William J. Gradishar MD

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1 Northwestern University Feinberg School of Medicine Adjuvant Endocrine Therapy For Postmenopausal Women SOBO 2013 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

Recurrence hazard rate The Long Tail of ER-Positive Breast Cancer 0.3 0.2 0.

3 Recurrence hazard rate The Long Tail of ER-Positive Breast Cancer Initial Peak ER/PgR+ (n=2257) ER/PgR (n=1305) Long Tail PgR = progesterone receptor. Saphner et al. J Clin Oncol. 1996;14:2738. Years

4 Recurrence hazard rate Risk of Breast Cancer Recurrence: Two Cell Populations )Proliferating Micromets (CT-sensitive) ER/PgR+ ER/PgR 2)Relapsing Dormant Cells PgR = progesterone receptor. Saphner et al. J Clin Oncol. 1996;14:2738. Years

5 FDA-Indications: Tamoxifen The most important drug worldwide for hormone receptor positive breast cancer Adjuvant postmenopausal node+ Postmenopausal metastatic Premenopausal metastatic Adjuvant node negative Male metastatic Prevention DCIS

6 TAMOXIFEN 2010 EBCTCG OVERVIEW TAMOXIFEN VS NOT 1 yr vs not 2 yr vs not 5 yr vs not EBCTCG OVERVIEW No of women LONGER VS SHORTER TAM 2 4 vs 1 2 y 5 vs 1-2 y 10 vs 5 y No of women Median follow-up = 15y 22% are ER- PR- Median follow-up = 5y 50% are ER?

7 2010 EBCTCG OVERVIEW 5y in ER+ disease TAMOXIFEN Reduces Recurrence by 38%, BC death by 30% All deaths by 22% Contralateral BC by 40% Benefits all women with ER+ disease Unclear benefits in ER-PgR+ disease Benefits women with ER very rich tumors more Increases endometrial cancer by 2.3 fold

8 2010 EBCTCG OVERVIEW Tamoxifen for 5y: Benefits in subgroups

9 2010 EBCTCG OVERVIEW Tamoxifen for 5y vs same management but no Tam

10 2010 EBCTCG OVERVIEW?

11 2010 EBCTCG OVERVIEW Tamoxifen for 5y : Benefit over time

12 5 years of tamoxifen versus no tamoxifen* RECURRENCE ER+ BREAST CANCER MORTALITY Recurrence Yrs 0-4 Yrs 5-9 Yrs 9-14 Reduction 47% 31% 4% p< p< p=0.7 BrCaMort. Yrs 0-4 Yrs 5-9 Yrs 9-14 Reduction 29% 33% 34% p< p< p< *EBCTCG, Lancet 2011; 378:

13 Optimal Duration of Tamoxifen

14 % of patients % of patients NSABP B-14: No Benefit of Extending Tamoxifen Beyond 5 Years DFS OS Placebo Tamoxifen P= % 78% Placebo Tamoxifen P= % 91% 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:

15 20,187 women with ER-positive or ERunknown disease randomised in 5 trials of 10 vs 5 years of tamoxifen: ECOG, Scottish & NSABP B-14 1,588 ATLAS* 11,646 attom 6,953 ALL TRIALS 20,187 *ATLAS, Lancet 2013; 381:

16 Number randomised/year Recruitment by ER status Year of randomisation

17 10 vs 5 years of tamoxifen: effect on breast cancer recurrence ASCO vs 456 recurrences RR=0.95 (95%CI ) p=ns

18 10 vs 5 years of tamoxifen: Recurrence by treatment ASCO vs 672 recurrences RR=0.85 (95%CI ) p=0.003 An additional 143 vs 216 recurrences since 2008

19 10 vs 5 years of tamoxifen: Recurrence by year of follow-up

20 10 vs 5 years of Tamoxifen: Breast Cancer Death by Treatment Allocation 404 vs 452 breast cancer deaths RR=0.88 (95%CI ; p=0.05) p=0.06

21 10 yrs vs 5 yrs BREAST CANCER MORTALITY IN ER+ rate ratio* by period in attom and ATLAS 10 yrs tam. vs 5: attom trial (n=6934 ER+/UK) 10 yrs tam. vs 5: ATLAS trial* (n=10,543 ER+/UK) 10 yrs tam. vs 5: attom & ATLAS combined (n=17,477 ER+/UK) years ( ) 0.92 ( ) 0.97 ( ) years ( ) 0.75 ( ) 0.75 ( ) All years 0.88 ( ) 0.83 ( ) 0.85 ( ) p=0.007 p=0.002 p= p=0.1 p=0.004 p=0.001 *Inverse variance weighted estimate of the effect in ER+.(ATLAS, Lancet 2013)

22 ER+ 10 yrs vs 5 yrs OVERALL SURVIVAL rate ratio* by period in attom and ATLAS 10 yrs tam. vs 5: attom & ATLAS combined (n=17477 ER+/UK) years ( ) years ( ) All years 0.91 ( ) p= p=0.008 *Inverse variance weighted estimate of the effect in ER+ (ATLAS, Lancet 2013)

23 [TITLE] Presented By Rebecca Alexandra Dent, MD at 2013 ASCO Annual Meeting

24 [TITLE]

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

26 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) % EM/EM, EM/IM EM/PM, IM/IM, PM/IM PM/PM P< Years after randomization Goetz et al., Updated NCCTG , SABCS 2008 HR 4.0 PM relative to EM (n=65) (n=16)

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

28 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)

29 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 N=6,182 Enrolled N=8, YEARS Monotherapy Population N=4,922 (2459 T; 2463 L) 76 Months Median Follow-Up

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

31 ASCO Guidelines

33 % of patients % of patients Significant risk of recurrence remains even with tamoxifen therapy Recurrences Breast cancer deaths 15% 17% 9% 18% Tamoxifen Control 20 Tamoxifen Control Years Years Adapted with permission. Early Breast Cancer Trialists Collaborative Group Meeting, 2000 Early Breast Cancer Trialists Collaborative Group. Lancet. 2005;365:

34 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 adjuvant trial Tamoxifen Aromatase inhibitor Aromatase inhibitor Tamoxifen Aromatase inhibitor Tamoxifen Aromatase inhibitor Tamoxifen Aromatase inhibitor Randomisation MA.17, ABCSG-6A, NSABP B-33 5 years prior tamoxifen 0 Time (years) 5 TEAM BIG 1-98 Aromatase inhibitor Placebo

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

36 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 JCO LET 0.82 (0.007) 0.91 (>0.05) ITA JCO AGT NR (0.6) NR (0.005) ITA IES 4742 Ann Oncol 2006 Lancet ANA 0.57 (0.005) 0.56 (0.1) 56 EXE 0.76 (0.0001) ARNO JCO ANA 0.66 (0.049) Sequencing ABCSG SABCS (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%

37 Recurrence Rate after Endocrine Therapy in ATAC Trial Cuzick J, et al. Lancet 11:1135, 2010

38 ER+ Breast Cancer: Different Risk Factors for Early and Late Recurrence? Early Recurrence High grade Low ER receptor expression PgR negative HER-2 positive High recurrence score Late Recurrence Low to intermediate grade High ER receptor expression PgR positive or PgR negative HER-2 negative (Low recurrence score) High Disease Burden -- Large Tumor -- Multiple Positive Nodes High Disease Burden -- Large Tumor -- Multiple Positive Nodes

39 Nodal status and tumor size both predictors of recurrence in years 0-5 and Sestak I et al. JNCI 2013; published online Sept 12.

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

41 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, quality of life Goss PE, et al. Cancer Res. 2010;70(24 Suppl): Abstract S

42 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 ( ).64 DDFS 157 (4.1) 164 (4.3) 0.95 ( ).46 DSS 89 (2.4) 98 (2.6) 0.93 ( ).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 S

43 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.

44 NCCN Version

45 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?

46 Do All ER+ Tumors Benefit Equally from Extended Adjuvant Therapy?

47 HR MA.17: Efficacy by ER and PgR Status Exploratory retrospective analysis of efficacy (DFS, distant DFS, OS) of letrozole vs placebo in MA.17 according to ER and PgR status* HR (95% Cl), letrozole vs placebo ( ) ( ) +ER+/PgR (n=3809/5187) 73% ER+/PgR (n=636/5187) 12% ( ) ( ) ( ) ( ) DFS DDFS OS *Receptor positivity defined as 10 fmol/mg protein, or a positive immunocytochemical assay; only 8 patients had ER /PgR status. Update of Goss et al. Breast Cancer Res Treat. 2005;94(suppl 1):S98. Abstract 2042.

48 BIG 1-98 Monotherapy Update Median Follow-up 76 months A B 2-Arm Option Tamoxifen Letrozole N=911 N=917 N=1,828 Enrolled Arm Option N=4,922 A B C Tamoxifen Letrozole Tamoxifen Letrozole N=1548 N=1546 N=3,094 Enrolled D Letrozole Tamoxifen YEARS

49 BIG 1-98 Monotherapy Update Median Follow-up 76 months *Let:Tam: breast cancer events, 321:363 second (non breast) malignancy, 101:115 deaths without prior cancer event, 87:87

50 Filho, et al. SABCS 2012

52 BIG 1-98 Letrozole vs Tamoxifen: OS Regan MM, Lancet Oncology, 2012

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

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

55 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?

56 [TITLE] Presented By Rebecca Alexandra Dent, MD at 2013 ASCO Annual Meeting

57 No Benefit If Not Taking The Drug!

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61 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

William J. Gradishar MD

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