William J. Gradishar MD - PDF Free Download

Northwestern University Feinberg School of Medicine Adjuvant Endocrine Therapy For Postmenopausal Women SOBO 2011 William J. Gradishar MD Betsy Bramsen Professor of Breast Oncology Director, Maggie Daley Center for Women s Cancer Care Robert H. Lurie Comprehensive Cancer Center

Risk of Early Breast Cancer Recurrence Annual hazard of recurrence by estrogen receptor status Patients received CT, ET, or both (10 ECOG trials) Recurrence e hazard ra atio ER negative (n = 1,305) ER positive (n = 2,257) 257) Time, years Abbreviations: CT, chemotherapy; ET, endocrine therapy; ECOG, Eastern Cooperative Oncology Group. Adapted from Saphner T, et al. J Clin Oncol. 1996;14:2738-2746. 2

Distant Metastases Comprise the Majority of Early Recurrences During Tamoxifen Therapy 4,245 postmenopausal women with ER + operable breast cancer, all treated with TAM recurrence rate Annual 0.05 Overall Locoregional 0.04 Distant Contralateral 0.03 0.02 0.01 0 0 1 2 3 4 5 Years from diagnosis Cumulative recurrence rate, (% of overall) 2.5 years 5 years Overall 6.2 13.9 Distant 4.5 (73) 9.8 (71) Locoregional 1.0 (16) 2.7 (19) Contralateral 05(8) 0.5 13(9) 1.3 Updates of Doughty JC, et al. Breast Cancer Res Treat. 2007;106(suppl 1):S145. Abstract 3057; Mansell J, et al. Breast Cancer Res Treat. 2006;100(suppl 1):S111. Abstract 2091. Adapted from Mansell J, et al. Poster presented at: 29th Annual San Antonio Breast Cancer Symposium. December 14-17, 2006; San Antonio, Texas. Poster 2091. 3

Questions to settle! Is there still a role for tamoxifen? Yes Are all Aromatase Inhibitors the same and superior to tamoxifen? If used with tamoxifen, is there an optimal sequence? Is there an optimal duration of therapy?

FDA-Indications: Tamoxifen The most important t drug worldwide for hormone receptor positive breast cancer Adjuvant postmenopausal node+ Postmenopausal metastatic Premenopausal metastatic Adjuvant node negative Male metastatic Prevention DCIS 1977 86 89 90 93 98 2000

Benefits of adjuvant endocrine therapy: tamoxifen

Tamoxifen Useful regardless of menopausal status In postmenopausal women, reduces Recurrence by 37% to 54%, and Death by 11% to 33% Optimal duration (5 years) established (?) Long-term side effects characterized Carryover effect documented

Tamoxifen reduces recurrence in ER+ but not ER disease ER status Hazard ratio of logrank annual events * (SE) 2p value ER-poor 1.04 (0.07) ER-positive 0.59 (0.03) ER-unknown 0.69 (0.07) Subtotal 0.69 (0.03) < 0.00001 *About 5 years tamoxifen vs placebo Early Breast Cancer Trialists Collaborative Group. Lancet 2005;365:1687 717

~5 years Tamoxifen vs not, split by ER status only: RECURRENCE ER-poor disease ER+ disease ER+ disease

~5 years Tamoxifen vs not, ER+ split by PgR status: RECURRENCE

Greater absolute risk reduction with tamoxifen in N+ vs N disease Early Breast Cancer Trialists Collaborative Group. Lancet 2005;365:1687 717

~5 years tamoxifen vs not: MORTALITY 5 years tamoxifen vs. Not, ER+ only BREAST CANCER MORTALITY

Risk reduction with tamoxifen therapy Tamoxifen highly effective in ER+ breast cancer Proportional risk reductions for recurrence and mortality are unaffected by Age Use of chemotherapy Other tumor characteristics Tamoxifen has little effect in ER-poor tumors Early Breast Cancer Trialists Collaborative Group. Lancet 2005;365:1687 717

Optimal Duration of Tamoxifen

NSABP B-14: Trial Design ER+ operable breast cancer, node-negative (initial randomization to tamoxifen vs placebo) Tamoxifen n=1172 Second randomization (disease-free after 5 y tamoxifen) Double-blinded Tamoxifen n=593 Placebo n=579 Median f/u 7 y 5 years adjuvant therapy 5 years additional therapy Fisher B. J Natl Cancer Inst. 2001;93:684.

NSABP B-14: No Benefit of Extending Tamoxifen Beyond 5 Years DFS OS % of patient ts 100 90 80 70 60 P=0.03 82% 78% Placebo Tamoxifen % of patien ts 100 90 80 70 60 Placebo Tamoxifen P=0.07 94% 91% 50 50 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 Years Years 7 Tamoxifen arm had higher rates of endometrial cancer, and more deaths from ischemic heart disease and cerebrovascular disease. Fisher B. J Natl Cancer Inst. 2001;93:684-690.

Duration of Adjuvant Tamoxifen ATLAS: Adjuvant Tamoxifen Longer Against Shorter (International) ATTOM: Adjuvant Tamoxifen Treatment Offers More? (United Kingdom) Completely resected early-stage breast cancer or DCIS At least 2 years of prior tamoxifen therapy Relapse-free at time of randomization R A N D O M I Z E Stop Tamoxifen Continue tamoxifen for another 5 years

% Recurred At risk: Primary Endpoint: Disease Recurrence 40 No. No. Events Patients Obs. Exp. 35 Continue 3468 437 447-9 Stop 3484 456 445-1 30 25 20 RR = 0.95 15 (0.83-1.09; P = NS) 10 continue 5 stop 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Years from randomization continue 3468 3152 2831 2320 1803 1303 916 629 422 254 139 54 8 stop 3484 3160 2829 2308 1786 1284 916 635 412 250 122 49 11 35% 34% Gray R, et al. J Clin Oncol. 2008;26(15S): Abstract 513.

Tamoxifen (TAM) 4-hydroxy-TAM CYP3A N-desmethyl-TAM Genetic Variants, Inhibitors Stearns et al. JNCI 2003;95:1758 64 Reduced d concentrations of Endoxifen, 4-hydroxy-N-desmethyl- TAM (Endoxifen) Active and Abundant Antiestrogen

CYP2D6 Genotypes Highly polymorphic Normal activity: *1 (wt), *2, *33, *35 No activity: *3, *4, *5, *6, *11-*16, *18, *20, *38, *40, *42, *44 Decreased activity: *9, *10, *17, *29, *36, *37, *41 Increased activity via multiple copies: *1, *2, *35, *41 Substantial ethnic variability: eg e.g., *4: whites, *10: Asians, *17: blacks Inhibitors, e.g., SSRIs

CYP2D6 Genotype and Endoxifen Plasma Endoxifen (nm) 180 P<0.001, r 2 =0.24 160 140 120 100 80 60 40 20 0 Wt/Wt Wt/*4 *4/*4 CYP2D6*4 (most common genetic variant associated with the CYP2D6 poor metabolizer state) Jin Y et al: J Natl Cancer Inst 97:30, 2005 CP1229323-4

Endoxifen Plasma Concentration in EMs Compared to PMs 160 Endoxif fen plasma co oncentration (n nm) 140 120 100 80 60 40 20 0 No inhibitor Venlafaxine Weak inh. Potent inh. PMs N = 35 N = 3 N = 10 N = 5 N = 7 Borges S, Desta Z et al. Clin Pharmacol Ther 2006;80:61-74.

Time to Recurrence According to CYP2D6 Metabolizer Status in Women Receiving Adjuvant Tamoxifen 100 Alleles examined: *3, *4, *5, *6, *10, *17, *41 80 (n=108) % 60 40 20 0 EM/EM, EM/IM EM/PM, IM/IM, PM/IM PM/PM P<0.001 HR 4.0 PM relative to EM 0 2 4 6 8 10 12 14 Years after randomization Goetz et al., Updated NCCTG 89-30-52, SABCS 2008 (n=65) (n=16)

Agency for Healthcare Research and Quality (AHRQ) Analysis (2010) There were no consistent associations between CYP2D6 polymorphisms and outcomes in tamoxifen treatedwomen with breast cancer across 16 studies included in this systemic review review.

International Tamoxifen Pharmacogenomics Consortium Overall data from 4804 patients, 2880 after exclusions; adjuvant ER+ Main findings: No difference in DFS based on CYP2D6 status (p = 0.73) No difference in OS based on CYP2D6 status (p = 0.69)

Phase III Data: The Biggies Quantity has a quality all of its own What do the large adjuvant hormonal therapy trials tell us? ATAC and BIG 1 98

Abstract S1 7; Rae: CYP2D6 in ATAC ATAC Postmenopausal women with invasive breast cancer (n = 9366) Surgery radiotherapy chemotherapy Randomisation1:1:1 for 5 years X Anastrozole Tamoxifen Combination (n = 3125) (n =3116) n=3125x TransATAC HR+ subpopulation from Great Britain* CYP2D6 = 615 (19.7%) UGT2B7 = 606 (19.4%) CYP2D6 = 588 (18.8%) UGT2B7 = 603 (19.4%) DNA derived from FFPE tumor *Dowsett M, et al. J Clin Oncol. 26(7):1059-65, 2008 Rae, J.M.

Rate Recu urrence CYP2D6*4 Does Not Predict Recurrence 25% 20% 15% 10% 5% in Tamoxifen Arm Wt / *4 (n=149) Wt / Wt (n=402) *4 /*4 (n=37) 0% Overall P for Trend=0.688 0 1 2 3 4 5 6 7 8 9 10 Years Rae, J.M.

Rate Recu urrence CYP2D6 Score Does Not Predict Recurrence in Tamoxifen Arm 40% IM 35% 30% 25% EM Overall P for Trend= 0.107 PM 20% IM 15% IM 10% 5% 0% 0 1 2 3 4 5 6 7 8 9 10 Years Rae, J.M.

Abstract S1 8; Leyland Jones: CYP2D6 in BIG 1 98 BIG 1 98 S U R G E R Y Stratify Institution CT (Adjuvant/ Neoadjuvant) -Prior -None -Concurrent R A N D O M I Z E R A N D O M I Z E A B A B C D Tamoxifen Letrozole 2-Arm Option Tamoxifen Letrozole 4-Arm Option Tamoxifen Letrozole Letrozole Tamoxifen N=911 N=917 N=1548 N=1546 N=1548 N=1540 N=1,828 Enrolled 1998-2000 N=6,182 Enrolled 1999-2003 N=8,010 0 2 5 YEARS Monotherapy Population N=4,922 (2459 T; 2463 L) 76 Months Median Follow-Up

8010 enrolled BIG 1 98 Analytic Cohort 4861 DNA for genotyping 4628 CYP2D6 genotyping 2675 monotherapy 2111 no Chemotherapy 564 Chemotherapy 1029 T; 1082 L DNA derived from FFPE tumor 98% Caucasian Worldwide collaborative group 57% node-negative ER+ ( 1% immunostained cells by central review) 77% no chemotherapy

Outcome by CYP2D6 TAMOXIFEN No Chemotherapy 9% PM 27% IM

*4 Genotype TAMOXIFEN No Chemotherapy

Extensive Metabolizers (EM)

Strong CYP2D6 Inhibitors Medications to limit while taking tamoxifen 1. Drug Information Handbook, 2006 2. Pharmacist s Letter 2006 Chlorpromazine 1 Paroxetine 1 Cinacalcet 2 Pergolide 1 Cocaine 1 Propranolol 2 Darifenacin 2 (also listed as weak 1 ) Quinidine 1,2 Delavirdine 1 Quinine 1 Dexmedetomidine 1 Ritonavir 1,2 Fluoxetine, 2 Ropinirole 1 Miconazolel 1 Terbinafine 1

ASCO Guidelines

ECOG Trial: E3108 PI: Vered Stearns, MD A Phase II Prospective Trial Correlating Progression-Free Survival with CYP2D6 Activity in People with Metastatic Breast Cancer Treated with Single Agent Tamoxifen

E3108 Schema Tamoxifen 20 mg PO daily Eligible: Metastatic breast cancer starting tamoxifen Measureable/ Evaluable disease G E N O T Y P E CYP2D6 1 2 CYP2D6 0 R E S P O N S E S C i Continue tamoxifen until progression Stratify: Menopausal status Prior AI use N = 240 3 months: tamoxifen/ metabolite concentration

Significant risk of recurrence remains even with tamoxifen therapy Recurrences Breast cancer deaths 100 15% 17% 85.2 100 9% 18% 91.4 80 68.2 80 87.8 73.0 % of pati ients 60 40 20 73.7 Tamoxifen Control 54.9 % of patie ents 60 40 20 Tamoxifen Control 64.0 0 0 0 5 10 15 0 5 10 15 Years Years Adapted with permission. Early Breast Cancer Trialists Collaborative Group Meeting, 2000 Early Breast Cancer Trialists Collaborative Group. Lancet. 2005;365:1687 717

Third-Generation AIs NC N N N N N N Exemestane O Letrozole NC CN H 3 C CH3 H 3 C CH 3 CN Anastrozole CH 2 O Third Generation AIs High Selectivity Efficacy Safety Profile

St. Gallen 2009: Endocrine therapy in Postmenopausal Patients A majority of the Panel considered that an aromatase inhibitor should form part of standard endocrine therapy for postmenopausal women with receptor-positive breast cancer, though acknowledging that there were certain patients for whom tamoxifen alone can be considered adequate. The majority of the Panel preferred aromatase inhibitors as up- front endocrine treatment particularly in patients at higher risk of early relapse. Goldhirsch et al. Ann Oncol 2009;20:1319-29

Initial adjuvant trial Adjuvant Aromatase Trials Randomization Tamoxifen Aromatase inhibitor Trial ATAC, BIG 1-98 Randomization Randomization Switching trial 2-3 years prior tamoxifen Tamoxifen Aromatase inhibitor ARNO 95, ITA, IES ABCSG 8 Randomization Upfront vs. Switching Initial and sequencing trial Extended d adjuvant trial Tamoxifen Aromatase inhibitor Aromatase inhibitor TEAM Tamoxifen Aromatase inhibitor Tamoxifen Aromatase inhibitor Tamoxifen BIG 1-98 Aromatase inhibitor Randomisation MA.17, ABCSG-6A, NSABP B-33 Aromatase inhibitor 5 years prior tamoxifen 0 Placebo Time (years) 5

Adjuvant Endocrine Trials: Efficacy Aromatase Inhibitor Versus Tamoxifen Strategy RCTs Pts Update Up-Front Early Switch ATAC 6186 Lancet Oncol 2008 Median FU (mo.) AI Efficacy [HR, p] DFS/EFS OS 100 ANA 0.90 (0.025) 1.00 (0.99) BIG-1-98 4922 JCO 2007 51 LET 0.82 (0.007) 007) 0.91 (>0.05) ITA-1 380 JCO 2001 61 AGT NR (0.6) NR (0.005) ITA-2 448 Ann Oncol 64 ANA 0.57 (0.005) 005) 056(01) 0.56 (0.1) 2006 IES 4742 Lancet 2007 56 EXE 0.76 (0.0001) ARNO 95 979 JCO 2007 30 ANA 0.66 (0.049) Sequencing ABCSG 8 2926 SABCS 2005 0.85 (0.08) 0.53 (0.045) 28 ANA 0.76 (0.07) NR Absolute DFS Reductions at 3-6 years Up-Front Early Switch Sequence 2-4 % 3-5% 1.5%

Adjuvant Endocrine Trials: Efficacy Aromatase Inhibitor Versus Placebo or No Treatment Strategy RCTs Pts Update Median Efficacy [HR, p] FU AI (mo.) DFS/EFS OS MA.17 5157 JNCI 2005 30 LET 0.58 (0.001) 0.82 (0.3) Extended Switch ABCSG 6a 856 ASCO 2005 60 ANA 0.64 (0.047) NR NSABP B-33 1598 JCO 2008 30 EXE 0.68 (0.07) 1.20 (0.64) Absolute DFS Extended reductions at 3-6 Switch years 6%

MA.27 Study Design Eligibility: Postmenopausal ER-positive Early breast cancer Stratification Lymph node status Adjuvant chemotherapy Trastuzumab use Celecoxib use Aspirin use Open-label R A N D O M I Z E Anastrozole 1 mg/day x 5 years N = 7576 patients May 2003 July 2008 Exemestane 25 mg/day x 5 years Study Objectives: Primary: Event-free survival (EFS) Secondary: Overall survival (OS), distant disease-free survival (DDFS), time to distant recurrence, incidence of contralateral breast cancer, incidence of clinical fractures, evaluation of breast density, cardiovascular events, toxicities, iti quality of life Goss PE, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-1. 48

MA.27 Event-Free Survival Stratified HR All patients t 102(0871 1.02 (0.87-1.18) 18).85 Lymph node status Node-negative (71%) 1.04 (0.85-1.27).726 Node-positive/unknown (29%) 0.99 (0.79-1.23).896 Adjuvant chemotherapy use No (69%) 101(084-1 1.01 (0.84 1.23).894 Yes (31%) 1.02 (0.80-1.29).887 P Goss PE, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-1. 49

MA.27: Secondary Efficacy Outcomes Outcome Number (%) of Events Exemestane Anastrozole Stratified HR (95% CI) P Value OS 208 (5.5) 224 (5.9) 0.93 (0.77-1.13).64 DDFS 157 (4.1) 164 (4.3) 0.95 (0.76-1.18).46 DSS 89 (2.4) 98 (2.6) 093(0701 0.93 (0.70-1.24).62 CI = confidence interval; DDFS = distant recurrence; DSS = disease-specific survival; HR = hazard ratio; OS = overall survival Goss PE, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-1. 50

FACE: Letrozole vs Anastrozole Clinical Evaluation Phase IIIb Head-to-Head Comparison Study Design EBC ER+ Postmenopausal Node+ Postmenopausal FSH/LH/E 2 levels De novo adjuvant ET R A N D O M I Z E Letrozole 2.5 mg/qd Anastrozole 1 mg/qd N=~4000 Primary end point DFS Secondary end points Safety OS Time to distant metastasis Time to contralateral disease Breast cancer specific survival FSH = follicle-stimulating hormone; LH = luteinizing hormone; ET = endocrine therapy.

Comparison of Tamoxifen and an Aromatase Inhibitor Designs of Cohort 1 and Cohort 2 Tamoxifen Aromatase inhibitor Cohort 1: direct comparison as monotherapy R 5 yr Trials ATAC BIG 1-98/IBCSG 18-98 Cohort 2: comparison after 2-3 years of tamoxifen Dowsett, JCO 2011 R Trials GABG/ARNO IES/BIG 2-97 ITA ABCSG VIII 2-3 yr 2-3 yr ABCSG VIII 5 yr

Life-table curves of (A) recurrence; (B) breast cancer mortality; (C) death without recurrence; and (D) any death, for estrogen receptor positive patients in trials of approximately 5 years of aromatase inhibitor (AI) versus tamoxifen. Dowsett M et al. JCO 2010;28:509-518 2010 by American Society of Clinical Oncology

Life-table curves of (A) recurrence; (B) breast cancer mortality; (C) death without recurrence; and (D) any death, for estrogen receptor positive patients in trials of 2 to 3 years of tamoxifen and then 2 to 3 years of aromatase inhibitor (AI) versus tamoxi... Dowsett M et al. JCO 2010;28:509-518 2010 by American Society of Clinical Oncology

BIG 1-98 Overall Design S U R G E R Y Stratify Institution CT (Adjuvant/ Neoadjuvant) -Prior Pi -None -Concurrent R A N D O M I Z E R A N D O M I Z E A B A 2-Arm Option Tamoxifen Letrozole 4-Arm Option Tamoxifen B Letrozole C Tamoxifen Letrozole D Letrozole Tamoxifen N=911 N=917 N=1548 N=1546 N=1548 N=1540 N=1,828 Enrolled 1998-2000 N=6,182 Enrolled 1999-2003 N=8,010* *ITT: excludes 18 patients who withdrew consent and did not receive study treatment 0 2 5 YEARS Previous Analyses: Is 5 years Let superior to 5 years Tam as initial therapy? Primary Core Analysis (PCA), Median follow-up 26 months Monotherapy Arm Analysis, Median follow-up 51 months

Breast Cancer Events Tam Let vs. Let Overall By Nodal Status* *42% of the population is node positive; 58% node negative

Breast Cancer Events Let Tam vs. Let Overall By Nodal Status* *42% of the population is node positive; 58% node negative

Extended Adjuvant Therapy with AIs After ~5 Years Tamoxifen MA 17 (5000pts) 5 years 5 years Placebo Tamoxifen Letrozole NSABP-B33 (1598pts) 5 years Tamoxifen ABCSG-6a (856pts) 5 years Tamoxifen + AG 5 years Placebo Exemestane 3 years Placebo Anastrozole HR 4 Year DFS 058 0.58 46% 4.6% Goss et al. JNCI 2005. 0.44 p 0.004 Mamounas et al. JCO 2008 26; 1965. 0.64 p 0.05 Update of Jakesz et al. J Clin Oncol 2005;23(16S):10s.

Current Clinical Trials of AIs: Duration of AI Therapy MA.17R Tamoxifen Placebo (n=800) Letrozole* n=900 n=900 NSABP Any AI x 5 Placebo x 5 B42 Tam x 2 Any AI x 3 Letrozole x 5

Risk of recurrence at 5 years 38% experience recurrence with no adjuvant treatment (EBCTCG) 50% risk reduction with tamoxifen Further 20 30% risk reduction with AIs EBCTCG Lancet 2005;365:1687