Adjuvant endocrine therapy (essentials in ER positive early breast cancer)

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1 Adjuvant endocrine therapy (essentials in ER positive early breast cancer) Giuseppe Curigliano MD, PhD Breast Cancer Program Division of Experimental Therapeutics

2 Outline Picking optimal adjuvant endocrine therapy for premenopausal women Picking optimal adjuvant endocrine therapy for post-menopausal women Who benefits from endocrine therapy?

3 H&E ER PR Ki67 A. Ductal Grade 1 ER 100% PR 100% Ki67 7% B. Ductal Grade 2 ER 95% PR 60% Ki67 15% C. Ductal Grade 3 ER 70% PR <1% Ki67 30% D. Lobular Grade 1 ER 100% PR 100% Ki67 <5% E. Lobular Grade 2 ER 100% PR <1% Ecadherin neg * E-cadherin

4 Grade/ER and Prognostic factors Histologic Grade Low ( I of III) Intermediate (II of III) High (III of III) Biomarkers ER expression to to ++ Genetic / Genomic / multipanel markers PR expression ++ to to to ++ Proliferation (Ki-67 / S phase fraction) Low (<10%) Intermediate (10-20%) High (>20%) HER2 Overexpression Never Occasional Occasional 21-gene recurrence score Intrinsic subtype Low (< 18) Luminal A Intermediate (18-25) Luminal B Genomic Grade Lower Higher IHC4 Lower Higher risk MammaPrint Low High High ( >25) Tumor DNA ploidy Mostly diploid Mostly aneuploid

5 Adjuvant ET in ER+ EBC: premenopausal What is the role of ovarian function suppression (OFS) for women receiving tamoxifen? SOFT and E3193 What is the role of aromatase inhibitors (AI) for women treated with OFS? SOFT, TEXT and ABCSG 12 What is the role of chemotherapy in women receiving combined endocrine therapy? PERCHE

6 SOFT: SUPPRESSION of OVARIAN FUNCTION TRIAL 3047 Patients Randomized in ITT (Dec Jan 2011) Two Patient Cohorts No Chemotherapy (47%) Premenopausal, within 12 weeks of surgery (Median time since surgery = 1.8 months) Prior Chemotherapy (53%) Premenopausal* after completing chemotherapy; Randomization within 8 months of completion (Median time since surgery = 8.0 months) *According to locally-determined E 2 level in premenopausal range R A N D O M I Z E Median follow-up=5.6 y Tamoxifen x 5y Tamoxifen+OFS x 5y Exemestane+OFS x 5y Primary Analysis (n= 2033) OFS=ovarian function suppression (oophorectomy, triptorelin or XRT) (n=1018) (n=1015) (n=1014)

7 SOFT: SUPPRESSION of OVARIAN FUNCTION TRIAL 5.6 years median follow-up Primary analysis in overall population not significant (p=0.10) Multivariable Cox model HR=0.78 (95% CI ) p=0.03 > 95% overall survival Francis et al, N Engl J Med, 2015

8 SOFT: SUPPRESSION of OVARIAN FUNCTION TRIAL T+OFS v T: 19% relative reduction in recurrence, p=0.09 E+OFS v T: 36% relative reduction in recurrence with 5-yr BCFI >90% Francis et al, N Engl J Med, 2015

9 Enrolled: Nov03-Apr11 Premenopausal 12 wk after surgery Planned OFS ± Planned chemo Premenopausal 12 wk after surgery No chemo OR Remain premenopausal 8 mo after chemo TEXT and SOFT Joint Analysis R A N D O M I Z E R A N D O M I Z E TAMOXIFEN AND EXEMESTANE TRIAL (N=2672) Tamoxifen+OFS x 5y Exemestane+OFS x 5y SUPPRESSION OF OVARIAN FUNCTION TRIAL (N=3066) TEXT SOFT Tamoxifen x 5y Tamoxifen+OFS x 5y Exemestane+OFS x 5y Joint Analysis (N=4690) Tamoxifen+OFS x 5y Exemestane+OFS x 5y Median follow-up 5.7yr OFS=ovarian function suppression

10 TEXT and SOFT Joint Analysis Difference 3.8% at 5 years 5.7 years median follow-up Pagani et al, N Engl J Med, 2014

11 Accrual ABCSG 12 1,803 premenopausal breast cancer patients Endocrine-responsive (ER and/or PR positive) Stage I&II, <10 positive nodes Neoadjuvant chemo only Treatment duration: 3 years Surgery (+RT) Goserelin 3.6 mg q28d Median Gnant et follow-up=94 al NEJM 2009 mo Randomize 1 : 1 : 1: 1 Median age (yrs) 45 T1 tumor 75% N0 66% Grade 1/2 75% Preop chemo 5% Tamoxifen 20 mg/d Tamoxifen 20 mg/d + Zoledronic acid 4 mg q6m Anastrozole 1 mg/d Anastrozole 1 mg/d + Zoledronic acid 4 mg q6m Gnant et al, Ann Oncol, 2014

12 TAM ANA TAM ANA ABCSG 12 HR vs Tam 1.13 ( ) P=0.33 HR vs Tam 1.63 ( ) P=0.03 Importance of BMI? Gnant et al, Ann Oncol, 2014

13 Reconciling Results of SOFT, TEXT, ABCSG-12 Shared strengths Focus on premenopausal patients Limited to ER and/or PR-positive tumors Incorporated tamoxifen in some fashion Some limitations Different AIs exemestane vs anastrozole Different forms of OFS Different treatment duration 3 vs 5 yr Different patient characteristics Use and timing of chemotherapy Variable duration of follow-up

14 Adjuvant ET for premenopausal Not every premenopausal woman needs chemotherapy. Several evidence-based choices now available: Tamoxifen X 5-10 yr (ATLAS, attom) Tamoxifen X 5 yr to AI X 5 yr (MA-17) OFS + Tamoxifen (SOFT, E3193) OFS + AI (SOFT/TEXT) Tamoxifen alone X 5-10 yr sufficient for low risk women

15 Adjuvant ET for premenopausal Consider use of OFS+Tamoxifen or OFS+AI for higher risk women like: Chemotherapy recipients who remain premenopausal Multiple positive nodes Age < 35 yrs Optimal duration of OFS-based therapy uncertainsuggest 3-5 years Long term follow-up of pivotal trials for adherence, toxicity & benefit critical

16 Adjuvant ET for premenopausal Adequacy of OFS with LHRH agonists Role of oophorectomy vs OFS Use of bisphosphonates Role of obesity and other host factors Better predictive biomarkers

17 Endocrine therapy: Postmenopausal Years Since Diagnosis Trials Oxford Overview ATAC, BIG 1-98 TAM AI BIG 1-98 AI TAM IES, BIG 1-98, ITA, ARNO, ABCSG8, NSAS BC-03, TEAM TAM AI MA.17, NSAPB B-33, ABCSG 6a TAM AI ATLAS, ATTOM TAM TAM

18 Prognostic factors Type Factor Risk Early recurrence years 0-5 Stage Tumor size Larger > Smaller Histopathology Molecular Signatures Nodal status Positive > Negative Grade Higher > Lower Proliferation (Ki67) Higher > Lower ER / PgR expression Lower > Higher IHC4 Higher > Lower Recurrence score Higher > Lower Intrinsic subtype Luminal B > A ROR Higher > Lower BCI Higher > Lower EndoPredict Higher > Lower

19 Prognostic factors Type Factor Risk Early Late recurrence Recurrence years 0-5 years 5-10 Stage Tumor size Larger > Smaller Nodal status Positive > Negative Histo- Grade Higher > Lower pathology Proliferation (Ki67) Higher > Lower ER / PgR expression Lower > Higher IHC4 Higher > Lower Molecular Recurrence score Higher > Lower Signatures Intrinsic subtype Luminal B > A ROR Higher > Lower BCI Higher > Lower EndoPredict Higher > Lower

20 Risk Factors Associated with Early Recurrence in BIG 1-98 Risk Factor Measurement Hazard Ratio P value T Stage > 2 cm vs < 2 cm N Stage 4+ vs < vs < LVI + vs Grade 3 vs vs ER / PgR +/- vs +/ < Mauriac L, et al. Ann Oncol 2007;18: /+ vs +/ < 0.001

21 10-Year EFS % Risk Factors Associated with Grade Late Recurrence Stage 1 Stage 2 Stage 3

22 Risk Factors Associated with Late Recurrence RS Group N (%) of pts % distant recurrence 5 to 10 years Low 289 (58%) 4.7% 6.8% Intermediate 111 (22%) 4.1% 11.2% High 97 (20%) 12.6% 16.4% Wolmark N, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 11024) % distant recurrence 5 to 15 years

23 # of genes tested Genomic Tools CT yes or CT no Recurrence Score Oncotype Dx GENE70 MammaPrint Tissue used FFPE Fresh frozen/ffpe Sampling technique Samples used in development Genomic Grade Index MapQuant Dx Prosigna CE PAM50 ROR Breast Cancer Index (BCI SM ) qrt-pcr 447 N0/+ ER+/- HER2+ Tam +/- Chemo +/- DNA microarrays 78 N0 ER+/- HER2+ untreated Fresh frozen/ffpe FFPE FFPE qrt-pcr ncounter qrt-pcr 64 N0 ER+ HER2+? Tam +/- Subtypes: 514 N0/+; ER+/-; HER2+/- with mixed therapy ROR: 304 N0/+; ER+/-; HER2+/- tumor samples w/o adj. therapy 314 N0 ER+ HER2+ Tam treated

24 TransATAC: ROR Score Discriminates Recurrence Risk Within Nodal Subgroups Patients, % Node-Negative Patients Luminal A, nodes 0 Luminal B, nodes Follow-up Time, years Node-negative, luminal B patients had a higher risk of RFS events (HR = 4.8 [ ]) % Without Distant Recurrence Node-Positive Patients (1-3 nodes) Luminal A 1-3 node (132) Luminal A, 4+ nodes (31) Luminal B, 1-3 nodes(69) Luminal B, 4+ nodes (20) Follow-up Time, years Luminal B patients with 1 to 3 positive nodes had a higher risk of RFS events (HR = 2.0 [ ]) Dowsett, M. et al. J Clin Oncol. 2013;31(22): Similar results were seen in patients with 4+ positive nodes (HR = 3.4 [ ])

25 Probability of distant recurrence-free survival (%) ABCSG-8: PAM50 Analysis after 10 years FU Low Intermediate High 96.7% ( ) Follow-up time (years) Risk Group Patients (%) Number of Events through 10 years Estimated Percentage without Recurrence at 10 years (95%) 498 (34%) % ( ) 478 (32%) % ( ) 502 (34%) % ( ) Total 1,478 (100%) % ( ) 79.9% ( )

26 Risk and choice There are no predictive markers to guide choices about the type or duration of adjuvant endocrine therapy In the absence of predictive markers, most clinical recommendations are made by extrapolating results from large clinical experiments onto the assessment of risk based prognostic features In lower risk patients, treatment outcomes are more similar regardless of choices In higher risk patients, optimizing the type / duration may make more difference The patient s voice and history are critical and essential in these choices

27 Initial Choice: Years 0-5 Adjuvant endocrine therapy is essential AI-based therapy is preferred Caveats: Sequential outcomes essentially the same Differences in outcome are small, especially for lower risk patients Differences in patient experiences are marked and should affect clinical management

28 Later Choices: Years 5 and beyond Extended adjuvant endocrine therapy should be discussed with all women and encouraged for many Caveats: Is extended therapy a general principle or unique to patients with 5 years of tamoxifen? There are no data for use of AI beyond 5 years I do consider ongoing AI treatment for women at higher risk even in the absence of data For women with good prognosis tumors, in particular, the benefits of extended therapy may be quite modest Patients are uniquely positioned to tell you their preferences Knowing that they have a choice is quite empowering for patients

29 Decision process beyond 5 years Gauge approx LT risk based on stage / biology Assess symptoms Would you consider ongoing endocrine therapy for modest but real benefits and persistent side effects? Yes Maybe No Extended adjuvant therapy Continue therapy; reassess periodically based on symptoms and data Stop at 5 years

30 Clinical conversation Baseline 0.6 cm, N0, grade 1, ER+ / PR+ Low Risk Intermediate Risk High Risk 2.1 cm, N0, grade 2, ER+ PR lo Initial AI or tamoxifen AI or tam AI AI Extended Probably not Probably yes Yes 1.8 cm, 4+ LN, grade 2, ER+ PR+

31 A Phase III, Randomized Clinical Trial of Standard Adjuvant Endocrine Therapy +/- Chemotherapy in Patients with Positive Nodes, ER+ and HER2- Breast Cancer With Recurrence Score (RS) of 25 or Less. Opened 2011, Estimated Accrual = 4000

32 Evaluate Clinical-Pathological Risk and 70-Gene Signature Risk 55% 35% 10% N=3300 N=600 Clinical-pathological and 70-gene both HIGH risk Chemotherapy EORTC-BIG MINDACT TRIAL 6,600 Women with N0-3+ (Results expected 2014/15) N=2100 Discordant cases Clin-Path HIGH 70-gene LOW Use Clin-Path risk to decide Chemo or not Clin-Path LOW 70-gene HIGH R1 Clinical-pathological and 70-gene both LOW risk Use 70-gene risk to decide Chemo or not Albain, KS. St. Gallen 2013 Potential CT sparing in 20-28% pts Endocrine therapy

33 TAILORx Study Design ECOG/Inter-group PI: J. A. Sparano Secondary Study Group 1 RS < 11 ~29% of Population ARM A Hormonal Therapy Alone Albain, KS. St. Gallen 2013 ARM B 21 Gene RS Assay REGISTER Specimen Banking Primary Study Group RS ~44% of Population ER+/HER2-/Node- RANDOMIZE n = 4390 Stratified by: T, menopausal status, planned CT/RT Hormonal Therapy Alone ARM C Chemotherapy + Hormonal Therapy Accrual completed on Oct 25 th 2010 Target: 10,000 expected to report in Secondary Study Group 2 RS > 25 ~27% of Population ARM D Chemotherapy + Hormonal Therapy

34 Prospective Validation of a 21-Gene Expression Assay in Breast Cancer Sparano JA et al. N Engl J Med 2015;373:

35 Generally YES High grade High Ki67 Low ER and PR Bad Signature Luminal B or surrogate Early recurrence risk Consider CT Disease Burden Chemotherapy M A Y B E Consider: Preference Comorbidity Generally NO Low grado Low Ki67 High ER e PR Good signature Luminal A or surrogate Late recurrence risk Limited indication To CT

36 Treatment recommendations

37 Treatment options Clinical grouping Therapy Note ER positive & HER2-negative ( luminal disease ) Luminal A Like Endocrine therapy SOFT e TEXT according to menopausal status Premenopausal low risk Tamoxifen 5 years Premenopausal others Postmenopausal low risk Postmenopausal Luminal B-like Factors supporting omission of CT in luminal B like Tamoxifen 5 10 years with OFS or exemestane with OFS Tamoxifen 5 years AI (consider extended adjuvant therapy) Chemotherapy and ET SOFT e TEXT No evidence of AI beyond 5 years Good prognosis Gene signature

38 Thank you