management of er-positive postmenopausal early breast cancer

Management of ER-Positive Postmenopausal Early Breast

Cancer

Current Hormonal Therapy Strategies for ER-Positive

Postmenopausal Breast Cancer

33

Adjuvant hormone therapy Adjuvant hormone therapy

(B) Postmenopausal(B) Postmenopausal

GNRH agonistsGNRH agonists

Breastcarcinoma

Breastcarcinoma

AntiestrogenAntiestrogen

Ovary

LHFSHLH

FSH

AntiestrogenAntiestrogen

(A) Premenopausal(A) Premenopausal

AdrenalAdrenalEstrogenEstrogen EstrogenEstrogen

AndrostenedioneAndrostenedione

AromataseinhibitorAromataseinhibitor

PeripheralaromatizationPeripheralaromatization

Adapted with permission from Tellez C, et al. Surg Oncol Clin North Am. 1995;4:751-777.

GNRH = Gonadotropin-releasing hormone; LH = Luteinizing hormone; FSH = Follicle-stimulating hormone.

clinicaloptions.com/oncology

Management of ER+ Postmenopausal Early Breast Cancer

Androstenedione

Steroidal Inactivators Androgen Substrate

OCH2

O

Exemestane

O

O

Nonsteroidal Inhibitors

CH3

CH3

CH3

CH3NC CN

AnastrozoleLetrozoleN

NC CNN

NNNN

Third-Generation Aromatase Inhibitors/Inactivators

Selective inhibitorsSelective inhibitors

Nonselective Nonselective inhibitorsinhibitorsMultiple steps involving P-450 enzymes and production of steroid Multiple steps involving P-450 enzymes and production of steroid

intermediatesintermediates

Cholesterol

Cortisol AndrostenedioneAldosterone

Testosterone

Estrone Estradiol

Federman, DD. The adrenal. Scientific American Medicine. Dale DC, Federman DD, eds. Section 3. Federman, DD. The adrenal. Scientific American Medicine. Dale DC, Federman DD, eds. Section 3. Subsection IV. ©1997 Scientific American Inc. All rights reserved.Subsection IV. ©1997 Scientific American Inc. All rights reserved.

Selective vs Nonselective Aromatase Inhibition

Recruitment: July 1996 - March 2000

Median follow-up: 100 months

84% hormone receptor positive

61% node negative

Anastrozole 1 mg/day + Tamoxifen 20 mg/day(n = 3215)

Tamoxifen20 mg/day (n = 3116)

Surgery ±RT ±

Chemotherapy

Anastrozole1 mg/day (n = 3125)

5-yrinterim analysis

Discontinued early

ATAC Trialists' Group. Lancet. 2004. Published online, December 8, 2004.

10-yranalysis planned

Postmenopausalwomen with

invasivebreast cancer

(N = 9366)

ATAC Trial

Pat

ien

ts (

%)

30

25

20

15

10

5

0

26182598

25412516

24532400

23612306

22782196

21592075

19951896

18011711

14921396

608547

At risk:AnastrozoleTamoxifen

13.9

16.4

25.8

29.9

0 1 2 3 4 5 6 7 8 9

30

25

20

15

10

5

0

TamoxifenAnastrozole

Follow-up Time (Yrs)

2.5 4.1

Reprinted from The Lancet Oncology, 2008;9:45-53, Forbes JF, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Copyright (2008), with permission from Elsevier.

DFS: Hormone Receptor–Positive Patients

HR 95% CI

P Value

Hormone Receptor-Positive 0.85 (0.76-

0.94) .003

Absolute difference

7.8

9.1 13.2

15.6

Absolute difference 1.3 2.4

Pat

ien

ts (

%)

30

25

20

15

10

5

0

26182598

25512533

24702440

23932363

23202263

22012151

20421982

18541809

15361484

636591

At risk:AnastrozoleTamoxifen

0 1 2 3 4 5 6 7 8 9

30

25

20

15

10

5

0

Tamoxifen Anastrozole

Follow-up Time (Yrs)

Reprinted from The Lancet Oncology, 2008;9:45-53, Forbes JF, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Copyright (2008), with permission from Elsevier.

HR 95%CI

P Value

Hormone Receptor-Positive 0.84 (0.72-

0.97) .022

Time to Distant Recurrence: Hormone Receptor–Positive Patients

ATAC: Endpoints HR+ Patients

Disease Free Survival

Time to Recurrence

Contralateral Br Ca

Time to Distant Recurrence

Death After Recurrence

Death: All Causes

FavorsAnastrozole

FavorsTamoxifen

Hazard Ratio(95%CI)

P Value

0.85 (0.76-0.94) 0.003

0.76 (0.67-0.87) 0.0001

0.60 (0.42-0.85) 0.004

0.84 (0.72-0.97) 0.022

0.90 (0.75-1.07) 0.2

0.97 (0.86-1.11) 0.7

0.2 0.4 0.6 0.8 1.0 1.2 1.5 2.0

Hazard ratio (A/T) and 95% CI

Forbes JF, et al. SABCS 2007. Abstract 41. Permission from author to print.

Significant long-term carryover effect for anastrozole

– Absolute difference in recurrence increased from 2.8% after 5 years to 4.8% after 9 years

– HR of anastrozole vs tamoxifen for Years 5-9: 0.75 (P = .01)

9-Yr Follow-up, %

Anastrozole Tamoxifen

Recurrence 17.0 21.8

HR: 0.76; P = .0001

Distant Recurrence 13.2 15.6

HR: 0.84; P = .022

Contralateral Breast Cancer 2.5 4.2

HR: 0.60; P = .004

DFS HR: 0.85; P = .003

Death After Recurrence HR: 0.90; P = .20

Forbes JF, et al. SABCS 2007. Abstract 41.

ATAC: Efficacy of Anastrozole vs Tamoxifen in HR+ Population

Tamoxifen

Letrozole

Tamoxifen Letrozole

Letrozole Tamoxifen

RANDOMIZE

0 2 5

YEARS

A

B

C

D

2-arm option3/98 - 3/001835 patients

4-arm option9/99 - 5/036193 patients

BIG 1-98: Study Design

T

0

20

40

60

80

100

0 1 2 3 4 5

Aliv

e an

d D

isea

se F

ree

(%)

Years From Randomization

97.797.6

LetTam

95.193.4

90.589.0

86.884.6

84.081.4

N HR (95% CI) P Value

8010 0.81 (0.70-0.93) .003

No. at Risk

38923896

29642926

12611238

892866

40034007

567544

Thurlimann B, et al. N Engl J Med. 2005;353:2747-2757. Copyright @ 2005 Massachusetts Medical Society. All rights reserved.

LetTam

Letrozole vs Tamoxifen: DFS

Years from RandomizationThurlimann B, et al. N Engl J Med. 2005;353:2747-2757. Copyright @ 2005 Massachusetts Medical Society. All rights reserved.

0 2 3 4 510

10

5

15

20

Fai

lure

(%

)

Letrozole

Tamoxifen

13.6

10.2

8.1

6.2

5-year difference (Letrozole-Tamoxifen): -3.4% (SE: 1.2%)Cumulative incidence: P = .0002

Cumulative Incidence: Breast Cancer Relapse

Year

BIG 1-98(BIG FEMTA)

TEAM EXE

ATAC

Tamoxifen

Anastrozole

Letrozole

Exemestane

Ongoing First-Generation Aromatase Inhibitor Adjuvant Trials

Exemestane(5162*)

Tamoxifen(5294*)

Tamoxifen(N = 4724)

Posttherapyfollow-up

2-3 years 2-3 years

5-yr total durationof endocrine therapy

Start of study

*Total women-years.

Postmenopausalwomen withcompletely

resected ER-positive or unknown statusearly-stage breast

cancer

Intergroup Exemestane Study: Trial Design

Intent-to-treat ER+/Unknown

Reprinted from The Lancet Oncology, 2006;7:991-996, Jonat W, et al. Effectiveness of switching from adjuvant tamoxifen to anastrozole in postmenopausal women with hormone-sensitive early-stage breast cancer: a meta-analysis. Copyright (2008), with permission from Elsevier.

Year

Abs diff, %(95% CI)

2.5 5.0

3.2(1.6-4.9)

3.4 (0.1-6.8)

2.5 5.0

3.4(1.8-5.1)

3.5(0.1-6.9)

End

oftreatm

ent

End

oftreatm

ent

HR: 0.75 (95% CI: 0.65-0.87)Log rank test: P = .0001

E = 339/2296

T = 438/2306

HR: 0.76 (95% CI: 0.66-0.88)Log rank test: P = .0001

E = 354/2352

T = 454/2372

Intent to treat ER+/Unknown

0102030405060708090

100

0 1 2 3 4 5

DF

S (

%)

0102030405060708090

100

0 1 2 3 4 5D

FS

(%

)

Exemestane After Tamoxifen: DFS

Time Since Randomization (Yrs) Time Since Randomization (Yrs)

End

oftreatm

ent

Year

Abs diff, % (95% CI)

2.5 5.0

0.8(-0.4 to 1.9)

1.2(-1.5 to 3.9)

2.5 5.0

0.7(-0.4 to 1.9)

1.6 (-1.2 to 4.3)


End

oftreatm

ent

HR: 0.83 (95% CI: 0.69-1.00)Log-rank test: P = .05

E = 210/2296

T = 251/2306

HR: 0.85 (95% CI: 0.71-1.02)Log-rank test: P =.08

E = 222/2352

T = 261/2372

Intent-to-treat ER+/Unknown

0102030405060708090

100

0 1 2 3 4 5Time Since Randomization (Yrs)

Wo

men

Ali

ve (

%)

0102030405060708090

100

0 1 2 3 4 5Time Since Randomization (Yrs)

Wo

men

Ali

ve (

%)

Exemestane After Tamoxifen: OS

ARNO 952 years of previous

tamoxifen (N = 979)

Jonat W, et al. Lancet Oncol. 2006;7:991-996.

Tamoxifen(n = 490)

Anastrozole (n = 489)

Year 5

ABCSG 82 years of previous

tamoxifen (N = 2579)

Tamoxifen(n = 1282)

Anastrozole (n = 1297)

ITA2-3 years of previous

tamoxifen (N = 448)

Tamoxifen 2-3 years(n = 225)

Anastrozole 2-3 years(n = 223)

Meta-analysis of Anastrozole Sequencing Studies

Time to DFS Event (Yrs)

2009 1522 1161 792 509 256 99 91997 1492 1109 764 460 241 78 9

Anastrozole

Tamoxifen


AnastrozoleTamoxifen

At risk:

0 1 2 4 5 6 70

60

70

80

90

100

Eve

nt

Fre

e (%

)

HR: 0.59 (95% CI: 0.48-0.74)

P < .0001

3 8

DFS: Anastrozole vs Tamoxifen (ITT Population)

0.2 0.4 0.6 0.8 1.0

ARNO 95

ITA

Meta-analysis

ABCSG 8

1.2 1.4 1.6

.726

.026

.094

.038

P value

2579

979

448

4006

Patients

0.93

0.48

0.50

0.71

HR

Favors anastrozole Favors tamoxifen

Hazard ratios and 95% confidence intervalsReprinted from The Lancet Oncology, 2006;7:991-996, Jonat W, et al. Effectiveness of switching from adjuvant tamoxifen to anastrozole in postmenopausal women with hormone-sensitive early-stage breast cancer: a meta-analysis. Copyright (2008), with permission from Elsevier.

OS: Anastrozole vs Tamoxifen (ITT Population)

Tamoxifen

Letrozole 2.5 mg daily (n = 2575)

Placebo(n = 2582)

5 years of early adjuvant 5 years of extended adjuvant

Node negative: n = 2581Node positive: n = 2370

30 months of follow-up

Extended Adjuvant TherapyMA.17: Trial Design

DFS* Distant* DFS

OS

Node-Negative Patients

Node-PositivePatients

HR: 0.61*(0.45-0.84)

HR: 0.45*(0.27-0.73)

HR: 0.63(0.31-1.27)

HR: 0.53*(0.36-0.78)

HR: 1.52(0.76-3.06)

HR: 0.61*(0.38-0.98)

*Statistically significant benefit of letrozole.

Goss PE, et al. J Natl Cancer Inst. 2005;17:1262-1271.

Extended Adjuvant Therapy:Letrozole After 5 Years of Tamoxifen

A similar reduction in local recurrences, new primaries, and distant recurrences occurred in node-positive and node-negative patients

Placebo (n = 2594)

5 years5 years

Letrozole (n = 1655)

1998 2003 Unblinding 2005

Letrozole (n = 2457)

No Letrozole (n = 613)

30 months 54 (16-86) monthsMedian follow-up

Goss PE, et al. SABCS 2005. Abstract 16.

Letrozole After Unblinding of MA.17

Tamoxifen(N = 5187)

Letrozole (n= 2593)

Goss PE, et al. SABCS 2005. Abstract 16.

DFS

Distant DFSOS

Contralateral breast cancer

HR

0.310.28

0.53

0.23

0

0.1

0.2

0.3

0.4

0.5

0.6

PLAC-LET to PLAC

P < .0001P < .002

P < .05

P < .012

Significant Advantage for PLAC-LET in Efficacy Outcomes

BIG 1-98(BIG FEMTA)

IES Trial

ITA

NSABP B33

Tamoxifen

Anastrozole

Placebo

Letrozole

Exemestane

MA-17

Ongoing First-Generation Aromatase Inhibitor Adjuvant Trials

Summary

Aromatase inhibitors offer a modest but significant benefit over tamoxifen in both the metastatic and adjuvant settings

In the adjuvant setting, it remains unclear whether upfront aromatase inhibitor therapy is superior to sequencing approach

High-risk premenopausal patients should receive an aromatase inhibitor as part of their adjuvant therapy (after 2 years, 5 years, or when off tamoxifen)

Endocrine Therapy for Metastatic Breast Cancer



Initial Treatment of HR-Positive Advanced Breast Cancer AIs are the current standard of care for initial treatment of postmenopausal women with

HR-positive advanced breast cancer

AIs have demonstrated improved efficacy compared with tamoxifen

– TTP, anastrozole vs tamoxifen: 10.7 vs 6.4 mos[6]

– TTP, letrozole vs tamoxifen: 9.4 vs 6.0 mos[5]

– PFS, exemestane vs tamoxifen: 9.9 vs 5.8 mos[7]

Fulvestrant has demonstrated improved efficacy compared with anastrozole

– TTP, fulvestrant vs anastrozole: 23.4 vs 13.1 mos [8]

– Fulvestrant has demonstrated similar efficacy compared with tamoxifen [9]

– Combination fulvestrant and anastrozole was more efficacious than anastrozole alone [10]

6. Bonneterre J, et al. Cancer. 2001;92:2247-2258. 5. Mouridsen H, et al. J Clin Oncol. 2003;21:2101-2109. 7. Paridaens RJ, et al. J Clin Oncol. 2008;26:4883-4890. 8. Robertson FJ, et al. Breast Cancer Res Treat. 2012;136:503-511. 9. Howell A, et al. J Clin Oncol. 2004;22:1605-1613. 10. Mehta RS, et al. N Engl J Med 2012;367:435-444.

First-line Letrozole vs Tamoxifen, Then Crossover

Median OSLetrozole: 34 mosTamoxifen: 30 mos

Time to Crossover Letrozole: 17 mos Tamoxifen: 14 mos

Mouridsen H, et al. J Clin Oncol. 2003;21:2101-2109.

P = .53 (long-rank test)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

00 6 12 18 24 30 36 42 48 54 60

Mos

Pro

po

rtio

n A

live

Letrozole 1st Tamoxifen 1st

In the CONFIRM trial, 500 mg of monthly fulvestrant was superior to 250 mg for which survival endpoints?

A. PFS, but not OS

B. Both PFS and OS

C. Neither PFS nor OS

CONFIRM: Fulvestrant 500 mg vs 250 mg in Postmenopausal Women With ER+ MBC

Fulvestrant 250 mg*(n = 374)

Fulvestrant 500 mg†

(n = 362)

Postmenopausal women

with ER-positive advanced

breast cancer (N = 736)

*Fulvestrant 250 mg: 1 injection of fulvestrant 250 mg IM + 1 placebo injection on Day 0; 2 placebo injections on Day 14; 1 injection of fulvestrant 250 IM + 1 placebo injection on Day 28, then every 28 days thereafter.†Fulvestrant 500 mg: 2 injections of fulvestrant 250 mg IM on Days 0, 14, 28, then every 28 days thereafter.

DiLeo A, et al. SABCS 2012. Abstract S1-4.

CONFIRM: Effect of Fulvestrant 500 mg vs 250 mg on Survival in Postmenopausal Women Baseline characteristics appeared well balanced between treatment arms

– Subsequent therapies were well balanced between arms, with approximately 60% of patients receiving subsequent chemotherapy and approximately one third receiving other hormonal therapy

OutcomeTiming of Analysis

Fulvestrant500 mg

Fulvestrant250 mg HR (95% CI)

Median PFS First* 6.5 mos 5.5 mos 0.80‡ (0.68-0.94)

Median OS First* 25.1 mos 22.8 mos 0.84§ (0.69-1.03)

Median OS Final† 26.4 mos 22.3 mos 0.81¶ (0.69-0.96)*First analysis was performed at 50% maturity.†Final analysis was performed at 75% maturity. ‡ P = .006 §P = .001 ¶P = .016

DiLeo A, et al. SABCS 2012. Abstract S1-4.

FIRST Study Design

Robertson JF, et al. Clin Oncol. 2009;27:4530-4535.

Endpoints at primary data cutoff

Primary endpoint

Clinical benefit rate

Secondary endpoints

ORR

TTP

Duration of response

Duration of clinical benefit

Safety

Exploratory endpoint

Best response to subsequent therapy

Open-label first-line ER+ postmenopausal patients with advanced breast cancer

(target, N = 200; actual, N = 205)

Fulvestrant 500 mg IMon Days 0, 14, 28, and

every 28 days thereafter

Anastrozole 1 mg/day PO

Progression

Follow-up

Progression

Follow-up

0

0.2

0.4

0.6

0.8

1.0

0 6 12 18 24

Mos

30 36 42 48

Fulvestrant 500 mgAnastrozole 1 mg

Pro

po

rtio

n o

f P

atie

nts

Aliv

ean

d P

rog

ress

ion

Fre

e

HR: 0.66 (95% CI: 0.47-0.92;P = .01)

Pts at Risk, nFulvestrant 500 mgAnastrozole 1 mg

102103

7469

6555

5239

4530

3421

208

62

00

Robertson JF, et al. Breast Cancer Res Treat. 2012;136:503-511.

FIRST: TTP at Follow-up Analysis

Postmenopausal women with hormone receptor–

positive MBC(N = 707)

Anastrozole 1 mg/day PO +Fulvestrant 500 mg on Day 1,

250 mg on Days 14 and 28, 250 mg every 28 days thereafter

(n = 355)

Anastrozole 1 mg/day PO(n = 352)

Treatment until disease progression

Stratified by previous adjuvant tamoxifen

Women with progression

encouraged to cross over to receive

fulvestrant

Mehta RS, et al. N Engl J Med. 2012;367:435-444.

SWOG S0226: Study Design

Primary endpoint: PFS Secondary endpoints: OS, safety

SWOG S0226: PFS and OS Overall and by Previous Adjuvant TamoxifenEndpoint Anastrozole

+ FulvestrantAnastrozole HR (95% CI) P

Value

Median PFS (n = 694), mos

15.0 13.5 0.80(0.68-0.94)

.007

No previous adjuvant tamoxifen (n = 414)

17.0 12.6 0.74(0.59-0.92)

.0055

Previous adjuvant tamoxifen (n = 280)

13.5 14.1 0.89(0.69-1.15)

.37

Median OS (n = 694), mos

47.7 41.3 0.81(0.65-1.00)

.049

No previous adjuvant tamoxifen (n = 414)

47.7 39.7 0.74(0.56-0.98)

.0362

Previous adjuvant tamoxifen (n = 280)

49.6 44.5 0.91 (0.65-1.28)

.59

Mehta RS, et al. N Engl J Med. 2012;367:435-444.

Finn RS, et al. SABCS 2012. Abstract S1-6.

Aromatase Inhibitor + CDK4/6 Inhibitor Improves PFS in ER+ MBC

0

0.2

0.4

0.6

0.8

1.0

0 6 1210 14Mos

16 20 22 28

PD 991 + LET (n = 84)21 (25)

26.1(12.7-26.1)

PF

S P

rob

abili

ty

Pts at Risk, nPD 991 + LETLET

8481

7557

6038

5329

4322

3517

2511

31

11

24 261882 4

0.3

0.5

0.7

0.9

0.1

LET (n = 81)40 (49)

7.5(5.6-12.6)

186

155

144

93

53

Events, n (%)Median PFS, mos(95% CI)HR(95% CI)P value

0.37(0.21-0.63)

< .001

EFFECT: Fulvestrant vs Exemestane After Progression of Nonsteroidal AI

MosPts at Risk, nFulvestrantExemestane

3.73.7Median, mos

HR: 0.963 (95% CI: 0.819-1.133; P = .6531)

Cox analysis, P = .7021

ExemestaneFulvestrant

FulvestrantExemestane

0 3 6 9 12 15 18 21 24 270.0

0.2

0.4

0.6

0.8

1.0

351 195 96 50 25 12 4 2

342 190 98 41 21 12 8 6

0

1

0

0Chia S, et al. J Clin Oncol. 2008;26:1664-1670.

Patients with which site of metastatic disease had the longest PFS with exemestane + everolimus vs exemestane in the BOLERO-2 trial?A. Bone only

B. Liver only

C. Lung only

D. Any visceral disease

E. No visceral disease

Reprinted by permission from the American Association for Cancer Research: Johnston SR. Clin Cancer Res. 2005;11:889s-899s.

ER target gene transcription

SOS

P PP P

PI3-K

akt

PP

RASRAF

MEK

MAPKp90RSK

ER

Pp160

BasaltranscriptionmachineryCBPERER

PPP

ERE

Plasmamembrane

Cytoplasm

Nucleus

E2

SERD

AI T

IGF1R

EGFR/HER2

Increased signalingthrough PI3-K pathway

Increased signaling throughEGFR and/or IGF1-R

VEGFR

Mechanisms of Hormone Resistance

BOLERO-2: Everolimus + Exemestane Improves PFS in HR+ MBC

Baselga J, et al. N Engl J Med. 2012;366:520-529.

0 6 12 18 24 30 36 42 48 54 60 66 72 78

Wks

Pro

bab

ility

of

Eve

nt

(%) Everolimus + exemestane

(median PFS: 10.6 mos)

Placebo + exemestane(median PFS: 4.1 mos)

HR: 0.36 (95% CI: 0.27-0.47;log-rank P < .001)

Patients at Risk, n

Everolimus

Placebo

485

239

385

168

281

94

201

55

132

33

102

20

67

11

43

11

28

6

18

3

9

3

3

1

2

0

0

0

100908070605040302010

0

Central Assessment

BOLERO-2: Final PFS Analysis (18-Mo Follow-up)PFS, Mos EVE + EXE PBO + EXE HR (95% CI) P Value

Local review 7.8 3.2 0.45(0.38-0.54)

< .0001

Central review 11.0 4.1 0.38(0.31-0.48)

< .0001

With visceral mets 6.83 2.76 0.47(0.37-0.60)

--

Without visceral mets 9.86 4.21 0.41(0.31-0.55)

--

Bone-only mets 12.88 5.29 0.33(0.21-0.53)

--

Progression after neo/adj therapy

11.50 4.07 0.39(0.25-0.62)

--

OS data still not mature (HR: 0.77; 95% CI: 0.57-1.04)

Most common grade 3/4 AEs were stomatitis (8%), hyperglycemia (5%), fatigue (4%)

Piccart, M, et al. SABCS 2012. Abstract P6-04-02.

Case

A 68-yr-old woman presents with a T4N2 left breast mass with associated contraction and fibrosis that had been developing over 3-4 yrs

Breast biopsy shows ER+/PgR+, HER2- IDC, grade 2

Staging evaluation shows bone metastases and multiple pulmonary nodules

The patient has mild DOE but no bone pain



An IV bisphosphonate or SC denosumab is recommended for this patient, but which of the following endocrine therapies is NOT recommended?

A. Fulvestrant 500 mg

B. Letrozole

C. Exemestane + everolimus

D. Fulvestrant + a nonsteroidal AI



Endocrine Therapy Sequencing in MBC: Which Order Is Best? AI or fulvestrant are most effective first-line single agents;

fulvestrant ± AI reasonable choice for endocrine therapy–naive patients with MBC

Continue endocrine therapies until resistance

mTOR inhibition with everolimus + exemestane is best second-line therapy after progression on nonsteroidal AI

After everolimus, back to anti-ER therapy alone or enhanced blockade of PI3K pathway

Addition of CDK4/6 inhibitor to first-line letrozole may become a new SOC; phase III trial under way

management of er-positive postmenopausal early breast cancer

Documents

stage breast cancer

invasive breast cancer

mgday tamoxifen

hormone lh

3215tamoxifen20 mgday

hormone receptor positive61

luteinizing hormone

adjuvant treatment