “Early” Switch ITA-1 380 JCO 2001 61 AGT NR (0.6) NR (0.005) ITA-2 448 Ann Oncol 2006 64 0.57 (0.005) 0.56 (0.1) IES 4742 Lancet 2007 56 EXE 0.76 (0.0001) 0.85 (0.08) ABCSG8/ARNO 3224 Lancet 2005 28 0.60 (0.0009) NR (0.16) “Late” Switch MA.17 5157 JNCI 2005 30 0.58 (0.001) 0.82 (0.3) ABCSG 6a 856 JNCI 2007 60 0.64 (0.047) NR NSABP B-33 1598 SABCS 2006 0.68 (0.07) 1.20 (0.63)

Adjuvant Aromatase Inhibitors Study therapy f.u. HR Abs d ATAC 03 upfront 4 0.82 3% ITA 04 switch 3 0.36 5.3% IES 04 2.7 0.68 4.7% MA17 04 extended 2.5 0.58 5 % ARNO -ABCSG 04 0.6 BIG 05 2.4 0.81 2.6%

Aromatase Inhibitors Adjuvant Trials. Distant metastases Study Reduction in distant metastases p ATAC Lancet 05 14% .01 BIG 1-98 NEJM 05 27% .0012 IES NEJM 04 34% .0004 ARNO/ABCSG Lancet 05 39% .0067 ITA JCO 05 51% .06 MA 17 JNCI 05 40% .002

ATAC: recurrences* before 2.5 years (HR+ patients) 25 HR+ A 282 T 370 HR 0.74 95% CI (0.64–0.87) p-value 0.0002 Patients (%) 20 15 ‘Arimidex’ (A) 10 Tamoxifen (T) 5 In agreement with the 1998 EBCTCG overview of adjuvant tamoxifen trials, the endpoint of Time to Recurrence excludes death prior to recurrence There was a significantly greater benefit with respect to recurrence for the anastrozole group than for the tamoxifen group. As with disease-free survival, the absolute difference between treatment arms with respect to recurrence increased out beyond completion of treatment to 6 years. 1 2 3 4 5 6 Follow-up time (years) At risk: A 2618 2540 2448 2355 2268 2014 830 T 2598 2516 2398 2304 2189 1932 774 Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351:1451-67. * Censoring non-BC deaths before recurrence

Pre-defined adverse events*: ATAC Median follow-up 68 months Hot flushes p<0.0001 Vaginal bleeding p<0.0001 Vaginal discharge p<0.0001 Anastrozole Endometrial cancer p=0.02 Tamoxifen Ischemic cerebrovascular events p=0.03 Venous thromboembolic events p=0.0004 Deep venous thromboembolic events p=0.02 Joint symptoms p<0.0001 Total fractures p<0.0001 10 20 30 40 50 Incidence (%) * Other Pre-defined AE’s with NO significant differences seen between groups: Ischemic Cardiovascular Disease, Cataracts, Nausea & Vomiting, Mood Disturbances, Fatigue ATAC Trialists’ Group. Lancet 2005;365:60-62

ATAC 100 mo.: SAEs: on and off treatment (Number – safety population) On treatment Off treatment Serious adverse event Anastrozole Tamoxifen Anastrozole Tamoxifen Treatment-related 153 284 49 57 Endometrial cancer 4 12 1 Myocardial infarction 34 33 26 28 Key point: The occurrence of any serious adverse events were similar in both arms but treatment-related serious adverse events were significantly* lower with anastrozole compared with tamoxifen during treatment. * Need to check if 153 vs. 284 is statistically significant After treatment completion, treatment-related serious adverse events were similar leading to a lower overall prevalence for treatment-related serious adverse events for anastrozole in this study. Endometrial cancer – The difference in endometrial cancer was statistically significantly lower with anastrozole compared with tamoxifen (5 vs 24 events, p=0.0004). MI – similar in both arms during treatment and after treatment completion. Cerebrovascular accidents – Lower number seen with anastrozole during treatment for those reported as serious compared with tamoxifen. Previously, for all AEs on treatment there is a significantly larger number of cerebrovascular accidents on tamoxifen and this is still the case in the final analysis of all AEs on treatment (see pre-specified table in back up) Back-up slide information: All adverse events occurring on treatment were recorded. After treatment (or up to 14 days after treatment termination) all fractures and serious adverse events continued to be recorded blindly up to the time of recurrence or death. Cerebrovascular accident 20 34 22 20 Fracture episodes* 375 234 146 143 *A fracture episode comprised one or more fractures on the same day based on adverse events and serious adverse event reports 43

Predefined adverse events at any time on treatment or any severity Anastrozole (N = 3092) Tamoxifen (N = 3094) Hot flushes Nausea and vomiting Fatigue / tiredness (asthenia) Mood disturbances Musculo-skeletal disorders Vaginal bleeding Vaginal discharge Ischaemic cardiovascular disease Ischaemic cerebrovascular event Venous thromboembolic events Deep venous thromboembolic events Cataracts Carpal tunnel syndrome† 1102 (35.6) 394 (12.7) 578 (18.7) 599 (19.4) 1104 (35.7) 167 (5.4) 110 (3.6) 130 (4.2) 64 (2.1) 87 (2.8) 48 (1.6) 189 (6.1) 79 (2.5) 1263 (40.8) 358 (12.4) 544 (17.6) 555 (17.9) 915 (29.6) 319 (10.3) 409 (13.2) 106 (3.4) 91 (2.9) 141 (4.6) 75 (2.4) 218 (7.0) 22 (0.7) Predefined side effects during treatment (or within 14 days of cessation) were very similar to those previously published,1 as 92% of patients had completed treatment by that time. No new safety concerns were identified with longer follow-up. Reference 1The ATAC Trialists' Group. Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: long-term safety analysis of the ATAC trial. Lancet Oncol 2006;7:633-43. †included as a non-predefined adverse event of interest

Deaths according to treatment group (ITT population) No. patients (%) Cause of death Total deaths Deaths after recurrence Deaths without recurrence Cardiovascular Cerebrovascular Second primary non-breast cancer Other Anastrozole (n = 3125) 629 (20) 350 (11) 279 (9) 67 (2) 25 (1) 84 (3) 103 (3) Tamoxifen (n = 3116) 624 (20) 382 (12) 242 (8) 66 (2) 29 (1) 60 (2) 87 (3) No differences were seen in overall survival between treatment groups. This may be partly because there was a non-statistically significant excess of deaths from other causes without a previous recurrence, which were a major component of overall survival (approximately 44% and 39% of the total deaths in the anastrozole and tamoxifen arms, respectively, were non-breast cancer deaths).

Fracture episode rates throughout the study Annual fracture episode rates (%) 4 Anastrozole (A) Tamoxifen (T) 3 2 1 Key point: The increase in fracture rates appears to only be associated with the active treatment period and does not continue after treatment completion. Q: Why is the carryover effect not seen with bones ? Q: Were any of these patients receiving bisphosphonates or other relevant medications ? Q: How do these fracture rates compare with an age-matched population ? Q: Wouldn’t you expect the tamoxifen patients to begin to do worse with respect to fractures as they come off treatment and the protective effect of tamoxifen is lost ? 1 2 3 4 5 6 7 8 9 Time since randomization (years) At risk: A T 2984 2976 2859 2824 2745 2699 2640 2572 2496 2419 2306 2208 2077 2000 1713 1645 702 659 46

ATAC 100: benefits continue and detrimental effects decline after treatment cessation Time to recurrence Fracture episode rates Patients (%) 30 Annual fracture episode rates (%) 4 Tamoxifen (T) Anastrozole (A) Tamoxifen (T) Anastrozole (A) 25 21.8% 3 20 15 12.5% 2 17.0% 10 The carryover effect seen for the efficacy endpoints is a reflection of the patients who have been “cured” plus those for whom the hormonal treatment prevents recurrences during therapy. The likely mechanism of the increased fracture risk during the active phase of AI treatment is an increase in bone turnover and an acceleration of bone loss due to suppression of oestrogen (Eastell 2005). There is evidence suggesting that the residual levels of oestrogen during menopause are important in maintaining bone health. Therefore when anastrozole treatment is completed and oestrogen levels rise, it is not surprising that the increased fracture risk disappears. References Eastell R, Hannon R. Long-term effects of aromatase inhibitors on bone. J Steroid Biochem Mol Biol. 2005;95:151-154. 1 9.7% 5 Absolute difference 2.8% 4.8% 1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7 8 9 Follow-up time (years) Time since randomisation (years)

BIG 1-98: cumulative incidence of breast cancer relapse Proportion failing (%) 20 5-year difference (L-T) = -3.4% (SE 1.2) Cuminc p=0.0002 15 13.6% Tamoxifen (T) Letrozole (L) 10 8.1% 10.2% 5 6.2% 1 2 3 4 5 Time since randomisation (years) SE = standard error Thürlimann B et al. The Breast 2005;14:S3, abs S4

BIG 1-98 DFS by Local Pathological Assessment 0.81 All patients (n=8010) 0.84 ER+ / PgR+ (n=5055) 0.83 ER+ / PgR- (n=1631) 0.72 ER+ / PgR unk (n=1154) 0.5 0.75 1.0 1.25 1.5 Favors L Favors T Hazard Ratio (L:T)

“Endometrial events” : Tamoxifen vs Aromatase Inhibitor Hysterectomy Endometrial biopsies ATAC 5% vs 1% BIG 1 7.2% vs 1.9%

Trial Design RANDOMIZE Exemestane 5162* Post Treatment Follow-up 10335* Tamoxifen Tamoxifen 5294* 2-3 years study treatment 2-3 years Start of study Diagnosis Total 5 years endocrine therapy * Total women years

Results-event- and recurrence-free survival Results-survival Results-secondary outcomes Cancer Treatment Reviews (2006) 32, 325– 332

TAM AIs

Aromatase Inhibitors: Tox Issues Bone Fractures Cardiovascular Disease

Bone Health: Issues Protective Effects of TAM Steroidal vs Non-Steroidal Predictive role of BMD on fracture Other fracture risk factors: Patient’ characteristics Bone turnover Steroid use (abuse?) What about bisphosphonates?

Fracture incidence

Incidence of fracture reported in different adjuvant aromatase inhibitor trials

CV Disease - Background References: 1Howell JSBMB 2005 The earliest publications of the RCTs using AIs provided conflicting results about the supposed higher risk of ischaemic cardiovascular toxicity The pathogenesis of cardiac damage induced by AIs is still definitively unclear, while some pathways seem to be involved1: The reduction of circulating estradiol The unbalanced lipid metabolism References: 1Howell JSBMB 2005

Lipid effects Increase of: Colestherol TG LpA LDL-C Decrease of: HDL-C

End-Points Primary Secondary Grade 3-4 as defined by NCIC Cardiovascular Adverse Events Rate (CVAE) Grade 3-4 as defined by NCIC Secondary Thromboembolic Adverse Events Rate (TEAE) Cerebrovascular Adverse Events Rate (CBVAE) In order to reduce heterogeneity across AIs, the analysis has been carried on considering: all AIs (Overall analysis) only 3rd generation AIs (CVAE-New) Cuppone F, Cancer 2008

Selected RCTs Cuppone F, Cancer 2008

Results – CVAE Rate (Cardiovascular Adverse Events) Cuppone F, Cancer 2008

Results – CVAE Rate (Cardiovascular Adverse Events) Cuppone F, Cancer 2008

Results - CVAE Rate-3rd Generation AIs (Cardiovascular Adverse Events) Cuppone F, Cancer 2008

Results - CVAE Rate-3rd Generation AIs (Cardiovascular Adverse Events) Cuppone F, Cancer 2008

Results – TEAE Rate (Thromboembolic Adverse Events) Cuppone F, Cancer 2008

Results – CBVAE Rate (Cerebrovascular Adverse Events) Cuppone F, Cancer 2008

…..free for lack of evidences ‘Trial’ Verdict Controversial ‘Motive’ (not clear background) Overestimated risk (0.5%) when AI vs TAM No difference AIs vs placebo Protective effect of TAM really ‘guilty’ …..free for lack of evidences

Cardio-protective effect of tamoxifen Metanalysis 32 trials comparing tamoxifen against a control group (metastatic, adjuvant, and prevention settings) 12 reported on myocardial infarction death > 52,000 patients; 66% postmenopausal; mean age 54.8 yrs; mean treatment duration: 4.3 yrs; mean FU: 5.6 yrs Relative risk ratio for fatal MIs (tamoxifen / control): 0.62 (95% CI: 0.41-0.93) Risk ratio without the Scottish trial: 0.81 (95% CI: 0.48-1.37) Braithwaite et al JGIM 2003;18:937-47

Myocardial Infarction

Cognitive Function, Fatigue and Menopausal Symptoms HSCS* (impairment) FACT-F FACT-ES FACT-G Adjuvant CT 16% 31 58 77 Control 4% 46 64 93 0.008 0.0001 * High Sensitivity Cognitive Screen N Tchen, JCO 2005

LONG TERM TREATMENT WITH A.I. POTENTIAL BENEFIT RISK SUPERIOR EFFICACY LOSS SEVER LONG TERM EFFECTS Endometrial cancer Thromboembolism FEWER HYSTERECTOMIES INCREASED FRACTURE RATE TREATMENT-INDUCED BMD LOSS ARTHROMYALGIA LIPID DISTURBANCES COGNITIVE DISTURBANCES VASOMOTOR SIDE EFFECTS

Tailoring the treatment on the basis of the clinical histories? Which patients should we deny the advantage linked to AI treatment on the basis of their characteristics?