Exemestane in Early and Advanced Breast Cancer

Slide Reference

Endocrine Treatment in Breast Cancer

• In up to 75% of breast cancers, ER signaling is a key promoter of tumor proliferation

• Endocrine therapy is an effective and well-tolerated treatment for ER+ advanced breast cancer

• Adjuvant endocrine treatment significantly improves outcomes in ER+ early breast cancer

Cleator SJ et al. Clin Breast Cancer. 2009;9(Suppl 1):S6–S17.

ER=estrogen receptor.

Hormonal Therapy Options

Mechanism Therapeutic modality examples

ER blockade Selective estrogen-receptor modulators (SERMs)Selective estrogen-receptor down-regulators (SERDs)

Estrogen synthesis suppression (postmenopausal women)

Aromatase inhibitor/inactivator (AI)

Hormonal ablation (premenopausal women)

LHRH analogs, radiation, surgery

Other Androgens, progesterone, progestational agents

LHRH=luteinizing hormone-releasing hormone.Hayes DF et al. In: Robertson et al., eds. Endocrine Therapy of Breast Cancer. 2002:3–10.Robertson JF. Clin Ther. 2002;24(suppl A):A17–A30.

3

Differences in AI and Tamoxifen Differences in AI and Tamoxifen Mechanisms of ActionMechanisms of Action

AndrostenedioneAndrostenedione

TamoxifenTamoxifen

ProliferationProliferation

ER target genesER target genesEREsEREs

ERER ERER

EREs, estrogen response elements.EREs, estrogen response elements.Johnston. Johnston. Nat Rev Cancer.Nat Rev Cancer. 2003;3:8212003;3:821--831. Adapted with permission: 831. Adapted with permission: http://www.nature.com..

TestosteroneTestosterone

Aromatase AIsAIs Aromatase AIsAIs

EstroneEstrone EstradiolEstradiol

Differences in AI and Tamoxifen Mechanisms of Action

EREs=estrogen response elements.Johnston S. Nat Rev Cancer. 2003;3:821–831.

6

Aromatase Inhibitors: Enzyme InteractionAromatase Inhibitors: Enzyme InteractionType IType I

ExemestaneExemestaneType IIType II

AnastrozoleAnastrozoleLetrozoleLetrozole

FeFe FeFe

NN

NCNC CNCN

IRREVERSIBLEIRREVERSIBLE REVERSIBLEREVERSIBLE

Adapted from Lang M, et al. J Steroid Biochem Mol Bio. 1993;44:421-428; Furet P, et al. J Med Chem. 1993;36:1393-1400.Adapted from Lang M et al. J Steroid Biochem Mol Biol. 1993;44:421–428; Furet P et al. J Med Chem. 1993;36:1393–1400.

AIs: Enzyme Interaction

Early Breast Cancer

Guidelines

ASCO Guidelines 2010

• Postmenopausal women with HR-positive breast cancer should consider incorporating AI therapy at some point during adjuvant treatment• Either up-front or as sequential treatment after

tamoxifen

• Data suggest that both strategies yield similar outcomes

Burstein HJ et al. J Clin Oncol. 2010;28:3784–3796.

St Gallen 2011

• Both tamoxifen and AIs are accepted options for adjuvant therapy of HR+ breast cancer in postmenopausal patients

• Switch and up-front AI strategies are both acceptable

Gnant M et al. Breast Care. 2011;6:136–141.

NCCN Guidelines 2013: Adjuvant Endocrine Therapy for Invasive Breast Cancer

• Premenopausal at diagnosis• Tamoxifen for 5 years ± ovarian suppression or ablation

– If still premenopausal, consider Tamoxifen for an additional 5 years OR no further endocrine therapy

– If postmenopausal, AI for 5 years OR consider Tamoxifen for an additional 5 years

• Postmenopausal at diagnosis• AI for 5 years or• Tamoxifen for 2–3 years followed by AI to complete

5 years or up to 5 years of an AI or • AI for 2–3 years then tamoxifen to complete 5 years or• If AI is contraindicated, tamoxifen for 5 years OR consider

Tamoxifen for up to 10 years

NCCN Guidelines. Breast Cancer. 2013 version 3.

Summary of Guideline Recommendations

• All guidelines recommend an AI as part of the adjuvant treatment of postmenopausal women with early breast cancer• NCCN gives the strongest recommendation for AI

use, with tamoxifen alone recommended only in patients intolerant of AIs

• All consider the switch and up-front strategies to be equivalent• NCCN recommends both sequences: tamoxifen AI

and AI tamoxifen switch

Burstein HJ et al. J Clin Oncol. 2010;28:3784–3796.NCCN Guidelines. Breast Cancer. 2013 version 3.Gnant M et al. Breast Care 2011;6:136–141.

Tamoxifen has been the Standard of Care

Meta-analysis of 55 trials and approximately 30,000 women with ER+ (or untested) tumors followed up for ~10 years:

• 21%, 29% and 47% relative risk reduction for recurrence in 1-year, 2-year and 5-year trials of tamoxifen therapy over placebo, respectively

• 26% reduction of death with 5 years of tamoxifen therapy over placebo

• 47% relative risk reduction of contralateral breast cancer with 5 years of therapy over placebo

• Current standard of tamoxifen treatment is 5 years. However, the absolute benefit per year decreases over the duration on therapy

Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1998;351:1451–1467.Fisher B et al. J Natl Cancer Inst. 2001;93:684–690.

Recurrence-free and Overall Survival Benefit of ~5 years of Tamoxifen in ER+ Breast Cancer

Early Breast Cancer Trialists' Collaborative Group. Lancet. 2011;378:771−784.

New challenge for a new class of AI in postmenopausal patients

At the time of treatment initiation 3 situations

• Patient that has already started tamoxifen

• “Naïve” patient, never received hormone therapy

• Patient that has finished 5 years of hormone therapy, tamoxifen or AI

Adjuvant Setting

AIs asInitial therapy

5 yrs

AIs after2–3 yrs of TAM

TAM x 5 yrs

AI x 5 yrs TAM x 2–3 AI x 2–3

TAM x 5 yrs

Two Strategies

ATAC (Anastrozole)BIG 1-98 (Letrozole)TEAM (Exemestane)MA 27 (Exemestane/Anastrozole)

IES (Exemestane)

Clinical Trials of the Two Strategies: AIs Up-front or Switch vs. 5 Years Tamoxifen

Overview of Switch Trials Showing Significant Overall Survival Benefit

Trial IES

(Exemestane)1–3 ARNO 95

(Anastrozole)4

n 4724 979Design Double-blind Open-labelCT Y (32%) NNode pos 48% 26%Follow-up 91 months 30 months

HR – DFS 0.82 (0.73–0.92) p=0.0009

0.66 (0.44–1.00)p=0.049

Overall survival benefit

0.86 (0.75–0.99)p=0.04

0.53 (0.28–0.99) p=0.045

1. Coombes RC et al. Lancet. 2007;369:559–570; 2. Coombes RC et al. N Engl J Med. 2004;350:1081–1092; 3. Bliss JM et al. J Clin Oncol. 2012;30:709–717; 4. Kaufmann M et al. J Clin Oncol. 2007;25:2664–2670.

IES Trial Design

Total follow-up available from randomization at June 2009 analysis = 32,296 women years

Coombes RC et al. N Engl J Med. 2004;350:1081–1092.

Tamoxifen

Exemestane(2–3 years)

Tamoxifen(2–3 years)

Post-treatment follow-up

RANDOMI ZE

2–3 years

Diagnosis Start of study Total 5 years endocrine therapy

Median follow-up from randomization = 91 months (June 2009)

Overall Survival – ER+/unknown

Bliss JM et al. J Clin Oncol. 2012;30:709–717.

Number of events/at risk

E 0/2294 17/2229 40/2177 42/2105 63/2006 36/1926 47/1781 42/1434 38/821 22+5*/291T 0/2305 23/2249 52/2181 53/2094 63/1996 42/1912 61/1767 38/1411 44/767 23+6*/294

100908070605040302010

0

Wom

en a

live

(%)

0 1 2 3 4 5 6 7 8 9Time from randomization (years)

HR=0.86 (95% CI: 0.75–0.99); p=0.04

Absolute differenceat 5 years = 1.4%(95% CI: 0.1–2.5)

Absolute differenceat 8 years = 2.4%(95% CI: 0.1–4.8)

ExemestaneTamoxifen

E=352/2294

T=405/2305

End of treatm

ent

Tamoxifen duration prior to randomization

ER status

Chemotherapy use

DFS Subgroup Analysis – ER+/unknownFavors Exemestane Favors Tamoxifen

N– (n=2382)N+ (n=2037)

No (n=3101)Yes (n=1498)

Positive (n=4052)Unknown (n=547)

≤2.5 years (n=2763)>2.5 years (n=1836)

<60 years (n=1479)60–69 years (n=1967)70+ years (n=1153)

DFS (adjusted)

0.79 (0.65–0.95)0.78 (0.67–0.90)

0.85 (0.73–0.99)0.77 (0.63–0.92)

0.83 (0.73–0.94)0.79 (0.57–1.08)

0.68 (0.74–1.00)0.77 (0.64–0.92)

0.86 (0.69–1.07)0.77 (0.64–0.92)0.88 (0.72–1.08)

0.81 (0.72–0.91)p<0.001

Hazard ratio (95% CI)0.5 0.6 0.7 0.8 0.9 1.0 1.2

HR (95% CI)

Bliss JM et al. J Clin Oncol. 2012;30:709–717.

Nodal involvement

Age at randomization

DFS=disease-free survival

Causes of Death – ITT Analysis

Exemestane Tamoxifen TotalTotal deaths 373 420 793

Breast cancer deaths 262 302 564Cause of death unknown 26 39 65

Intercurrent deaths Other cancer

Vascular* Cardiac

Other*Includes 3 thrombotic events (E=2, T=1)

111

35232330

118

53192125

229

88424455

Bliss JM et al. J Clin Oncol. 2012;30:709–717.ITT=intention-to-treat

Long-Term Adverse Effects

BMD: Lumbar Spine and Femur

10

-1-2-3-4-5-6

0 6 12 18 24 EOT EOT+12 EOT+24

Visit (months from randomization)

-2.637

-3.081-3.132

-2.774

-0.925

-4.166-3.933

-3.147-2.689

-0.622-0.179

-0.290

Exemestane Tamoxifen

10

-1-2-3-4-5-6

0 6 12 18 24 EOT EOT+12 EOT+24

Visit (months from randomization)

-2.989

-3.947

-3.421

-2.976

-1.531

-3.110-2.882

-2.304-1.359

-0.994

-0.179

-0.180

Exemestane Tamoxifen

Coleman RE et al. Breast Cancer Res Treat. 2010;124:153–161.BMD=bone mineral density

If BMD is Normal at the Start of Treatment, 80% Patients do not Develop Osteoporosis

Coleman RE et al. Breast Cancer Res Treat. 2010;124:153–161.

Normal (n=36)

Osteopenic (n=26)

Normal (n=41)

Osteopenic (n=25)

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Status 24 months post study treatment completion (%)

Normal Osteopenic Osteoporotic

Tam

oxife

nEx

emes

tane

Sta

tus

at b

asel

ine

by tr

eatm

ent g

roup

Reversal of Skeletal Effects in IES

• 206 patients in substudy

• BMD and markers obtained at 6, 12, 24 months and 12 or 24 months after end of treatment

• The number of patients with osteopenia and osteoporosis at 24 months after end of treatment were similar

• BMD loss experienced during therapy with exemestane reversed at 24 months after treatment

• 80% patients with normal BMD at baseline do not developed osteoporosis

Coleman RE et al. Breast Cancer Res Treat. 2010;124:153–161.

Endometrial Effects in Women in the IES

• 219 patients in the substudy

• TVUS scans in 90% of patients

• Transition from abnormal endometrial thickness to normal in 53% of women

Bertelli G et al. Ann Oncol. 2010;21:498–505.TVUS=transvaginal ultrasound

Bertelli G et al. Ann Oncol. 2010;21:498–505.

Mean Change in Endometrial Thickness and Uterine Volume from Baseline

Baseline

-1.9

12M 24M EoT EoT+12M

EoT+24M

2

1

0

-1

-2

-3

-4

-5

Mea

n ch

ange

(mm

) fro

m b

asel

ine

-2.1-2.9

-2.5 -2.7 -2.5

-1.9-2.2

-0.2-0.6

-0.1 -0.2

p=0.01 p=0.02 p=0.01 p=0.03

p=0.56p=0.52

6M

Number of patientsExemestaneTamoxifen

6969

6061

6155

5353

5149

4538

Exemestane Tamoxifen

Baseline

-15.3

12M 24M EoT EoT+12M

EoT+24M

10

0

-10

-20

-30

-40M

ean

chan

ge (c

m3 )

from

bas

elin

e

-22.6 -19.3 -2.5-25.0

-1.8

p=0.002 p=0.0001 p=0.001 p=0.001

p=0.01p=0.06

6M

6968

5858

5556

4956

4545

4033

Exemestane Tamoxifen

-24.2

-15.6

-9.0

-1.8 -0.5 -0.4

Number of patientsExemestaneTamoxifen

IES: Gynecological Events

Coombes RC et al. ECCO15/ESMO 34 2009. Abstract 5.010.

Favors Exemestane Favors Tamoxifen

Odds ratio (99% CI)0.2 0.4 0.8 1.0 1.7

Endometrial hyperplasia/

uterine polyps and fibroids

Vaginal bleeding

Serious gynecological

(incl. hysterectomy

and uterine D&C)

Population key

All

On

Post

E%* v T%¥; p-value

*N=2319 ¥N=2338 for vaginal bleeding; *N=2038 ¥N=2059 for others

6.8 v 10.4; <0.001

4.9 v 7.2; 0.001

1.5 v 3.9; <0.001

Relationship Between Adverse Events and Efficacy of Exemestane

Hot flashes: HR 0.39, 95% CI 0.19–0.81 p=0.012

Musculoskeletal: HR 0.68, 95% CI 0.39–1.17 p=0.16

Fontein DB et al. Ann Oncol. 2012;23:3091–3097.

Fontein DB et al. Ann Oncol. 2012;23:3091–3097.

Relapse-free Survival for Specific Adverse Events vs. Non-specific or No Adverse Events

No. at riskNo. of eventsNo AEsNonspecific AEsSpecific AEs

0.5

0.4

0.3

0.2

0.1

0.0

543210Follow-up (years) (corrected for 6 months)

Cum

ulat

ive

inci

denc

e of

di

seas

e re

laps

e or

dea

th

from

bre

ast c

ance

r (%

) No AEsNonspecific AEsSpecific AEs

1561 1500

24117

1426

3154

1358

2626

1190

253

11

632

801

QoL in IES

Tools Used:

FACT-B 3-monthly for a yearES 6-monthly for 5 years

582 patients from 8 countries

Questionnaire compliance in 84.5%

Primary Endpoint: The Trial Outcome Index (TOI), a summation of physical,functional and breast-cancer concerns subscale

Fallowfield LJ et al. Br J Cancer. 2012;106:1062–1067.QoL=quality of life.

Fallowfield LJ et al. Br J Cancer. 2012;106:1062–1067.

12

8

4

0

-4

-8

-12

Months from randomization

Mea

n ch

ange

from

bas

elin

e

604836302418129630

End oftreatment

QoL in IES

QoL: IES Summary

1. No difference in TOI at 2 years (p=0.24)2. Post-treatment: at 30–60 months (p=0.68)3. All time points: No difference

Secondary Endpoints: 4. Endocrine subscale: p=0.54; mean change at 60 months:

(p=0.82)5. FACT-B + ES score: no difference at any time point

(p=0.73)6. Individual symptom difference: only gynecological

Fallowfield LJ et al. Br J Cancer. 2012;106:1062–1067.

↓ Contralateral BC↓ Deep vein thrombosis↓ Endometrial cancer↓ Hot flashes

↑ Arthralgia/myalgia↑ Osteoporosis risk↑ Cardiovascular ?

AI

¯ Contralateral BC ¯ Osteoporosis risk¯ Myalgia ¯ Hyperlipidemia

↑ Hot flashes↑ Thromboembolic↑ Endometrial cancer↑ Genitourinary adverse effects

NeurocognitionSexual function

Cardiovascular diseaseTamoxifen

AIs and Tamoxifen Potential Risks and Benefits

Burstein HJ et al. J Clin Oncol. 2010;28:3784–3796.Amir E et al. J Natl Cancer Inst. 2011;103:1299–1309.Phillips KA et al. Breast Cancer Res. 2011;13:203.

Adjuvant Therapy in HR+ Breast Cancer

1. Tamoxifen alone for 5 years is indicated in patients who are clearly premenopausal

2. In perimenopausal patients who become menopausal on chemotherapy, it is appropriate to start with tamoxifen and switch to an AI at 2–3 years

3. In postmenopausal patients at lower risk of relapse, it is reasonable to start with tamoxifen and switch to an AI after 2–3 years

4. The switch strategy may balance the different adverse event profiles of tamoxifen and AIs

Burstein HJ et al. J Clin Oncol. 2010;28:3784–3796.NCCN Guidelines. Breast Cancer. 2013 version 3.Gnant M et al. Breast Care. 2011;6:136–141.

Advanced / Metastatic Breast Cancer

ABC Guidelines: HR+ Advanced Breast Cancer

• Endocrine therapy is the preferred treatment for all hormone receptor positive (HR+) advanced breast cancer (Level 1A)• Even in the presence of visceral disease• Unless there is concern or proof of endocrine resistance or a fast response is

needed• Premenopausal

• Ovarian suppression + additional endocrine therapy (1A)• Postmenopausal

• AI is preferred first-line treatment (1A)• Tamoxifen also an option• Consider type and duration of adjuvant endocrine therapy

• Optimal post-AI treatment is uncertain• Options include tamoxifen, another AI, fulvestrant and megestrol acetate (1A)

• Addition of everolimus to an AI may be beneficial but more data are needed (Expert opinion)

Cardoso F et al. Breast. 2012;21:242–252.

NCCN Guidelines 2013

• Premenopausal patients with ER+ disease• Ovarian ablation/suppression, then follow

postmenopausal guideline• Postmenopausal patients

• Non-steroidal AI (anastrozole, letrozole)• Steroidal AI (exemestane)• Fulvestrant• Tamoxifen or toremifene• Megestrol acetate• Fluoxymesterone• Ethinyl estradiol

NCCN Guidelines. Breast Cancer. 2013 version 3.

*Bone metastases: + bisphosphonates

Bossung V, Harbeck N. Curr Opin Obstet Gynecol. 2010;22:79–86.

Symptoms/Metastases location*

Rapid therapy response requiredSlow disease progression

ChemotherapyHER2-positive: +

trastuzumab/lapatinibHER2-negative: +

bevacizumab

Steroid hormonereceptor status

(ER, PR)

HER2 status

HER2 status

Endocrine therapy

Depending on clinical situation(response, disease progression)

+ trastuzumab / lapatinib (HER2 pos.)

Hormonereceptorstatus

ER/PR-positive

ER- and PR-negative

Treatment of MBC

MBC=metastatic breast cancer.

Endocrine Treatment in MBC

• Challenge: Use different available treatment options in a wise manner

• AI treatment most used adjuvant treatment in early breast cancer• What is appropriate in MBC?

• In non-symptomatic patients, use endocrine treatment for as long as possible to balance efficacy and QoL

• What data are available to aid in the treatment choice?

Sequential Use of AIs

• Steroidal AIs bind irreversibly leading to permanent inactivation of the enzyme

• Non-steroidal AIs bind reversibly

• This difference might result in (partial) non-cross resistance between non-steroidal AIs and steroidal AIs

Hong YB et al. Mol Endocrinol. 2007;21:401–414. Miller R et al. Oncologist. 2008;13:829–837.

Sequential Use of AIs• A small Phase III trial examined cross-resistance between non-steroidal AIs (letrozole,

anastrozole) and the steroidal AI exemestane

• Treatment was well tolerated, the most common side effects were arthralgia and hot flushes• These results indicate partial non-cross resistance between non-steroidal and steroidal AIs:

exemestane is active after failure of letrozole or anastrozole and patients who receive exemestane first still benefit from letrozole or anastrozole after progression

Regimen Results

Disclaimer: Exemestane is not yet approved and indicated for upfront or after failure of letrozoleor anastrozole in advanced breast cancer.  

Bertelli G et al. Oncology. 2005;69:471–477.

Conclusion

• Endocrine therapy is preferred in patients with ER+ breast cancer without life-threatening metastases

• Efficacy is as good as or may be even better than chemotherapy in ER+ disease

• Endocrine therapies can be used in sequence

• Resistance occurs eventually and new approaches are needed to prolong endocrine response and delay the need for chemotherapy

Cardoso F et al. Breast. 2012;21:242–252.NCCN Guidelines. Breast Cancer. 2013 version 3.Johnston SR. Clin Cancer Res. 2010;16:1979–1987.