Cecilia NisticòCecilia NisticòDipartimento di Oncologia MedicaDipartimento di Oncologia Medica

Oncologia Medica COncologia Medica CDirettore: Prof. E. TerzoliDirettore: Prof. E. Terzoli

IRE - Istituto Nazionale TumoriIRE - Istituto Nazionale TumoriRegina ElenaRegina Elena

RomaRoma

Roma, 28 Novembre 2008

Endocrinoterapia adiuvante del

carcinoma nel 2008

Ritmi circadiani e qualità di vita: actigrafia e uovi orizzonti nel carcinoma della mammella

Mediterranean Scholl of Oncology

Breast Cancer TreatmentBreast Cancer Treatment

• Final Outcomes:Final Outcomes:

• Adjuvant settingAdjuvant setting Treatment Goal:Treatment Goal: to Cureto Cure

• Advanced DiseaseAdvanced Disease Treatment Goal:Treatment Goal: to Careto Care

• Chemotherapy• Endocrine therapy

• Biologic targeted therapy

• Bisphosphonates–Organ specific therapy

Adjuvant Therapy- Early Breast Cancer -

Modified from Peto et al. Lancet 355:1822, 2000

Recent decrease in UK and USA breast cancer mortality at ages 35 69 years

Adj CTX

Adj HT

Screening

13%18%

12%15%

25%30%

!

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

Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) 15-Year Reductions in Recurrence and Disease-Specific Mortality

EBCTCG. Lancet. 2005;365:1687-17.

Treatment Comparison

Breast Cancer Recurrence, %

Log Rank 2P

Breast Cancer Mortality, %

Log Rank 2P

Tamoxifen 5 yrs vs none, ER-positive women

11.8 < .00001 9.2 < .00001

Meta-analysis of 194 randomized trials

Meta-analysis of 144,939 women

EFFICACY OF ADJUVANT TAMEFFICACY OF ADJUVANT TAM5 YEARS, ER +/UNKNOWN5 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%)

> 7038%(+18%)p=.00001

26%(+15%) p=.00001

EBCTCG, Lancet 2005;365:1687EBCTCG, Lancet 2005;365:1687-17-17

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

Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) 15-Year Reductions in Recurrence and Disease-Specific Mortality

EBCTCG. Lancet. 2005;365:1687-17.

Treatment Comparison

Breast Cancer Recurrence,

%

Log Rank 2P

Breast Cancer

Mortality, %

Log Rank 2P

Ovarian ablation or suppression vs none

4.3 .00001 3.2 .004

Meta-analysis of 194 randomized trials

Meta-analysis of 144,939 women

Treatment Comparison Breast Cancer Recurrence, %

Log Rank 2P Breast Cancer Mortality, %

Log Rank 2P

Ovarian ablation or suppression vs none

4.3 .00001 3.2 .004

EBCTCG. Lancet. 2005;365:1687-1717.

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.

J Clin Oncol 2005;23:5973-82

Retrospective subset analysis suggests that women younger than 40 years seemed to benefit from the addition of goserelin to CAF.

Vantaggio72/6465/5554/485/ 9 yrs DFS

< 40

PCAF-ZT

( % )

CAF-Z

( % )

CAF

( % )

Follow up

ASCO 1999/2003

Nessun Vantaggio

79/6973/6272/615/ 9 yrs DFS

40

Davidson N, ASCO 2007

1. TAM standard all pts2. TAM for 5 yrs3. Chemo + TAM better than whatever alone4. OS beneficial in youger pts continuing to

menstruate after chemo or TAM5. Optimal LHRH duration uncertain6. AIs in Meno after chemo: caution!7. No data of AIs + LHRH vs TAM (RCTs

ongoing)

AIs & TAM: mechanism of action

Placebo

Tamoxifen

Aromatase Inhibitors

Tamoxifen

Tamoxifen

Arom. Inhibitors

Aromatase InhibitorsR

R

Tamox. R

Hormonal Adjuvant Treatment Strategies in Early Breast

Cancer“Up-Front”

“Extended Switch”

“Early Switch”

2-3 years 3-2 years

5 years

10 years

StrategyStrategy RCTsRCTs PtsPts UpdateUpdateMedian Median

FU FU (mo.)(mo.)

AIAI

Efficacy [HR, Efficacy [HR, p]p]

DFS/EFSDFS/EFS OSOS

Up-FrontUp-FrontATACATAC 61866186 Lancet Lancet

20062006 6868 ANAANA 0.87 (0.01)0.87 (0.01) 0.85 (0.7)0.85 (0.7)

BIG-1-98BIG-1-98 49224922 JCO 2007JCO 2007 5151 LETLET 0.82 (0.007)0.82 (0.007) 0.91 (>0.05)0.91 (>0.05)

““Early” Early” SwitchSwitch

ITA-1ITA-1 380380 JCO 2001JCO 2001 6161 AGTAGT NR (0.6)NR (0.6) NR (0.005)NR (0.005)

ITA-2ITA-2 448448 Ann Oncol Ann Oncol 20062006 6464 ANAANA 0.57 (0.005)0.57 (0.005) 0.56 (0.1)0.56 (0.1)

IESIES 47424742 Lancet Lancet 20072007 5656 EXEEXE 0.76 (0.0001)0.76 (0.0001) 0.85 (0.08)0.85 (0.08)

ABCSG8/ABCSG8/ARNOARNO 32243224 Lancet Lancet

20052005 2828 ANAANA 0.60 (0.0009)0.60 (0.0009) NR (0.16)NR (0.16)

““Late” Late” SwitchSwitch

MA.17MA.17 51575157 JNCI 2005JNCI 2005 3030 LETLET 0.58 (0.001)0.58 (0.001) 0.82 (0.3)0.82 (0.3)

ABCSG 6aABCSG 6a 856856 JNCI 2007JNCI 2007 6060 ANAANA 0.64 (0.047)0.64 (0.047) NRNR

NSABP B-33NSABP B-33 15981598 SABCS SABCS 20062006 3030 EXEEXE 0.68 (0.07)0.68 (0.07) 1.20 (0.63)1.20 (0.63)

RCTs – AIs Adjuvant BCRCTs – AIs Adjuvant BC

Adjuvant Aromatase Adjuvant Aromatase InhibitorsInhibitors

StudyStudy therapytherapy f.u.f.u. HRHR Abs dAbs d

ATAC 03ATAC 03 upfrontupfront 44 0.820.82 3%3%

ITA 04ITA 04 switchswitch 33 0.360.36 5.3%5.3%

IES 04IES 04 switchswitch 2.72.7 0.680.68 4.7%4.7%

MA17 04MA17 04 extendedextended 2.52.5 0.580.58 5 %5 %

ARNO -ARNO -ABCSG 04 ABCSG 04

switchswitch 0.60.6 3%3%

BIG 05BIG 05 upfrontupfront 2.42.4 0.810.81 2.6%2.6%

Aromatase Inhibitors Aromatase Inhibitors Adjuvant Adjuvant Trials. Distant Trials. Distant metastasesmetastases

StudyStudy Reduction in Reduction in distant distant

metastasesmetastases

pp

ATAC ATAC Lancet 05Lancet 05 14%14% .01.01

BIG 1-98 BIG 1-98 NEJM 05NEJM 05 27%27% .0012.0012

IES IES NEJM 04NEJM 04 34%34% .0004.0004

ARNO/ABCSG ARNO/ABCSG Lancet Lancet 0505

39%39% .0067.0067

ITA ITA JCO 05JCO 05 51%51% .06.06

MA 17 MA 17 JNCI 05JNCI 05 40%40% .002.002

Patients (%)

Follow-up time (years)

20

25HR

0.74HR+

95% CI

(0.64–0.87)

p-value

0.0002

A

282

T

370

At risk:A 2618 2540 2448 2355 2268 2014 830T 2598 2516 2398 2304 2189 1932 774

ATAC: recurrences* before 2.5 ATAC: recurrences* before 2.5 years years (HR+ patients)(HR+ patients)

* Censoring non-BC deaths before recurrence

0

5

10

15

0 1 2 3 4 5 6

‘Arimidex’ (A)Tamoxifen (T)

Pre-defined adverse events*: Pre-defined adverse events*: ATACATACMedian follow-up 68 monthsMedian follow-up 68 months

Incidence (%)

Anastrozole

Tamoxifen

ATAC Trialists’ Group. Lancet 2005;365:60-62

Total fractures p<0.0001

Joint symptoms p<0.0001

Deep venous thromboembolic events p=0.02

Venous thromboembolic events p=0.0004

Ischemic cerebrovascular events p=0.03

Endometrial cancer p=0.02

Vaginal discharge p<0.0001

Vaginal bleeding p<0.0001

Hot flushes p<0.0001

0 10 20 30 40 50

* Other Pre-defined AE’s with NO significant differences seen between groups: Ischemic Cardiovascular Disease, Cataracts, Nausea & Vomiting, Mood Disturbances, Fatigue

*A fracture episode comprised one or more fractures on the same day based on adverse events and serious adverse event reports

ATAC 100 mo.: SAEs: on and off treatment (Number – safety population)

Serious adverse event

On treatment

Anastrozole

Off treatment

Tamoxifen Anastrozole Tamoxifen

Treatment-related 153 284 49 57

Endometrial cancer 4 12 1 12

Myocardial infarction 34 33 26 28

Cerebrovascular accident 20 34 22 20

Fracture episodes* 375 234 146 143

†included as a non-predefined adverse event of interest

Predefined adverse eventsat any time on treatment or any severity

Hot flushesNausea and vomitingFatigue / tiredness (asthenia)Mood disturbancesMusculo-skeletal disordersVaginal bleedingVaginal dischargeIschaemic cardiovascular diseaseIschaemic cerebrovascular eventVenous thromboembolic eventsDeep venous thromboembolic eventsCataractsCarpal 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)

Anastrozole(N = 3092)

Tamoxifen(N = 3094)

Deaths according to treatment group (ITT population)

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. patients (%)

Fracture episode rates throughout the study

29842976

At risk:AT

28592824

27452699

26402572

24962419

23062208

20772000

17131645

702659

Time since randomization (years)

Annual fracture episode rates (%)

Anastrozole (A)Tamoxifen (T)

0 1 2 3 4 5 6 7 8 90

2

3

4

1

ATAC 100: benefits continue and detrimental effects

decline after treatment cessation

Time to recurrence Fracture episode rates

Patients (%)

30

25

20

15

10

5

00 1 2 3 4 5 6 7 8 9

12.5%17.0%

21.8%

Follow-up time (years)

9.7%

2.8% 4.8%Absolutedifference

Tamoxifen (T)Anastrozole (A)

Time since randomisation (years)

Annual fracture episode rates (%)

Tamoxifen (T)Anastrozole (A)

0 1 2 3 4 5 6 7 8 90

2

3

4

1

BIG 1-98: cumulative incidence BIG 1-98: cumulative incidence of breast cancer relapseof breast cancer relapse

Proportionfailing(%)

Time since randomisation (years)

5-year difference (L-T) = -3.4% (SE 1.2)Cuminc p=0.0002

0 1 2 3 4 5

0

5

10

15

20

13.6%

10.2%

6.2%

8.1%

Letrozole (L)

Tamoxifen (T)

SE = standard error

Thürlimann B et al. The Breast 2005;14:S3, abs S4

BIG 1-98 DFS BIG 1-98 DFS by Local Pathological by Local Pathological AssessmentAssessment

Favors L Favors T

1.00.5 0.75 1.25 1.5

Hazard Ratio (L:T)

ER+ / PgR+ (n=5055)

ER+ / PgR- (n=1631)

0.84

0.83

All patients (n=8010)0.81

ER+ / PgR unk (n=1154)0.72

““Endometrial events” :Endometrial events” :Tamoxifen vs Aromatase Tamoxifen vs Aromatase InhibitorInhibitor

HysterectoHysterectomymy

EndometrialEndometrial

biopsiesbiopsies

ATACATAC 5% vs 1%5% vs 1%

BIG 1BIG 1 7.2% vs 7.2% vs 1.9%1.9%

Trial Design

Tamoxifen

RANDOMIZE

Exemestane

5162*

Tamoxifen

5294*

Post Treatment Follow-up

10335*

Diagnosis

2-3 years2-3 years study

treatment

Total 5 years endocrine therapy

Start of study

* 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: Aromatase Inhibitors: Tox IssuesTox Issues

1.1. Bone FracturesBone Fractures

2.2. Cardiovascular Cardiovascular DiseaseDisease

Bone Health: Bone Health: IssuesIssues

Protective Effects of TAMProtective Effects of TAM Steroidal vs Non-SteroidalSteroidal vs Non-Steroidal Predictive role of BMD on fracturePredictive role of BMD on fracture Other fracture risk factors:Other fracture risk factors:

Patient’ characteristicsPatient’ characteristics Bone turnoverBone turnover Steroid use (abuse?)Steroid use (abuse?)

What about bisphosphonates?What about bisphosphonates?

Fracture incidenceFracture incidence

Incidence of fracture reported in different adjuvant aromatase inhibitor trials

1. The earliest publications of the RCTs using AIs provided conflicting results about the supposed higher risk of ischaemic cardiovascular toxicity

2. 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

CV Disease - CV Disease - BackgroundBackground

References: 1Howell JSBMB 2005

Lipid effectsLipid effects Increase of:Increase of:

ColestherolColestherol TGTG LpALpA LDL-CLDL-C

Decrease of:Decrease of: HDL-CHDL-C

PrimaryPrimary Cardiovascular Adverse Events Rate Cardiovascular Adverse Events Rate

(CVAE)(CVAE)

Grade 3-4 as defined by NCICGrade 3-4 as defined by NCIC

SecondarySecondary Thromboembolic Adverse Events Rate Thromboembolic Adverse Events Rate

(TEAE)(TEAE)

Cerebrovascular Adverse Events Rate Cerebrovascular Adverse Events Rate

(CBVAE) (CBVAE)

End-Points

In order to reduce heterogeneity across AIs, In order to reduce heterogeneity across AIs,

the analysis has been carried on the analysis has been carried on

considering:considering: all AIs (Overall analysis)all AIs (Overall analysis) only 3only 3rdrd generation AIs (CVAE-New) 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

Cuppone F, Cancer 2008

Results – TEAE Rate(Thromboembolic Adverse Events)

Results – CBVAE Rate(Cerebrovascular Adverse Events)

Cuppone F, Cancer 2008

• Controversial ‘Motive’ (not clear background)

• Overestimated risk (0.5%) when AI vs TAM

• No difference AIs vs placebo

• Protective effect of TAM really ‘guilty’

‘Trial’ Verdict

…..free for lack of evidences

Cardio-protective effect of Cardio-protective effect of tamoxifen tamoxifen MetanalysisMetanalysis

32 trials comparing tamoxifen against a 32 trials comparing tamoxifen against a control group (metastatic, adjuvant, and control group (metastatic, adjuvant, and prevention settings) prevention settings) 12 reported on myocardial infarction death12 reported on myocardial infarction death

> 52,000 patients; 66% postmenopausal; > 52,000 patients; 66% postmenopausal; mean age 54.8 yrs; mean treatment mean age 54.8 yrs; mean treatment duration: 4.3 yrs; mean FU: 5.6 yrsduration: 4.3 yrs; mean FU: 5.6 yrs

Relative risk ratio for fatal MIs (tamoxifen / Relative risk ratio for fatal MIs (tamoxifen / control): 0.62 (95% CI: 0.41-0.93)control): 0.62 (95% CI: 0.41-0.93)

Risk ratio without the Scottish trial: 0.81 Risk ratio without the Scottish trial: 0.81 (95% CI: 0.48-1.37)(95% CI: 0.48-1.37)

Braithwaite et al JGIM 2003;18:937-47

Myocardial Infarction

Cognitive FunctionCognitive Function, , Fatigue and Menopausal Fatigue and Menopausal SymptomsSymptoms

HSCS*HSCS*

(impairment)(impairment)FACT-FFACT-F FACT-ESFACT-ES FACT-GFACT-G

Adjuvant Adjuvant CTCT

16%16% 3131 5858 7777

ControlControl 4%4% 4646 6464 9393

0.0080.008 0.00010.0001 0.00010.0001 0.00010.0001

* High Sensitivity Cognitive Screen

N Tchen, JCO 2005

LONG TERM TREATMENT WITH LONG TERM TREATMENT WITH A.I.A.I.

POTENTIALPOTENTIAL

BENEFITBENEFITPOTENTIAL POTENTIAL

RISKRISK

SUPERIOR EFFICACYSUPERIOR EFFICACY

LOSS SEVER LONG TERM EFFECTSLOSS SEVER LONG TERM EFFECTS Endometrial cancerEndometrial cancer ThromboembolismThromboembolism

FEWER HYSTERECTOMIESFEWER HYSTERECTOMIES

INCREASED FRACTURE RATEINCREASED FRACTURE RATE

TREATMENT-INDUCED BMD TREATMENT-INDUCED BMD LOSSLOSS

ARTHROMYALGIAARTHROMYALGIA

LIPID DISTURBANCESLIPID DISTURBANCES

COGNITIVE DISTURBANCESCOGNITIVE DISTURBANCES

VASOMOTOR SIDE EFFECTSVASOMOTOR SIDE EFFECTS

Tailoring the treatment on Tailoring the treatment on the basis of the clinical the basis of the clinical histories?histories?

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