(Neo)Adjuvant Endocrine Therapy · Financial disclosures: Personal financial interest in form of consultancy role for: Amgen, ... Overview 2011[76] TAM 5 y vs no TAM 10 645 ER+ 15

F. Cardoso, MDDirector, Breast Unit, Champalimaud Clinical Center, Lisbon, Portugal

ESMO Board of Directors & Director of MembershipChair, ABC Global Alliance and ABC Guidelines

ESO Breast Cancer Program Coordinator

(Neo)Adjuvant Endocrine Therapy

DISCLOSURES SLIDE

Financial disclosures: Personal financial interest in form of consultancy role for: Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Medscape, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, prIME Oncology, Roche, Sanofi, Seattle Genetics, Teva.

Institutional financial support for clinical trials from: Amgen, Astra-Zeneca, Boehringer-Ingelheim, Bristol-Myers-Squibb, Daiichi, Eisai, Fresenius GmbH, Genentech, GlaxoSmithKline, Ipsen, Incyte, Nektar Therapeutics, Nerviano, Novartis, Macrogenics, Medigene, MedImmune, Merck, Millenium, Pfizer, Pierre-Fabre, Roche, Sanofi-Aventis, Sonus, Tesaro, Tigris, Wilex, Wyeth.

Non-Financial disclosures: Chair ABC Global Alliance and ABC Consensus Conference and Guidelines. Member/Committee Member of ESMO, ESO, EORTC-BCG, IBCSG, SOLTI, ASCO, AACR, EACR, SIS, ASPIC

St. Gallen 2019Escalating and de-escalating treatment in Early Breast Cancer across subtypes

and treatment modalities

Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) (“Oxford Overview”)

ESMO Early Breast Cancer Guidelines 2019

EARLY BREAST CANCER: WHO NEEDS ADJUVANT ET?

(almost) All ER+ EARLY BREAST CANCER patients!

Until the early 90’s: decision was based on menopausal status:

All post-menopausal: YesAll pre-menopausal: No

EBCTCG, The Lancet 2011

• HR the only predictive factors

• Levels of positivity also important

PREDICTIVE MARKERS FOR ENDOCRINE THERAPY

▪ ER (Tam and AIs)

▪ PgR (Tam and AIs)

▪ HER-2

▪ PROLIFERATION (Ki67)

▪ Bcl-2 (Tam)

▪ AIB-1 (Tam)

▪ ER-beta (Tam)

▪ MTA1s (Tam)

▪ Cyclin E (Tam)

▪ Intratumoral Aromatase (AIs)

▪ Genomic signatures

▪ ESR1 mutations

• HR are the only predictive factors with Level 1 evidence for ET

• NO BIOMARKER CAN HELP DECIDE BETWEEN TAM & AI

✓Efficacy of 5 years Tam

WHICH TYPE OF ENDOCRINE THERAPY?

Messages from the EBCTCG overview & individual trials

Ribeiro, Sousa and Cardoso, ECCO-ESMO 2013 Educational Book

Study Treatment arms/ Population (n)

MedianFU

Recurrence Mortality

Tamoxifen 5 yearsOverview 2011[76]

TAM 5 y vs no TAM10 645 ER+

15 y RR 0.53 [SE 0.03] years 0–4

RR 0.68 [SE 0·06] years 5–9

2p<0·00001RR 0.97 [SE 0.10] years

10–14

RR 0.71 [SE 0.05] years 0–4,

RR 0.66 [SE 0.05] years 5–9

RR 0.68 [SE 0.08] years 10–14

p<0·0001

CARRY-OVER EFFECT

9% ABSOLUTE BENEFIT

MCBS: A

Time to recurrence: smoothed hazard estimates

HR+ patients

Annual

hazard

rates

(%)

4.0

3.0

2.0

1.0

0.0

4.0

3.0

2.0

1.0

0.0

0 1 2 3 4 5 6 7 8 9

Follow-up time (years)

Tamoxifen (T)

Anastrozole (A)

▪ In the HR+ subgroup, the absolute difference in recurrence

increased from 2.8% after 5 years to 4.8% after 9 years

▪ There is a statistically significant larger carryover effect for

anastrozole (HR=0.75, 95% CI 0.61-0.94, p=0.01)

✓Efficacy of Aromatase Inhibitors: Upfront

WHICH TYPE OF ENDOCRINE THERAPY?Messages from the EBCTCG overview & individual trials

Study Treatment arms/Population (n)

MedianFU


AIs 5 years ATAC TAM 5y vs ANA 5y

3116/ 3125120 months

HR= 0·91 (95% CI 0·83-0·99)p = 0·04

0.97 (95% CI 0.88–1.08)

p = 0·6BIG 1.98 TAM 5y vs LET 5y

2459/ 246376 months

HR=0·88 (95% CI 0·78–0·99)p = 0.03

HR 0.87 (95% CI 0.75-1.02)p = 0.08

TEAM EXE 5y vs TAM 2-3y followed EXE 2-3y4868/4898

5.1 y HR=0·97 (0·88–1·08)p=0·60

HR=1.00 (0·89–1·14)p>0.9

Meta-analysis

Cohort 1

AIs initial monotherapy vs TAM

9,856

5.8 y 9.6% AI v 12.6% TAM

2.9% absolute decrease (SE 0.7%)

2P <.00001

4.8% AI v 5.9% TAM

1.1% (SE =0.5%) absolute decrease

2P =0 .1MA.27 EXE 5y vs ANA 5y

7,5764.1y HR=1.02 ( 95% CI, 0.87 to

1.18)

P =0 .85

HR=0.93 ( 95% CI,0.77 -1.13)

P= 0 .46


✓Efficacy of Tam & Aromatase Inhibitors in Sequence


MedianFU


AIs and Tamoxifen in switching strategiesBIG 1.98 LET 5 y

TAM 2 y followed by LET 3 y

LET 2 y followed by TAM 3 y

1546/ 1548/ 1540

71 months

HR=1·05 (95% CI 0·84–1·32)HR=0·96 (95% CI 0·76–1·21)

HR=1.13 (95% CI 0·83–1·53)HR=0.90 (95% CI 0·65–1·24)

ABCSG-8/ARNO 95

TAM 5y vs Tam f 2y followed by ANA

for 3 years

28 months

HR=0·60 (0·44–0·81)p=0·0009

p=0·16

ITA TAM 5y vs Tam f 2y followed by ANA

128 months

HR=0·64 (0·44–0·94)p = 0.023

HR=0.72 (0·44–1.17)p = 0.3

IES TAM 5y vs Tam f 2-3y followed by EXE 2-3y

55·7 months

HR=0·76 (95% CI 0.66–0·88)p=0·0001

HR 0.·85 (95% CI 0·71–1·02)p=0·08

Meta-analysis

Cohort 2AIs T after 2-3 y of TAM vsTAM9,015

3.9y 5.0% AI v 8.1% TAM


2P <.00001

1.7% AI v 2.4% TAM


2P =0 .2


AROMATASE INHIBITORS vs. TAMOXIFEN in EBC: EBCCTG data

✓Efficacy of Aromatase Inhibitors: Upfront

Study Treatment arms/Population (n)

MedianFU


AIs 5 years ATAC TAM 5y vs ANA 5y

3116/ 3125120 months

HR= 0·91 (95% CI 0·83-0·99)p = 0·04

0.97 (95% CI 0.88–1.08)

p = 0·6BIG 1.98 TAM 5y vs LET 5y

2459/ 246376 months

HR=0·88 (95% CI 0·78–0·99)p = 0.03

HR 0.87 (95% CI 0.75-1.02)p = 0.08

TEAM EXE 5y vs TAM 2-3y followed EXE 2-3y4868/4898

5.1 y HR=0·97 (0·88–1·08)p=0·60

HR=1.00 (0·89–1·14)p>0.9

Meta-analysis

Cohort 1

AIs initial monotherapy vs TAM

9,856

5.8 y 9.6% AI v 12.6% TAM


2P <.00001

4.8% AI v 5.9% TAM


2P =0 .1MA.27 EXE 5y vs ANA 5y

7,5764.1y HR=1.02 ( 95% CI, 0.87 to

1.18)

P =0 .85

HR=0.93 ( 95% CI,0.77 -1.13)

P= 0 .46


✓Efficacy of Tam & Aromatase Inhibitors in Sequence


MedianFU


AIs and Tamoxifen in switching strategiesBIG 1.98 LET 5 y

TAM 2 y followed by LET 3 y

LET 2 y followed by TAM 3 y

1546/ 1548/ 1540

71 months

HR=1·05 (95% CI 0·84–1·32)HR=0·96 (95% CI 0·76–1·21)

HR=1.13 (95% CI 0·83–1·53)HR=0.90 (95% CI 0·65–1·24)

ABCSG-8/ARNO 95

TAM 5y vs Tam f 2y followed by ANA

for 3 years

28 months

HR=0·60 (0·44–0·81)p=0·0009

p=0·16

ITA TAM 5y vs Tam f 2y followed by ANA

128 months

HR=0·64 (0·44–0·94)p = 0.023

HR=0.72 (0·44–1.17)p = 0.3

IES TAM 5y vs Tam f 2-3y followed by EXE 2-3y

55·7 months

HR=0·76 (95% CI 0.66–0·88)p=0·0001

HR 0.·85 (95% CI 0·71–1·02)p=0·08

Meta-analysis

Cohort 2AIs T after 2-3 y of TAM vsTAM9,015

3.9y 5.0% AI v 8.1% TAM


2P <.00001

1.7% AI v 2.4% TAM


2P =0 .2


MAJOR ADVANTAGE:• Side effects profiles are different; major serious side effects are after long-

term use• Different patients have different tolerability to each of these class of agents• For such a long duration of therapy (5 to 10 years), having 2 family of

agents is a major advantage

Estimated bone loss with AI’s

Comparing different strategies

Arthralgia Endometrial polyp

Co-Morbidity & Side effects

MBC UZ Leuven Abstr. 4056, Neuven et al

Surprisingly: Tam was worse than AI

Also seen in the TEAM study

ADJUVANT ENDOCRINE THERAPY WITH AN A.I. :COMPLIANCE AND COST ISSUES

Treatment with an AI will often necessitate:

✓ Earlier initiation of lipid-lowering drugs, antihypertensivesand aspirin to reduce cardiac and cerebrovascular events

✓ Earlier initiation of medication for osteopenia/osteoporosis

✓The use of pain medication, such as anti-inflammatory for myalgia / arthralgia

Courtesy of M. Trudeau

✓Routine follow-up of lipids

✓Monitoring of blood pressure

✓Routine assessment of bone mineral density & frequently preventive therapy

Fulvestrant IM 500mg on day 0, 250mg day 14 and 28 and

250mg every 28 days thereafter for the first 3 years

+ Anastrozole PO 1mg/day for 5 years

Stratification factors:

• No. of lymph nodes (0 vs.

1-3 vs. >4)

• (Neo)Adjuvant

chemotherapy (yes vs. no)

• HR status (both positive vs.

only one positive)

• Site

HR+/HER2- postmenopausal patients with early breast cancer that have undergone

surgery with or without neo/adjuvant chemotherapy

RAnastrozole PO 1 mg daily for 5 years

1:1

GEICAM 2006-10 TRIAL

Courtesy of M. Ruiz-Borrego et al

Primary endpoint: DFSSecondary endpoints: BCSS, OS, Safety, Time to recurrence

872 pts

Disease Free Survival

Anastrozole

n = 437

Anastrozole + Fulvestrant

n = 433

Total

n = 870

Total number at risk 434 417 851

Events 62 49 111

Censored n (%) 372 (85.7) 368 (88.2) 740 (87.0)

HR: 0.839 (0.576-1.220)

Arm Event Total

Anastrozole 62 434

Anastrozole + Fulvestrant 49 417


BC Specific Survival

Anastrozole

n = 437


n = 433

Total

n = 870


Events 47 39 86

Censored n (%) 387 (89.2) 378 (90.6) 765 (89.9)

HR: 0.884 (0.578-1.352)

Arm Event Total

Anastrozole 47 434



Overall Survival

Anastrozole

n = 437


n = 433

Total

n = 870


Events 34 28 62

Censored n (%) 400 (92.2) 389 (93.3) 789 (92.7)

HR: 0.863 (0.523-1.424)

Arm Event Total

Anastrozole 34 434



GEICAM 2006-10 TRIAL

WHICH DURATION OF ENDOCRINE THERAPY?

Recurrences Breast cancer deaths

EBCTCG, Lancet. 2005

Years

85.2

73.7

0

20

40

60

80

100

0 5 10 15

Tamoxifen

Control

15% 17%

0

20

40

60

80

100

0 5 10 15

87.8

Years

Tamoxifen

Control

9% 18%

91.4

% o

f p

ati

en

ts

% o

f p

ati

en

ts

54.9

68.2 73.0

64.0

More than Half of all Breast Cancer Recurrences

and Deaths Occur Post- 5y Tamoxifen

Annual Risk of Recurrence by ER Status

Saphner T et al., J Clin Oncol 1996

Hormone receptor positivity is a strong predictor for late recurrence !

• Over half of breast cancer recurrences occur >5 years post-surgery!

• The annual risk of late recurrence is particularly high in ER+ tumors (5.2%

between years 5 and 8, 4.6% between years 8 and 12).

Years

0

0.1

0.2

0.3

0 1 2 3 4 5 6 7 8 9 10 11 12

Recu

rren

ce

ha

zard

rate

ER– (n = 1305)

ER+ (n = 2257)

N Engl J Med 2017;377:1836-46

Data from about 70,000 women with ER+ T1/T2, with 5 years of adjuvant ET

N Engl J Med 2017;377:1836-46

Courtesy M. Gnant, SABCS 2016

Meta-analysis on Five or More Years of

Adjuvant Tamoxifen: Safety Profile

Al-Mubarak M et al.,PLOS One 2014

Extended adjuvant Tamoxifen:

• Higher incidence of hot flushes, vaginal discharge and fluid retention.

• Higher incidence of thromboembolic events.

• Significant increase in endometrial carcinoma (OR 2.06, p< 0.001) ,

absolute risk increase from 1.1 to 2.2%; without significant influence on

death from endometrial cancer.

• Non- significant reduction in death from cardiovascular diseases (OR

0.89, p=0.25), absolute reduction from 3.2 to 2.8%;

• No association between extended Tamoxifen and other (non-

endometrial) second cancers.

EBCTCG “summary” 10 years Tam vs 5 years(at the current FU):

Relative benefit: 15%Absolute benefit: 3%

Increase in mortality: 0.4%

All patientsPremenopausal

(n=889)

Postmenopausal

(n=4,277)

HR= 0.57;

p ≤ 0.001

Absolute benefit 10.1%

HR = 0.25

p<0.0001

Absolute benefit 3.3%

HR = 0.69

p = 0.0008

Goss PE et al. SABCS 2009; Goss PE et al., Ann Oncol 2013

• Premenopausal (n=889)

▪ < 50 years of age with menses, but underwent subsequent bilateral oophorectomy

or became amenorrhoic during adjuvant Cht or Tam.

• Postmenopausal (n=4,277)

MA.17: DFS by Menopausal Status

Women who had been premenopausal at diagnosis experienced significantly

greater benefit of extended letrozole in terms of DFS; significant interaction

between treatment and menopausal status (p = 0.03).

NSABP B-42: Schema

Letrozole X 5 yrs Placebo X 5 yrs

• Postmenopausal Pts with ER+ or PR+ Breast Cancer

• Stage I, II, or IIIa invasive BC at diagnosis

• Disease-free After 5 Years of Endocrine Therapy

Stratification:

Pathological nodal status (Negative, Positive)

Prior adjuvant TAM (Yes, No)

Lowest BMD T score: spine, hip, femur (>-2.0, ≤ -2.0 SD)

AI X 5 yrs or

R

San Antonio Breast Cancer Symposium - December 6-10, 2016

This presentation is the intellectual property of the author/presenter. Contact them at [email protected] for permission

to reprint and/or distribute.

→ AI to Complete 5 yrsTAM X < 3 yrs

mailto:[email protected]

San Antonio Breast Cancer Symposium,

December 6-10, 2016

NSABP B-42: Overall Survival


This presentation is the intellectual property of the author/presenter. Contact them at

[email protected] for permission to reprint and/or distribute

Letrozole

Placebo

100

80

60

40

20

0

0 2 4 6 8 Years After Randomization

Dis

ease

-Fre

e S

urv

iva

l

Letrozole

Placebo

100

80

60

40

20

0

0 2 4 6 7 8 Years After Randomization

Letrozole 1959 1902 1781 1499 287

Placebo 1964 1902 1791 1528 291

Overa

ll S

urv

ival

92.3%

91.8%

HR=1.15 (0.92-1.44) P=0.22

# Deaths

164

146

San Antonio Breast Cancer Symposium,

December 6-10, 2016

NSABP B-42:Cum. Inc. of Arterial Thrombotic Events

Cu

m.

Inc.

of

Art

eri

al

Th

rom

bo

tic E

ven

ts12

10

8

6

4

2

00 2 4 6 7 8

4.0%

HR=1.21 (0.85-1.70) P=0.29

3.4 %

Letrozole

Placebo

Years After Randomization




# Events

71

59

Non-proportionality of

Hazards for AT: p=0.007

HR=0.55

p=0.054

HR=1.85

P=0.007

NSABP B-42:Cumulative Incidence of Osteoporotic Fx




Letrozole

Placebo

Cu

mu

lati

ve I

ncid

en

ce o

f

Oste

op

oro

tic F

x

12

10

8

6

4

2

0

0 2 4 6 7 8

5.4% HR=1.19 (0.88-1.60) P=0.27

Years After Randomization

4.8 %

# Events

91

78

MA.17R Trial Schema and Design <br />AI x 5 yrs - Following Prior 5 years of AI - preceded or not by Tamoxifen

Presented By Paul Goss at 2016 ASCO Annual Meeting

Slide 11

Presented By Paul Goss at 2016 ASCO Annual Meeting

EARLY BREAST CANCER: WHO NEEDS EXTENDED ADJUVANT ET?

All ER+ EARLY BREAST CANCER patients with sufficient high risk??!

•No proven biomarker•Role of some genomic signatures for determination

of late relapses risk?!PAM 50 (Prosigna Breast Cancer Assay)

Breast Cancer Index (BCI)

Endopredict /Endopredict Clin

http://www.google.si/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&docid=AKmttIuFIH4H5M&tbnid=eOix2DD6xX09tM:&ved=0CAUQjRw&url=http://prosigna.com/x-us/data-summary-analytical-validation/combined-analysis/&ei=bsg5U9TxEYbXtAbvuIDICw&psig=AFQjCNGYynwx9M2F8n33t6y6BMSGESI3GA&ust=1396382093695575

http://www.google.si/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&docid=CTVdAysKzyyxEM&tbnid=rAbV6GxnYQR1jM:&ved=0CAUQjRw&url=http://www.researchtopractice.com/5MJCSABCS2013/3/3&ei=fMc5U_DxE4bIsgbu54GoCw&bvm=bv.63808443,d.bGQ&psig=AFQjCNEpJCQ_RjhFBy4u0pWj6f02guIVZQ&ust=1396381928101066

http://www.google.si/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&docid=Vb1za6oNcL_9ZM&tbnid=uMXhcK_jAeb2sM:&ved=0CAUQjRw&url=http://www.endopredict.com/news/press-photos.html?L=2&ei=tcY5U4axPIGbtQbVn4CQCA&bvm=bv.63808443,d.bGQ&psig=AFQjCNHSG-OPAzkUg8wS7DMCVP5Ri6bWeQ&ust=1396381689571348

Trans-aTTom: Breast Cancer Index predicts benefit of extended endocrine therapy in HR+ breast cancers treated in the Adjuvant Tamoxifen – To Offer More? (aTTom) trialJ. Bartlett, D. Sgroi, K. Treuner, Y. Zhang, T. Piper, R. Salunga, I. Ahmed, K. Basnet, E. Brachtel, S. Pirrie, C.A. Schnabel, and D. Rea on behalf of the Trans-aTTom Study Group

Abstract 505

1John Bartlett, PhD <[email protected]>

• BCI is an 11-gene expression molecular signature comprised of two functional panels

• Molecular Grade Index (MGI) - 5 genes measuring tumor proliferative status

• HOXB13 and IL17BR (H/I) – 2 gene ratio measuring estrogen signaling

• The BCI test provides both a prognostic BCI score for the risk of cumulative (0-10 years) and late (post-5 years) distant recurrence, and a prediction of the likelihood of EET benefit based on BCI (H/I)

Bartlett et al, ASCO 2019

aTTom Parent Study

• 6956 early stage patients who completed at least 4 years of tamoxifen randomized to either stop or continue tamoxifen for an additional 5 years

• Demonstrated benefit from 10 years tamoxifen in disease-free interval (DFI) at a median 8.9 years of follow-up

• HR: 0.86, 95% CI 0.77-0.96, (p=0.006 )

• Extended tamoxifen treatment was associated with a significant increase in endometrial cancer (p<0.0001)

• Data available to 12.6 years median follow-up (2017)

Gray R et al. J Clin Oncol 2013; 31: (suppl; abstr 5). (78% ≥ 55 years old, 50% T1, 38% T2, 31% node-positive)

8863 enrolled

7324 randomized after 4+ years of

tamoxifen

1539 <4 years prior tamoxifen

87 DCIS/LCIS

95 ER-negative

3656 CONTINUE 3668 STOP

84 DCIS/LCIS

102 ER-negative

3470 CONTINUE 3486 STOP

N=6956

John Bartlett, PhD <[email protected]>5

Centralized testing of HR status• Blinded to clinical outcome• ER, PR, HER2

Trans-aTTom▪Planned ~2500 cases▪N0 and N+

▪Confirmed HR+▪HER2- or HER2+

Final Analysis

▪ Planned analysis N = ~1800 HR+▪ Final p value stopping boundary: 0.0336

Interim Analysis

Trans-aTTom Study Design

BCI testing• Blinded to clinical outcome

▪ Planned analysis N~1200 HR+ ▪ Prespecified p value stopping boundary: 0.0334

6John Bartlett, PhD <[email protected]>

aTTom trial

6956 patients12,6 years FU

Trans-aTTom

1800 patients583 N+

12,6 years FU


Hazard Ratio (mean 95% CI)

Relative Benefit

0.0 0.5 1.0 1.5 2.0 2.5 3.0

0.88 (0.65 - 1.18)

1.07 (0.69 - 1.65)

0.35 (0.15 - 0.86)

All N+ Patients

BCI (H/I)-Low

BCI (H/I)-High

Favors 10-year Favors 5-year

Relative Benefit of Extended Tamoxifen by BCI (H/I) Status: Trans-aTTom N+ cases

11

N=583

N=296 (51%)

N=287 (49%)

John Bartlett, PhD <[email protected]>

Absolute Benefit of Extended Tamoxifen by BCI (H/I) Status

13

R

ed

ucti

on

in

Ris

k o

f R

ecu

rren

ce

0%

5%

10

%1

5%

All N+

Patients

BCI (H/I)

-Low

BCI (H/I)

-High

4.7%

-0.2%

10.2%

p=0.388

p=0.768

p=0.027

John Bartlett, PhD <[email protected]>


R

A

N

D

O

M

I

Z

E

Intermittent letrozole over 5 yrs

0 6 12 18 24 3630 42 48 54 60

Continuous letrozole x 5 yrs

9 mos.9 mos.9 mos.9 mos. 12 mos.

4884 Patients Randomized in ITT, Nov 2007 - July 2012

Stratify

Institution

Prior ET:

SERM

AI

Both

SOLE TRIAL: Study of letrozole extension after 4 to 6 years of prior adjuvant endocrine therapy postmenopausal, HR+, N+

De-escalating

Presented ASCO, 2017Courtesy M. Colleoni

SOLE PRIMARY ENDPOINT: DFS

60 mos. median follow-up


SOLE QUALITY OF LIFE: CHANGE FROM BASELINE TO 12 AND 24 MONTHS


ROLE OF OFS & AI IN PREMENOPAUSAL WOMENTEXT & SOFT Trials

Francis et al, N Engl J Med, 2015

TEXT and SOFT Trials: Comparison of Tamoxifen or Exemestane With OFS

Tamoxifen 20 mg/day+ OFS* (n = 1328)

PremenopausalPatients with HR+ BC≤ 12 wks after surgery

(N = 2672)

Stratified by trial, use of chemotherapy, nodal status

*OFS▪ TEXT: triptorelin 3.75 mg IM every

28 days for 6 mos, then optional bilateral oophorectomy or irradiation

▪ SOFT: choice of method

TEXT

Exemestane 25 mg/day+ OFS* (n = 1014)

Tamoxifen 20 mg/day

Premenopausalpatients with HR+ BC≤ 12 wks after surgery

(if no chemo) or≤ 8 mos after chemo

(N = 3066)

SOFT

Tamoxifen + OFS*(n = 2344)


Exemestane + OFS*(n = 2346)


Joint Analysis

5 yrs

Pagani O, et al. ASCO 2014. Abstract LBA1.

Pagani et al, N Engl J Med, 2014

This presentation is the intellectual property of the presenter. Contact [email protected] for permission to reprint and/or distribute.

San Antonio Breast Cancer Symposium, December 9-13, 2014

Hazard Ratio of Relapse

0.5 1 1.5 2

ER+, 35+

ER-, 35+

ER+, <35

ER-, <35


0.5 1 1.5 2

ER+, 35+

ER-, 35+

ER+, <35

ER-, <35

Outcomes from Premenopausal Adjuvant Chemotherapy Trials with no Hormonal Rx

Goldhirsch A et al. JNCI Monogr 2001;30:44-51


0.5 1 1.5 2

ER+, 35+

ER-, 35+

ER+, <35

ER-, <35


0.5 1 1.5 2

ER+, 35+

ER-, 35+

ER+, <35

ER-, <35

• About 12% LESS RECURRENCES in PTS NOT TREATED WITH CT

• Not selected for ER!

EBCTCG Ovarian Suppression/AblationOFS/OFA Meta-analysis EBCTCG 2006

CT DECISION WITH PHYSICIAN


2017 SAN ANTONIO BREAST CANCER SYMPOSIUM December 5-9, 2017

INTERNATIONAL BREAST CANCER STUDY GROUP This presentation is the intellectual property of IBCSG. Contact [email protected] for permission to reprint and/or distribute.

SOFT DFS8 years median follow-up

T+OFS significantly improves DFS vs T-alone in the overall population

Francis et al, N Engl J Med, 2015Updated at SABCS 2017. Fleming et al



SOFT Secondary EndpointsDistant Recurrence-Free Interval Overall Survival

A small overall survival benefit is seen with T+OFS vs T, at 8 yrs median follow-up




SOFT Secondary Endpoints: No Chemo

No Chemo cohort remains at low risk of distant recurrence with T alone;

12 of 24 deaths were in setting of no distant recurrence

Distant Recurrence-Free Interval Overall Survival




Prior Chemo cohort has small absolute OS improvements in OFS arms at 8 yrs

SOFT Secondary Endpoints: Prior Chemo

Distant Recurrence-Free Interval Overall Survival




Protocol and Non-protocol Therapy

T T + OFS E + OFS

Stopped assigned oral endocrine

therapy early22.5% 18.5% 27.8%

Stopped triptorelin early* 21.4% 19.6%

Received OFS (in first 5 yrs) 15.5%

Used oral endocrine therapy at ≥6 yr** 24.7% 24.3% 12.6%

*and did not undergo oophorectomy or ovarian irradiation

**as adjuvant therapy; denominator is patients alive and in follow-up at 6 yrs


Compliance is a major issue

Absolute improvement at 5 years – HR (95% CI)

T+OFS vs T E + OFS vs T

BCFI 11,2% 15,7%

94% received CT

N=350


SOFT Trial: CONCLUSIONSSTRENGTHS:

1) LARGE, PROSPECTIVE, RANDOMIZED TRIAL

2) PRAGMATIC APPROACH TO USE OF CT

3) PROVIDES EVIDENCE THAT IN SOME PATIENTS WITH BETTER PROGNOSIS TAMOXIFEN ALONE IS A VERY GOOD TREATMENT

4) GIVES SUPPORT TO USE OF OFS IF NO AMENORRHEA IS OBTAINED WITH CT

5) HELPS DEFINING THE ROLE OF AIs IN PREMENOPAUSAL PATIENS, TOGETHER WITH THE TEXT TRIAL

OPEN QUESTIONS:

1) PATIENTS RECEIVING CT (higher risk) WITH AMENORRHEA

2) PATIENTS RECOVERING MENSES AFTER 8 MONTHS

3) <35 years AND no need for CT

4) OPTIMAL DURATION OF OFS: are 5 years really necessary ?

Combined analysis TEXT and SOFT Trials:Comparison of Tamoxifen or Exemestane With OFS


PremenopausalPatients with HR+ BC≤ 12 wks after surgery

(N = 2672)

Stratified by trial, use of chemotherapy, nodal status

*OFS▪ TEXT: triptorelin 3.75 mg IM every

28 days for 6 mos, then optional bilateral oophorectomy or irradiation

▪ SOFT: choice of method

TEXT


Tamoxifen 20 mg/day

Premenopausalpatients with HR+ BC≤ 12 wks after surgery

(if no chemo) or≤ 8 mos after chemo

(N = 3066)

SOFT

Tamoxifen + OFS*(n = 2344)


Exemestane + OFS*(n = 2346)


Joint Analysis

5 yrs


December 5-9, 2017

This presentation is the intellectual property of the IBCSG. Contact [email protected] for permission to reprint and/or distribute.

2017 SAN ANTONIO BREAST CANCER SYMPOSIUM


4.0% absolute improvement in 8-yr DFS for E+OFS after 9 years median follow-up

Exemestane With Ovarian Function

Suppression Improves DFS


Updated analysis: P. Francis and O. Pagani, SABCS 2017

December 5-9, 2017




Overall Survival

E+OFS did not improve Overall Survival vs T+OFS, after 9 years median follow-up



December 5-9, 2017




Adverse Events and Treatment Adherence

• Incidence of grade 3-4 targeted AEs was similar in the two groups

(32% and 31%)

• Overall, 15% of patients stopped all protocol-assigned treatment early

More patients on E+OFS stopped assigned oral ET early

• 14% vs 6% by 1 year

• 25% vs 19% by 4 years

No difference in the rate of triptorelin cessation

• 18% vs 19% by 4 years



Compliance is a major issue

NEOADJUVANT ENDOCRINE THERAPY

Endocrine Therapy Neoadjuvant Clinical Trials (AI vs. Tam)

Drug NClinical

Response

US

Response Increase BCS

P0241

4 months

Letrozole

Tamoxifen

154

170

55%

36%

35%

25%

45%

35%

IMPACT2

3 months

Anastrozole

Tamoxifen

Both

113

108

109

37%

36%

39%

24%

20%

28%

46%

22%

26%

PROACT3

3 months

Anastrozole

Tamoxifen

228

223

50%

46%

40%

35%

38%

30%

P = .022

P = .03

ns

1. Ellis M, et al. Breast Cancer Res Treat. 2007;105(Suppl 1):33-43. 2. Smith IE, et al. J Clin Oncol. 2005;23(22):5108-

5116. 3. Cataliotti L, et al. Cancer. 2006;106(10):2095-2103.

Neoadjuvant Endocrine Therapy (AI vs. AI): ACOSOG Z1031 Trial

ML, marginal for lumpectomy; MO, mastectomy only at baseline

Ellis M, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-2.

CR

CR CR

PR

PR PR ML

ML ML

MO MO MO

Clinical Response, % Breast Conservation, %

³Exemestane

“Conclusion: Over half of patients become BCS-eligible within 4 months of preoperative letrozole

treatment. While prolonged treatment for up to 8 months can result in further tumor volume

reduction in some patients, there is no clear optimum for treatment duration”1

Duration of Neoadjuvant Endocrine Therapy

²Duration letrozole % CR

3 months 9.5

6 months 29

12 months 36

1. Paepke S, et al. BMC Cancer. 2008;8:62. 2. Renshaw L, et al. Breast Cancer Res Treat. 2004;88(Suppl 1): Abstract

204. 3. Barnadas A, et al. Br J Cancer. 2009;100(3):442-449

¹

Response to treatment as evaluated by mammography.OR, objective response; PD, progressive disease; SD, stable disease.

NEO-ADJUVANT ENDOCRINE THERAPY

Is neoadjuvant endocrine therapy without cytotoxics a reasonable option for postmenopausal patients with endocrine responsive disease? YES 87.9%

If yes, for which duration?

1. 1 – 2 weeks “window” prior to surgery 71%

2. 3 – 4 months 3.6%

3. 4 – 8 months 42.9%

4. Until maximal response 42.9%

9. Abstain 3.6%

Ki67 Changes With Endocrine Neoadjuvant Can Surrogate for Results in Adjuvant?

Drug

Comparison

Neoadjuvant

Trial

Ki67 Results Adjuvant

Trial

Efficacy

Results

Let vs Tam P024

(n = 185)

Mean Ki67 @ 4 mos

RFS L > T

BIG 1-98

(n = 8010)

L > T

Ana vs Tam vs

Tam+Ana

IMPACT

(n = 259)

Mean Ki67 @ 2/12

weeks: RFS A>T or AT

ATAC

(n = 9366)

A > T or

A+T

Ana vs Let vs

Exe

ACOSOG

Z1031

(n = 266)

Mean Ki67 @12-16

weeks. No Diff

MA 27 (n =

7576)

A = E

POTENTIAL PREDICTIVE ROLE OF CHANGE IN Ki67 AFTER NEOADJUVANT ET

PREOPERATIVE ENDOCRINE PROGNOSTIC INDEX (PEPI)

Ellis et al, JNCI 2008

May help decision of adjuvant therapy:

PEPI Group 1 (0): No adjuvant CT needed

PEPI Group 3 (≥4): Adjuvant CT needed

PEPI Group 2 (1-3): unknown

Model built on only 158 pts P024 study

Validated in 203 pts IMPACT study

SOME LUMINAL A TUMORS BECAME LUMINAL B

AFTER NEOADJUVANT AI

Arm IS

U

R

G

E

R

Y

F

O

L

L

O

W

SURGERY

Arm II

Cycle 1 day 2 optional biopsy

(if receiving paclitaxel)

Neoadjuvant Chemotherapy GroupChemotherapy of physician choice

or weekly paclitaxel x 12

R

A

N

D

O

M

I

Z

E

Arm IA x 4.5 yrs

Arm IIF x 1.5 yrs then A x 3 yrs

FOLLOW

AFTER SURGERYTherapy of Physician Choice

Arm III

B

I

O

P

S

YArm III

(A+F) x 1.5 yrs then Ax3 yrs

Modified

PEPI 0Chemo NOT

recommended

Modified

PEPI > 0Chemo

recommended

Endocrine therapy of

Physician’s Choice

F

O

L

L

O

W

Arm I

Arm II

Arm III

Ki67

<10%

Ki67>10%

4w

12 w

B

I

O

P

S

Y

6 cycles (each cycle is 4 weeks)

BEFORE SURGERY AFTER SURGERY

Arm I: Anastrozole (A)

Arm II: Fulvestrant (F)

Arm III: Anastrozole + Fulvestrant

Red: required tissue collection

Blue: optional tissue collection

ALTERNATE Schema (A011106)

R

E

G

I

S

T

R

A

T

I

O

N

Eligibility

Post-menopausal

Clinical Stage II or III

ER+ (Allred 6-8) HER2-

Primary Endpoints:

1st Phase: Modified PEPI 0 rate

2nd Phase: RFS in Modified PEPI 0

Prognosis

Core-

biopsy

(RS,

Ki-67)

Endocrine

therapy3 weeks

Intermediate

RS risk

endocrine

therapy

Response

Surgery /

Core-

biopsy

(RS,

Ki-67)

good proliferation

response (Ki67 ≤10%)

low proliferation

response (Ki67 >10%)

chemotherapy

endocrine therapy

Principal investigators: N. Harbeck (LKP), Munich; U. Nitz, Mönchengladbach

WSG-ADAPT Trial:

HR+ Subprotocol

Hofmann et al, Trials 2013(courtesy Nadia Harbeck)

Neoadjuvant (Ph 2): Adding Everolimus to

Letrozole Improved Response Rates

Abbreviations: BC, breast cancer; ER+, estrogen receptor-positive; Ph, phase; RR , response rate; vs, versus.

Baselga J, et al. J Clin Oncol. 2009;27(16):2630-2637.

Primary endpoint: RR at 16 weeks (palpation)

270 Postmenopausal women with ER+ early BC

Everolimus 10 mg/day +Letrozole 2.5 mg/day

Placebo +Letrozole 2.5 mg/day

Surgery

RANDOMIZE

• Higher RR: 68% vs 59% (P = 0.062)

• Greater antiproliferative response: Ki67 by 57% vs 30% (P < 0.01)

70

neoMONARCH: Phase II study design

Abbreviations: HER2 = human epidermal growth factor receptor 2; HR = hormone receptor; Q12H = every 12 hours; QD = once dailyaParticipants receive loperamide with each dose of abemaciclibbParticipants who experience benefit following 14 weeks may remain on neoadjuvant therapy for up to 8 additional weeks

♦ Abemaciclib 150 mg BID is tolerable

when dosed on a continuous

schedule with endocrine therapy1

♦ The most common adverse event

has been diarrhea

♦ Typically occurred within the

first 7 days of treatment

♦ Manageable with use of

loperamide or dose reduction

♦ Loperamide was administered

prophylactically for the first 28 days

then at discretion of investigator

Post-menopausal women (N=220) HR+, HER2-

breast cancer stage: I (T ≥1 cm), II, IIIA or IIIB

suitable for neoadjuvant endocrine therapy

Primary endpoint:

Compare the change from baseline in Ki67

expression after 2 weeks of therapy

Randomization

Core biopsy at baseline

Core biopsy after 2 weeks of treatment

Abemacicliba 150 mg

Q12HAnastrozole 1 mg QD

Abemacicliba 150 mg Q12H

+ anastrozole 1 mg QD

Core biopsy after 14 weeks of treatmentb

Abemacicliba 150 mg Q12H

+ anastrozole 1 mg QD

Surgery (optional)1Patnaik A et al. Cancer Discovery 2016;6:740-5

*Key inclusion criteria : post menopausal women; ER Allred ≥ 4; not candidate for breast conservation**FNA or biopsy; no SLN allowed***Stratification factors (block permutation): T2 vs T3; Luminal A vs luminal B****Surgery was performed 24h after the last palbociclib dosing

Newly

diagnosed

stage II-III

BC*

Biopsy

ER+, HER2-

Nodal status available**

SU

RG

ER

Y**

**

R***

1 : 1Prosigna

Exclude non luminal

tumors

Luminal A N+

or Luminal B

3 FEC 100 fwd by

3 Docetaxel 100

(q3w)

Letrozole 2.5 mg/day

+ Palbociclib 125

mg/day, 3w/4

19 weeks

Cottu et al, ESMO 2017

LETROZOLE AND PALBOCICLIB VERSUS 3RD GENERATION CHEMOTHERAPY AS NEOADJUVANT TREATMENT OF LUMINAL BREAST CANCER.

RESULTS OF THE UNICANCER - NEOPAL STUDY LORELEI STUDY DESIGN

1:1

Letrozole 2.5 mg QD + taselisib 4 mg (2 x 2 mg tablets)

5 days on/2 days off

Letrozole 2.5 mg QD + placebo

5 days on/2 days off

S

U

R

G

E

R

Y

30-day safety

follow-up,

then investigator’s

choice of:

adjuvant endocrine

therapy and/or

chemotherapy

and/or

radiotherapy

Pre

treatment

Week 3 Week 9 Week 16 Surgery

(Week 17–18)

Tumor tissue

MRI *

Breast U/S

Mammogram

• Untreated

• Postmenopausal

• Estrogen receptor (ER)-

positive/HER2-negative

• Stage I–III operable BC

• ≥ 2 cm tumors by MRI

16 weeks

* MRI @ Week 9: only required if suspicion of progression or if unevaluable by U/S at baseline

KEY INCLUSION CRITERIA:

• Multifocal disease allowed

• Sample for centralized PIK3CA genotyping

• Fasting glucose ≤125 mg/dL

KEY EXCLUSION CRITERIA:

• cT4 or cN3 stage BC

• Bilateral invasive or multicentric BC

• Excisional biopsy of primary tumor and/or sentinel

lymph node biopsy prior to study treatment

• Stage IV BC

STRATIFICATION FACTORS:

• Tumor size (T1–2 vs T3)

• Nodal status

Saura et al, ESMO 2017

TAKE HOME MESSAGES and OPEN QUESTIONS regarding ADJUVANT ET

• Ovarian suppression/ablation is indicated in pts with high risk of recurrence needing CT and recovering menses after CT. Reserve AI+OFS to very high risk only

(toxicity!)

• Decision for the individual patient still difficult; optimal duration unknown

• 5 years is the minimal duration for all patients. In pts with “sufficiently high risk” consider extended adjuvant

• Optimal duration for the individual patient is unknown; Best strategy for extended adjuvant (10 y Tam; 10 y AI, sequence, “sandwich”, …) is unknown

• TAMOXIFEN is essential. AIs provide a small additional benefit and different toxicity profile

•No predictive markers to discriminate between Tam & AI

Documents

(Neo)Adjuvant Endocrine Therapy · Financial disclosures: Personal financial interest in form of consultancy role for: Amgen, ... Overview 2011[76] TAM 5 y vs no TAM 10 645 ER+ 15