CHEMOPREVENTION in BREAST CANCER

Transcription

1 CHEMOPREVENTION in BREAST CANCER Ozlem Er, M.D. Assc Prf f Medical Onclgy ESMO Curse Essentials f Medical Onclgy

2 Outline Risk Assessment Mlecular Targets ER psitive Breast Cancer Tamxifen Ralxifene Lasfxifene Armatase Inhibitrs ER negative Breast Cancer Retinids Lapatinib Metfrmin ASCO 2009 Guideline

3 Essential Elements fr Breast Cancer Preventin Trials Ppulatin with defined, quantifiable risk Gail mdel NCI Breast Cancer Risk Assessment Tl A reasnable target An acceptable interventin A measurable endpint Reductin in BC incidence Bimarker mdulatin

4 NCI Breast Cancer Risk Assessment Tl

5 Gail Mdel Prjecting individualized prbabilities f develping breast cancer fr white females wh are being examined annually T assist in medical cunseling, a methd t estimate the chance that a wman with given age and risk factrs will develp breast cancer ver a specified interval. The risk factrs used were age at menarche, age at first live birth, number f previus bipsies, number f first-degree relatives with breast cancer. Gail MH, et al. J Natl Cancer Inst. 1989

6 Appraches t Preventin Lifestyle factrs Diet Weight cntrl Exercise Reprductive factrs Exgenus hrmnes Chempreventin Surgical preventin

7 Management Plan Age Family histry Prir bipsy & histlgic results Fertility histry

8 Functinal Characterizatin Of Mlecular Targets Fr Breast Cancer Therapy Tamxifen -Five years f tamxifen (20 mg/d) - Wmen at increased risk f breast cancer t reduce their risk f ER psitive invasive breast cancers fr up t 10 years. -The benefit f taking tamxifen fr mre than 5 years is unknwn. -The greatest clinical benefit and the fewest side effects were derived frm the use f tamxifen in yunger (premenpausal) wmen 35 t 50 years f age wh are unlikely t experience thrmbemblic sequelae r uterine cancer, wmen withut a uterus, and wmen at high risk f breast cancer.

9 Tamxifen Preventin Trials Fur phase III randmized trials have prspectively evaluated tamxifen cmpared with placeb fr breast cancer risk reductin NSABP-P1 IBIS-I Ryal Marsden Tamxifen Preventin Trial Italian Randmized Tamxifen Preventin Trial

10 NSABP-P1 13,388 wmen 35 years r lder wh were at increased risk f breast cancer (ie, 35 t 59 years f age with a 1.66 risk using a mdified Gail mdel, 60 years ld, r with prir LCIS) Wmen were excluded if they were using HT, ral cntraceptives r andrgens, r if they had used these 3 mnths befre randmizatin. Placeb r tamxifen (20 mg/d) fr 5 years The initial results were based n a median f 4.6 years f fllwup. Invasive BC 89 vs 175 RR reductin f 49% Abslute risk reductin f 15 invasive breast cancers per 1,000 wmen Nninvasive cancers 50% reductin Abslute risk reductin f six invasive breast cancers per 1,000 wmen Fewer ER-psitive tumrs 41 vs 130 Overall RR reductin f 69% Reductin f 16 ER-psitive breast cancers per 1,000 wmen The incidence f ER negative tumrs was similar between grups, 38 vs 31 Fisher B, et al. JNCI 1998

11 NSABP-P1: 7 yr fllwup The reductin in bth invasive (RR 0.57) and nninvasive (RR 0.63) BC persisted. 250 invasive breast cancers vs nninvasive breast cancers vs 60 N statistically significant difference in stage distributin f invasive BC between the tw grups. There was a reductin in ER+ tumrs f 62% in the tamxifen grup (RR 0.38) 70 vs 182 N statistically significant difference in ER-negative tumrs (RR1.31). Tamxifen cnsistently reduced invasive BC risk, particularly ER-psitive tumrs, in all age strata, all 5-year predicted risk strata fr breast cancer (beginning at1.66%), and wmen with atypical hyperplasia (AH) r a histry f LCIS. The magnitude f the prtective benefit in the updated results was similar t the initial reprt. NSABP-P1 trial unblinded participants in 1998, with subsequent differential rates f withdrawal frm the placeb arm versus the treatment arm, and crss-ver frm the placeb arm t the tamxifen arm. These circumstances may have biased the reprted estimates f benefits and risks tward the null Fisher B, et al. JNCI 2005

12 IBIS-I 7,154 wmen age 35 t70 years, wh were at increased risk f BC, t receive either tamxifen (20 mg/d) r placeb fr 5 years Abslute risk reductin f 15 breast cancers per 1,000 wmen N difference in the risk f ER-negative invasive tumrs (35 in each grup) The risk f ER-psitive invasive BC 34% lwer in the tamxifen arm (87 cases v 132 cases) Abslute risk reductin f 13 ER-psitive breast cancers per 1,000 wmen A decrease in DCIS but nt statistically significant (17 wmen n tamxifen with DCIS cmpared with 27 wmen n placeb). These fllw-up results suggest that the risk-reducing effect f tamxifen persists fr at least 10 years. Cuzick J, et al. JNCI 2007

13 Ryal Marsden Tamxifen Preventin Trial 2,494 healthy wmen age 30 t 70 years t receive tamxifen (20 mg/d) r placeb fr 8 years. Initial results shwed n effect f tamxifen n the incidence f breast cancer. With a median f 13.2 years f fllw-up and a maximum f 20 years, als shwed n statistically significant effect f tamxifen n the verall incidence f breast cancer There was als n statistically significant difference in the incidence f invasive BC The incidence f ER-psitive invasive BC was 39% lwer in the tamxifen grup ver the entire perid, (53 vs 86 wmen) Abslute reductin f 26 ER-psitive BC per 1,000 wmen ver the 13.2 years median fllw-up perid There was n effect f tamxifen n the incidence f ER-psitive BC during active treatment The variable benefit f tamxifen in reducing the incidence f ER-psitive BC during and after treatment in this study is likely a reflectin f a small sample size rather than a meaningful difference when cmpared with the benefits bserved in the NSABP-P1 and IBIS-I studies. Pwles TJ, et al. JNCI 2007

14 Italian Randmized Tamxifen Preventin Trial 5,408 wmen age 35 t 70 years with a prir hysterectmy and n prespecified breast cancer risk t receive tamxifen (20 mg/d) r placeb fr 5 years. Their breast cancer risk was lwer than that f the general ppulatin, because 48% f participants had undergne a bilateral phrectmy. N statistically significant reductin in verall breast cancer risk bserved in the tamxifen grup 62 vs 74 A statistically significant reductin in prgesterne receptr psitive tumrs 27 vs 44 A reductin in breast cancer risk amng wmen at high risk with at least ne vary intact N effect f tamxifen n ER-negative breast cancer Vernesi U, et al. JNCI 2007

15 Meta-analysis f the Primary Results f the Fur Tamxifen Preventin Trials Overview f the main utcmes in breast-cancer preventin trials The cmbined reductin in breast cancer incidence (invasive and DCIS) with tamxifen use cmpared with placeb ranged frm a relative risk f 34% t 38% There was n reductin in the risk f ER-negative BC The incidence f ER-psitive BC decreased by 48% Age had n apparent effect n the relative degree f BC risk reductin. Cuzick J, et al.lancet 361: 2003

16 Adverse Events and Side Effects Related t Tamxifen Use Endmetrial cancer (grade I adencarcinma) Thrmbemblic events (PE, DVT, retinal v thrmbsis) Strke Cataracts Cgnitin (incnclusive) Gyneclgic and vasmtr symptms (vaginal discharge) Fractures Mrtality N verall effect f tamxifen n all-cause mrtality PE was the nly cause f death shwing an increase with tamxifen use Nne f the preventin trials have demnstrated an effect f tamxifen n breast cancer specific mrtality

17 Ralxifene Fr pstmenpausal wmen at increased risk fr BC, ralxifene (60 mg/d) fr 5 years may be ffered as anther ptin t reduce the risk f ER psitive invasive BC. Equally efficacius t tamxifen in reducing BC risk in pstmenpausal wmen. Nt as effective in reducing the incidence f nninvasive BC cmpared with tamxifen In the STAR trial, ralxifene was assciated with a mre favrable side-effect prfile cmpared with tamxifen, including a statistically significant lwer risk f thrmbemblic disease, benign uterine cmplaints, and cataracts as cmpared with tamxifen. Nt knwn t have an effect n verall r breast cancer specific mrtality in wmen at increased risk f BC Ralxifene may be used fr lnger than 5 years in wmen with steprsis in whm BC risk reductin is an additinal ptential benefit.

18 Ralxifene Fur randmized prspective trials have evaluated the influence f ralxifene n breast cancer risk. Risk reductin was the primary end pint f tw trials, STAR and RUTH trials, A secndary end pint f the MORE trial. Als the primary end pint f the CORE trial, which fllwed a subgrup f participants frm the MORE trial.

19 MORE and CORE Trials 7,705 pstmenpausal wmen with steprsis wh were <=80 years f age Ralxifene (60 r 120 mg/d) r placeb fr 4 years. Participants were entered regardless f BC risk, which was nt frmally assessed at study entry, althugh infrmatin n breast cancer family histry was cllected and presented. Breast cancer was a secndary utcme. 78 cases f BC in 7,682 wmen (44/2571 placeb vs 34/ 5111 Ralxifene) 59 were invasive BC and 19 were nninvasive. Wmen treated with ralxifene had a statistically significant reduced risk f invasive BC cmpared with wmen n placeb particularly ER psitive invasive BC

20 MORE and CORE Trials After the cmpletin f the MORE trial, cnsenting participants were bserved under an amended design called the CORE trial, which recnsented 4,011 MORE trial participants (52%) CORE participants had 5-year breast cancer risk assessed at study entry with the Gail mdel. 4 years f additinal ralxifene use reduced invasive BC by 59% cmpared with placeb and ER-psitive invasive BC by 66% cmpared with placeb. Thrugh 8 years f randmizatin frm the MORE trial t the end f the CORE trial, ralxifene cntinued t significantly reduce the risk f verall BC, invasive BC, and ERpsitive BC The incidence f ERnegative invasive BC was similar in the tw treatment grups thrughut the 8 years f treatment

21 RUTH Ralxifene (60 mg/d) vs placeb in 10,101 pstmenpausal wmen with crnary heart disease r multiple risk factrs fr crnary heart disease. The tw primary utcme measures were crnary events and invasive BC. Participants were entered regardless f BC risk, and nly 41% had a 5-year predicted BC risk f 1.66%. Nt influence the risk f primary crnary events Significantly reduced invasive BC risk primarily due t reduced ERpsitive BC

22 NSABP STAR 19,747 pstmenpausal wmen with a 5-year increased risk f BC Tamxifen (20 mg/d) r ralxifene (60 mg/d) fr 5 years. The same risk assessment used in NSABP-P1. The primary end pint was a reductin in BC risk. Baseline characteristics were substantially different frm the prir NSABP-P1 tamxifen preventin trial. 5-year prjected breast cancer risk was higher (58.7% had a 3% 5-year prjected breast cancer risk in the STAR trial, cmpared with 44% in the NSABP-P1 trial). Mre than 51% f STAR participants had a prir hysterectmy as cmpared with 37% f participants in the NSABP-P1 tamxifen preventin trial. Mre than 32% f STAR participants had a histry f breast LCIS r AH cmpared with 15% f NSABP-P1 participants. The incidence f invasive breast cancer in the tamxifen and ralxifene grups were nt significantly different. Mre nninvasive breast cancers in the ralxifene (n80) grup than in the tamxifen (n57) grup, nt statistically significant. Findings were als cmparable fr wmen diagnsed with ER-psitive tumrs

23 Adverse Events and Side Effects Related t Ralxifene Use Endmetrial cancer (Tmx > Ral) VTE (Tmx > Ral) Ischemic Heart Disease (n increase) (Tmx= Ral) Strke (wmen with underlying vascular disease shuld nt be treated with ralxifene) Cataracts (n increase) Cgnitin (incnclusive) Gyneclgic and vasmtr symptms (Tmx > Ral) Fractures (reduced) Mrtality N effect f ralxifene n the incidence f death in these trials Nne f the preventin trials have demnstrated an effect f ralxifene n breast cancer specific mrtality

24 Lasfxifene Third generatin SERM The randmised, placeb-cntrlled Pstmenpausal Evaluatin and Risk-Reductin With Lasfxifene (PEARL) study 8,556 therwise healthy wmen aged 59 t 80 years 0.5 mg/day vs placeb r 0.25 mg/day vs placeb, fr 5 years The primary endpints were incidence f estrgen receptr-psitive (ER+) breast cancer and vertebral fracture (at 3 years) and nnvertebral fracture (at 5 years) Increased prtectin against BC in pstmenpausal wmen with steprsis and a high risk f BC Pwles T, et al. St Gallen 2009

25 SERMs in the Preventin f Breast Cancer 35% reductin in BC 53% reductin in ER+ BC Cuzick J. SABCS, 2009

26 Adverse Events and Side Effects Related t SERM Use Inc endmetrial cancer (Tmx) N effect n clrectal, varian r ther cancer Inc DVT, PE & retinal vein thrmbsis Dec fractures (Las) Inc hysterectmy (Tmx) N effect n mrtality, incidence f strke, TIA, MI, cataract Cuzick J. SABCS, 2009

27 Armatase Inhibitrs The effects f armatase inhibitrs (anastrzle, letrzle) and inactivatrs (exemestane) n cntralateral BC risk supprt further evaluatin f these agents fr BC risk reductin. A meta-analysis f adjuvant breast cancer trials evaluating armatase inhibitrs identified a 48% relative reductin in cntralateral BC risk with five f the six cmparatrs being tamxifen. Cuzick J. J Clin Oncl, 2005

28 Cntralateral Tumrs in AI Trials Cuzick J. SABCS, 2009

29 Armatase Inhibitrs The cncept f using armatase inhibitrs as a BC risk reductin agent was strengthened by the recent update f the ATAC trial, in which, with 100 mnths f fllw-up, 5 years f anastrzle was assciated with fewer cntralateral breast cancers as a first event cmpared with 5 years f tamxifen (fr hrmne receptr psitive patients) Frbes JF, et al. Lancet Oncl, 2008

30 IBIS-II 6,000 pstmenpausal wmen at increased breast cancer risk t 5 years f placeb r anastrzle (1 mg/d)

31 ExCel 4560 pstmenpausal wmen either at increased BC risk r age 60 years t 5 years f exemestane (25 mg/d) r placeb

32 Direct Effects f Hrmnal Manipulatin

33 Preventin f ER-negative Breast Cancer

34 ER-Negative Breast Cancer All f the breast cancer risk reductin trials using SERMs demnstrate that these agents are effective in reducing the risk f nly ERpsitive breast cancer. They d nt prevent the develpment f ERnegative breast cancer, which accunts fr 30% f all breast cancers Tamxifen did, hwever, seem t increase the sensitivity f mammgraphy fr the detectin f ER-negative tumrs in the NSABP-P1 trial. ERnegative tumrs were fund earlier and were smaller in wmen treated with tamxifen in cmparisn with wmen n placeb. There is a need t develp agents that als prevent ER negative breast cancer.

35 ER-Negative Breast Cancer Several classes f chempreventive agents have been shwn t prevent ER-negative breast cancer in animal mdels. Retinids and rexinids (9-cis retinic acid, bexartene, and LG100268), Cx-2 inhibitr (celecxib) Tyrsine kinase inhibitrs (gefitinib and lapatinib). Several f these agents are nw being tested in early-phase risk reductin trials invlving bimarker mdulatin. In the future, these cancer risk reductin drugs will be cmbined with hrmnal agents (such as SERMs r armatase inhibitrs) t reduce the risk fr bth ER-psitive and ER-negative breast cancer.

36 Retinids Fenretinide is the nly retinid that has been evaluated in a phase III study fr secndary BC preventin. 3,000 wmen age 30 t 70 years with a diagnsis f DCIS r stage I BC 5 years f fenretinide (200 mg/d) r n treatment, in additin t standard tx The primary end pint f this study was the incidence f secnd BC At a median fllw-up time f 97 mnths, there was n statistically significant difference in verall BC incidence between the tw arms. Further fllw-up f a subset f wmen (59%) ver a median f almst 15 years cntinued t bserve n difference in verall BC incidence between the tw grups. In a subset analysis, a statistically significant reductin in secnd primary BC was bserved amng the premenpausal wmen treated with fenretinide N difference was bserved in verall mrtality between the study arms. Dermatlgic and dark-visin adaptatins were the mst cmmn adverse events. Nw being studied in cmbinatin with tamxifen fr the preventin f BC in high-risk wmen. (J Clin Oncl 24: , 2006)

37 ER-Negative Breast Cancer New subclassificatin scheme fr ERnegative breast cancer based upn kinmewide gene expressin prfiling, ptentially relevant fr bth treatment and clinical utcme. Speers et al. Clin Cancer Res 2009

38 Lapatinib

39 Lapatinib

40 Metfrmin Managing breast cancer with a diabetes drug? Epidemilgical data: Lwer cancer rates in diabetics taking metfrmin Ptentially better respnse t chemtherapy Plausible bilgic mechanism Grwing preclinical data Animal mdels Increased apptsis in cell culture

41 Metfrmin

42 Metfrmin

43 Metfrmin Preclinical and Clinical Studies

44 ASCO Clinical Practice Guideline Update n the Use f Pharmaclgic Interventins Including Tamxifen, Ralxifene, and Armatase Inhibitin fr Breast Cancer Risk Reductin Visvanathan K, et al. JCO 2009

45 Ozlem Er, M.D. Assc Prf f Medical Onclgy NBC