Endocrine Therapy In Advanced Breast Cancer

Ashok K Vaid MD,DM

Artemis Health InsttNational Capital Region

Gurgaon

Endocrine Therapy in Advanced Breast Cancer

Overview (Past to the present)

Breast cancerWorldwide

– >1.2 million new cases per year

– 350,000 deaths per year

Early disease - curable

– cure rates

stable from 1930 until 1990

slight improvement 1990s (screening, adjuvant therapy)

Metastatic disease - non-curable

– concept of chronic disease

Advanced / Metastatic Breast Cancer

Stage I

84%

Stage II

71%

Stage III

48%

Stage IV

18%

100

50

75

25

0

Stage of Disease

% a

live

aft

er f

ive

yea

rs

• Approx. 40% women diagnosed - Cancer spread to other parts of the body

• Five-year Survival - Low due to spread of disease - Incurable - Treatment goals for advanced disease differ from early stage

The Lancet 11 July 1896

On the treatment of inoperable cases of carcinoma of the mamma - suggestions for a new method of treatment, with illustrative cases

By George Thomas Beatson, MD, Edinburgh; Surgeon to the Glasgow Hospital; Assistant Surgeon, Glasgow Western Infirmary; Examiner in Surgery to the University of Edinburgh

Dear Dr Beatson

The bearer is, and has been, suffering, I fear, from a malignant breast. She has been in the Royal Infirmary before she came to me. My own opinion is that nothing can be done for her, but as she is a woman of great courage you might have a look at it for my sake, and perhaps you can order her something in the way of dressing. Even this little will be accepted by her as a great deal.

With kindest regards, yours very trulyJames W Wallace

Advanced / Metastatic Breast Cancer

Beatson removed ovaries of a 33 yr old lady

with advanced breast cancer in May 1895.

She responded to treatment for 42 months

The mechanism of response was unknown.

Ovary

Pituitary glandLHRH

(hypothalamus)

Pre-/postmenopausal

Premenopausal

Gonadotrophins(FSH + LH)

ACTH

Adrenalglands

OestrogensProgesterone

Progesterone

Androgens Oestrogens

Peripheral conversion

ACTH, adrenocorticotrophic hormone; FSH, follicle stimulating hormone; LH, luteinising hormone; LHRH, LH releasing hormone

LHRHa

Aromatase Inhibitors

Hormones affecting the breast

Ovary

Efficacy of endocrine agents in women with advanced breast cancer

Rose C et al. Acta Oncol 1988

Inhibitive

Therapy

Response data from a comprehensive review

Response rate (%)

Oophorectomy

Adrenalectomy

Hypophysectomy

Aminoglutethimide + HC

Oestrogens

Progestins

Androgens

Glucocorticoids

Tamoxifen

33

32

36

31

Competitive

Additive

Ablative

2629

21

25

32

HC, hydrocortisone

Antiestrogen vs Aromatase Inhibitor: Inhibition of Estrogen-Dependent Growth

Estrogenbiosynthesis

Tumor cell

Nucleus

Inhibition of cell

proliferation


Antiestrogens (PREMENOPAUSAL)

AromataseInhibitors

(POSTMENOPAUSAL)

Phase III trials comparing tamoxifen with other hormonal endocrine agents in advanced breast cancer

Meta-analysis of 35 randomized clinical trials (n=5160)

88% postmenopausal women

36% ER status unknown

– no difference in efficacy between tamoxifen and aromatase inhibitors, megestrol acetate and medroxyprogesterone

– toxicity profile in favour of tamoxifen

Tamoxifen - the hormonal therapy ‘gold standard’

– first-line therapy in the advanced setting

Fossati R et al. J Clin Oncol 1998ER, oestrogen receptor

The use of hormonal agents in advanced/metastatic disease in

pre-menopausal women

Endocrine use in premenopausal women

Tamoxifen (alone or with LHRHa) is the most prescribed endocrine agent

But…

Is tamoxifen still the optimal agent for younger women?

Published data shows that:

– Combining an LHRHa and tamoxifen confers better efficacy than either agent alone in premenopausal patients with advanced disease

Klijn et al, 2001, JCO (19); 343-353Klijn et al. JNCI 2000; 92:903-11

Goserelin 3.6mg in Pre-/perimenopausal Women with Advanced Breast Cancer: Phase III Trials

Reference Objective responserate (%)

Median overall survival

Taylor CW, et al ‘Zoladex’ 3.6mg Surgical oophorectomy ‘Zoladex’ 3.6mg Surgical J Clin Oncol oophorectomy 1998; 16: 994–9. (n=29*) (n=30*) (n=69) (n=67)

31 27 37 months 33 months

Boccardo F, et al ‘Zoladex’ 3.6mg Surgical oophorectomy ‘Zoladex’ 3.6mg Surgical Ann Oncol or ovarian irradiation oophorectomy 1994; 5: 337–42. or ovarian irradiation

(n=22*) (n=15*) (n=24) (n=18)27 (+19) 47 (+25) 36 months 38 months

Jonat W, et al ‘Zoladex’ 3.6mg ‘Zoladex’ 3.6mg ‘Zoladex’ 3.6mg ‘Zoladex’ 3.6mg + + tamoxifen tamoxifen

Eur J Cancer Part A (n=159) (n=159) (n=159) (n=159) 1995; 31A: 137–42. 31 38 29 months 32 months

* evaluable patients

Klijn JGM, et al. J Clin Oncol 2001; 19: 343–53.

Parameter LHRHagonist(n=256)

LHRH agonist + tamoxifen

(n=250)

Odds/hazardratio

p value

OR (CR+PR) 30% 39% 0.67 0.03PFS (median) 5.4 months 8.7 months 0.70 <0.001OS (median) 2.5 years 2.9 years 0.78 0.02

LHRH Agonist* + Tamoxifen in Pre-/perimenopausal Women with Advanced Breast Cancer:

An EORTC Meta-analysis

The combination of LHRH agonist + tamoxifen is superior to LHRH agonist alone in the treatment of advanced breast cancer in hormone-sensitive pre-/perimenopausal women

OR = Objective responsePFS = Progression-free survivalOS = Overall survivalMedian follow-up of 6.8 years

* 3 of the 4 studies used the LHRHa goserelin

Hormonal therapies for postmenopausal women with

advanced breast cancer

First-line Antioestrogens

(eg tamoxifen)

Second-line Aromatase inhibitors

Third-line Progestins

(eg megestrol acetate)

Fourth-line Androgens or oestrogens

Hortobagyi GN. N Engl J Med 1998

The use of aromatase inhibitors in metastatic disease in

post-menopausal women

Antiestrogen vs Aromatase Inhibitor: Inhibition of Estrogen-Dependent Growth


Tumor cell

Nucleus

Inhibition of cell

proliferation


Antiestrogens PREMENOPAUSAL

AromataseInhibitors

Postmenopausal

The development of aromatase inhibitors

Non-selective (first-generation)

– aminoglutethimide (competitive)

Selective - discovery late 1980s

– Competitive Non-competitive (non-steroidal) (steroidal)

Fadrozole

Anastrazole

Letrozole

Vorozole

Formestane(second generation)

Exemestane(third-generation)

ToxicityToxicity SpecificitySpecificity PotencyPotency

First generationFirst generationFirst generationFirst generation

Second generationSecond generationSecond generationSecond generation

Third generationThird generationThird generationThird generation

AminoglutethimideAminoglutethimide

Fadrozole

4-OHA

Fadrozole

4-OHA

Anastrozole

Exemestane

Letrozole

Anastrozole

Exemestane

Letrozole

Development of Aromatase InhibitorsDevelopment of Aromatase Inhibitors

Rash,etc.

Rash,etc.

No adrenalinsufficiency,

etc.

No adrenalinsufficiency,

etc.

1,000to

10,000

1,000to

10,000

100100

11

Aromatase inhibitors Mechanism of action

X

Cholesterol

Cortisol

Progesterone

Aldosterone

Oestrone Oestradiol

Testosterone

Aromatase Aromatase inactivatorsinactivators

andandaromatase aromatase inhibitorsinhibitors

X

Pregnenolone

Androstenedione

Inhibition (%)

85 / 92*

91

98.4 / 98.9*

96.7 / 98.1*

97.9

In vivo effect of Aromatase inhibition

Lønning P. Acta Oncol 1996Geisler J et al. Clin Cancer Res 1998

Anti-aromatase agent

Formestane (intramuscular)

Aminoglutethimide

Letrozole

Anastrazole

Exemestane

*Inhibition at different doses

Aromatase inhibitorsPhase III second-line metastatic breast cancer

versus megestrol acetate

No. patients

CR + PR (%)

CR + PR + SD >24 weeks (%)

Median TTP (months)

Median survival (months)

Letrozole 2.5 mg

174 vs. 189

23.6 vs. 6.4†

34.5 vs. 31.7

5.6 vs. 5.5

25.3 vs. 21.5

Anastrozole 1 mg (31mo)

263 vs. 253

12.4 vs. 12.2

42.2 vs. 40.3

4.8 vs. 4.6

26.7 vs. 22.5†

Exemestane 25 mg (12 mo)

366 vs. 403

15.0 vs. 12.4

37.4 vs. 34.6

4.7 vs. 3.8†

NR vs. 26.7†

Buzdar A et al. Cancer 1998Dombernowsky P et al. J Clin Oncol 1998

Kaufmann M et al. J Clin Oncol 2000

*Pooled data; †Statistical significance vs. MA;CR, complete response; MA, megestrol acetate; NR, median not reached; PR, partial response; SD, stable disease; TTP, time to progression

Evolution of aromatase inhibitors

The third-generation aromatase inhibitors have favorable efficacy and tolerability profiles compared with megestrol acetate

Median survival gain of 4.1 months (Messori A et al Anticancer Drugs. 2000;11:701-6)

This finding triggered further research which challenged tamoxifen in the first-line adjuvant treatment of postmenopausal patients with breast cancer

Anastrozole versus tamoxifen as first systemic therapy for advanced disease

Two large, randomized trials in North America / Europe / rest of world

Postmenopausal women with ABC eligible for endocrine therapy (ER+ve and / or PgR+ve or unknown)

Randomised 1:1 (double-blind, double dummy)Randomised 1:1 (double-blind, double dummy)

Anastrozole 1 mg dailyplus tamoxifenplacebo daily

Tamoxifen 20 mg dailyplus Anastrozole

placebo daily

Primary objectives– TTP– objective response– tolerability

Secondary objectives– TTF – TTP in responding patients– survival

Bonneterre J et al. Cancer 2001

ABC, advanced breast cancer; ER, oestrogen receptor; PgR, progesterone receptor; TTP, time to progressionTTF, time to treatment failure

TTP in hormone receptor-positive patientsCombined analysis of two trials

% not progressed

Median TTPAnastrozole 10.7 monthsTamoxifen 6.4 monthsp=0.022

TTP (months)

0

20

40

60

80

100

0 6 12 18 24 30 36 42

Anastrozole (n=305)

Tamoxifen (n=306)

TTP, time to progression Bonneterre J et al. Cancer 2001

Anastrozole versus tamoxifenTolerability Data (Predefined Adverse Events)

Anastrozole Tamoxifen1 mg 20 mg

(n=506) (n=511)n % n %

Depression 30 5.9 36 7.0Tumour flare 15 3.0 18 3.5Thromboembolic disease 27 3.6 46 9.0Gastrointestinal disturbance 184 36.4 207 40.5Hot flushes 139 27.5 123 24.1Vaginal dryness 16 3.2 11 2.2Lethargy 6 1.2 17 3.3Vaginal bleeding 5 1.0 13 2.5Weight gain 12 2.4 8 1.6

Bonneterre J et al. Cancer 2001

Anastrozole(n=121)

Tamoxifen 40(n=117)

CR + PR (%)

Median TTP (months)

Dead (%)

HR for TTP (95% CI)

HR for survival (95% CI)

27 (56)

5.3 (7)

92

(0.56-0.91)

(0.51-0.89)

34 (CBR 83)

10.6 (18)

61

0.77

0.63

-

-

-

p<0.05

p<0.05

Phase III trial comparing Anastrazole with tamoxifen in hormone-dependant advanced

breast cancer

Milla-Santos A et al. Am J Clin Oncol 2003

CI, confidence intervals; CR, complete response; HR; hazard ratio; PR, partial response; TTP, time to progression

p-value

Study 025 Letrozole vs. Tamoxifen

Study 025 Letrozole vs. Tamoxifen

All treatments:• Double-blind• Given until progression

All treatments:• Double-blind• Given until progression

Extension phaseExtension phase

Crossover treatmentif appropriate

Crossover treatmentif appropriate

All patients followedfor survival every 6 months

All patients followedfor survival every 6 months

Follow-upFollow-up

RANDOMIZE

RANDOMIZE

Core phaseCore phase

Letrozole 2.5 mg PO QDLetrozole 2.5 mg PO QD

Tamoxifen 20 mg PO QDTamoxifen 20 mg PO QD

PO = Orally; QD = Every day.

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time, months0 3 6 9 12 15 18 21 24

Pro

gre

ssio

n-f

ree

Study 025 - Median TTPLetrozole 9.4 months Tamoxifen 6.0 months

p=0.0001

Log-rank P < .0001Log-rank P < .0001

Events, Wald N n (%) HR 95% CI P value

453 308 (68) 0.70 0.60 - 0.82 < .0001

454 350 (77)

Events, Wald N n (%) HR 95% CI P value

453 308 (68) 0.70 0.60 - 0.82 < .0001

454 350 (77)

Letrozole

Tamoxifen

Letrozole

Tamoxifen

Exemestane(n=61)

Tamoxifen(n=59)

Objective response (%) (CR + PR)

Clinical benefit (%)

(CR + PR + SD >24 weeks)

Median duration of response (months)

95% CI

41

57

16

11-38

17

42

22

12-36

Exemestane versus tamoxifen as first-line treatment for metastatic breast cancer

Randomized Phase II trial

Paridaens R et al. Ann Oncol 2003

CR, complete response; PR, partial response; SD, stable disease; CI, confidence intervals

Correlation between TTP and hormone receptor status for non-steroidal AIs and tamoxifen

1Bonneterre J et al. J Clin Oncol 20002Bonneterre J et al. Cancer 2001

3Mouridsen H et al. J Clin Oncol 20014Milla-Santos A et al. Am J Clin Oncol 2003

5Nabholtz JM et al. J Clin Oncol 2000

A1 A2 L3 L3 AA220

20

40

60

80

100

-1

0

1

2

3

4

5

6% receptor-positivedifference in TTP

A4 A5

% receptor-positive

Difference in TTP between AI and tamoxifen(months)

A, anastrozoleAI, aromatase inhibitorL, letrozoleTTP, time to progression

Recent Meta analysis AI’s vs. tamoxifen for Survival

Mauri D et al. JNCI 2006; 98: 1285 – 91.

In postmenopausal patients with HR +ve advanced disease

Aromatase Inhibitors as first line hormonal therapy have an overall

better therapeutic index than tamoxifen

Sequential use of Hormonal Agents in Postmenopausal Women with

Metastatic Breast Cancer: Role of the novel anti-estrogen Fulvestrant

Fulvestrant: unique mechanism of action

A new type of oestrogen receptor (ER) antagonist with no oestrogen agonist activity

Removing cellular ER may impact the onset of hormone resistance that occurs via cross-talk between growth factor signalling pathways and the ER

Competitively inhibits binding of oestradiol to

the ER

Impaired dimerisation,

destabilisation and degradation

of the ER

transcription of ER-regulated

genes, including the

PgR

ER = oestrogen receptor; PgR = progesterone receptor

Fulvestrant vs. Anastrozole: Trial Design

Postmenopausal women with advanced breast cancer receiving prior endocrine treatment for early or advanced breast cancer

Trial 0020: International, randomised 1:1, open, parallel-groupTrial 0020: International, randomised 1:1, open, parallel-groupTrial 0021: North American, randomised 1:1, double-blind, double-dummy, Trial 0021: North American, randomised 1:1, double-blind, double-dummy,

parallel-groupparallel-group

Anastrozole 1mg daily orallyTrial 0020: (n=229)Trial 0021: (n=194)

Fulvestrant 250mg i.m. once monthlyTrial 0020: 1 x 5ml (n=222)

Trial 0021: 2 x 2.5ml (n=206)

Analysis after 340 eventsAnalysis after 340 events(progression or death prior to progression)(progression or death prior to progression)

Trials 0020 and 0021: Recruitment between May 1997 and August 1999Trials 0020 and 0021: Recruitment between May 1997 and August 1999

Robertson JFR et al. Cancer 2003; 98: 229–238.

Hazard ratio (95.14% CI):0.95 (0.82–1.10); p=0.48

Fulvestrant vs. Anastrozole: Time to progression

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30 36

Median follow-up 15.1 months

Time to progression (months)

Median TTP: Fulvestrant = 5.5 monthsAnastrozole = 4.1 months

Fulvestrant 250 mgAnastrozole 1 mg

Robertson JFR et al. Cancer 2003; 98: 229–238

Proportion not progressed

Duration of response from randomisationto progression (responding patients)


0 6 12 18 24 30 36 42


Duration of response (months)

0.0

0.2

0.4

0.6

0.8

1.0Median DoR: Fulvestrant = 16.7 months

Anastrozole = 13.7 months

Proportionresponding


Duration of response – without or with visceral metastases

Duration of objective response (days)

0 200 400 600 800 1000

Fulvestrant 250 mg (n=52)Anastrozole 1 mg (n=45)

0.0

0.2

0.4

0.6

0.8

1.0

Without visceral metastases

Pro

po

rtio

n w

ith

o

bje

ctiv

e re

spo

nse

0 200 400 600 800 1000

0.0

0.2

0.4

0.6

0.8

1.0

Fulvestrant 250 mg (n=30)Anastrozole 1 mg (n=25)

With visceral metastases

Mauriac L et al. Eur J Cancer 2003; 39: 1228–1233

0 60 660.0

0.2

0.4

0.6

0.8

1.0

Overall survival (months)

Proportionalive

Fulvestrant vs. Anastrozole: Overall survival

54484236302418126

Median survival: Fulvestrant = 27.4 months (n=428)Anastrozole = 27.7 months (n=423)

Hazard ratio (95% CI):0.98 (0.84–1.15); p=0.81



Howell, A et al. Cancer 2005; 104: 236–9.

Gastrointestinal disturbances

Hot flushes

Urinary tract infection

Joint disorders

Thromboembolic disease

Vaginitis

Weight gain

Withdrawn due to adverse event

Number of adverse events (%)

Anastrozole(n=423)

Fulvestrant(n=423)

p-value

Fulvestrant vs. Anastrozole: Tolerability: predefined adverse events


196

89

31

23

15

11

4

12

(46.3)

(21.0)

(7.3)

(5.4)

(3.5)

(2.6)

(0.9)

(2.8)

185

87

18

45

17

8

7

8

(43.7)

(20.6)

(4.3)

(10.6)

(4.0)

(1.9)

(1.7)

(1.9)

0.53

0.91

0.06

0.0036

0.68

0.51

0.35


Indirect comparison of clinical benefit rates in second-line hormonal treatment trials

CB (CR + PR + SD ≥24 weeks) rate (%)

Fulvestrant1Anastrozole1

Anastrozole2

Letrozole2

Exemestane3

1Robertson et al. Cancer 2003; 98: 229–238; 2Rose et al. Eur J Cancer 2003; 39: 2318-23273Kaufman et al. J Clin Oncol 2000; 18: 1399-1411; 4Buzdar et al. J Clin Oncol 2001; 19: 3357-3366

5Dombernowsky et al. J Clin Oncol 1998; 16: 453-461; 6Buzdar et al. Cancer 1998; 83: 1142-1152

0 10 20 30 40 50

Megestrol acetate3

Letrozole4

Megestrol acetate4

Letrozole5Megestrol acetate5

Anastrozole6

Megestrol acetate640% vs 42%

32% vs 35%

30% vs 30%

35% vs 37%

23% vs 27%

41% vs 44%

1st treatment

2nd treatment

4th treatment

3rd treatment

Non-steroidal AI

Fulvestrant/Tamoxifen?Exemestane?

ExemestaneFulvestrant Tamoxifen

Tamoxifen TamoxifenExemestaneor

Fulvestrant

Postmenopausal Patients with ER+ Advanced Breast Cancer and hormonal options after Non-steroidal AI

Exemestane after non-steroidal AIs

Phase II, multicentre trial in postmenopausal patients with ABC (second- to fourth-line)

Patients had received a non-steroidal AI as their last treatment

Overall CB rate: 24.3%; overall RR : 6.6%

Aminoglutethimide(n=136)

Exemestane(n=241)

CB 27%

Anastrozole (n=46),

letrozole (n=40) orvorozole (n=19)

CB 20%

Lønning et al. J Clin Oncol 2000;18:2234-2244

NCCTG study – efficacy of fulvestrant following failure of an AI and tamoxifen

Overall CB rate: 35.0%, overall response rate: 14.3%

Median duration of response: 11.4 months

Median survival: 20.2 months– 1-year survival rate: 70.5%

Tamoxifen Fulvestrant(n=56)

AI Tamoxifen

AI

Adjuvant Advanced

Tamoxifen

AI Tamoxifen

AI

CB 28.6%OR 8.9%

AI CB 52.4%OR 28.6%

Fulvestrant(n=21)

Ingle et al. J Clin Oncol 2006; 24: 1052-1056

Prior non-steroidal AI therapy

Fulvestrant LD* + 250

mg / month+ placebo for exemestane

(n=330)

Exemestane 25 mg po od

+ placebo for

fulvestrant (n=330)

*LD, loading dose regimen (500 mg day 0 + 250 mg day 14 and day 28 and 250 mg/month thereafter)

• Endpoints– primary

TTP– secondary

OR rate duration of response CB rate survival quality of

life

pharmacokinetics safety

• Eligibility– histological

confirmation– postmenopausal

status– progression or

recurrence on prior AI therapy

– ER+ and / or PgR+– measurable

disease– performance status

0–2

Gradishar W et al. SABCS 2006

EFECT: Time to progression (ITT)

Proportion of patients progression-free

MonthsAt risk:FulvestrantExemestane

HR = 0.963, 95% CI (0.819, 1.133), p=0.6531

Cox analysis, p=0.7021

Fulvestrant

Exemestane

0 3 6 9 12 15 18 21 24 27

0.0

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

0

Fulvestrant

3.7

Exemestane

3.7Median (months)


EFECT: Objective response and clinical benefit rate (evaluable for response population)

* Analyses are not adjusted for baseline covariates

OR rate

(CR + PR)

CB rate

(OR + SD ≥24 wks)

Fulvestrant

7.4%

(20/270)

32.2%

(87/270)

Exemestane

6.7%

(18/270)

31.5%

(85/270)

Odds ratio*(95% CI)

1.120

(0.578, 2.186)

1.035

(0.720, 1.487)

p-value

0.7364

0.8534


EFECT:Duration of response (from randomisation)

Proportion of patients responding

Months

At risk:FulvestrantExemestane

Fulvestrant

Exemestane

0 3 6 9 12 15 18 21 24 27

0.0

0.2

0.4

0.6

0.8

1.0

20 20 16 11 8 3 0 0

18 18 15 10 5 4 3 3

0 0

3 3

Fulvestrant

13.5

Exemestane

9.8Median (months)


EFECT: Adverse events

Patient had an AE

Drug-related AE

Withdrawal due to AE

AE of grade 3 or higher

Serious AE

Drug-related SAE

Death due to AE

Death due to drug-related AE

Fulvestrantn=351

Exemestanen=340

88.9%

45.9%

2.0%

21.7%

11.4%

1.1%

0.9%

0%

88.8%

48.8%

2.6%

22.6%

12.4%

0.6%

0.9%

0%


EFECT Summary

The first phase III trial in this population

Confirmed efficacy of Fulvestrant in patients who have progressed on a NSAI

Similar efficacy seen on both treatment arms

No differences were seen in reported AEs between Fulvestrant and Exemestane


Recent Evidence with Trastuzumab (Herceptin) plus Anastrozole (Arimidex) in Advanced Breast Cancer in

post-menopausal women: TAnDEM Study

TrAstuzumab in Dual HER2-positive Metastatic breast cancer ESMO 2006

TAnDEM: Study Design

HER2-positive, HR-positive MBC

(n=208)R

Anastrozole 1 mg daily +

Trastuzumab 4 mg/kg loading dose

2 mg/kg qw until disease progression

Anastrozole1 mg daily until

disease progression

ESMO 2006

PFS = time from randomisation to date of progressive disease or death

103 48 31 17 14 13 11 9 4 1 1 0 0A + H

104 36 22 9 5 4 2 1 0 0 0 0 0A

Probability 1.0

0.8

0.6

0.4

0.2

0 5 10 15 20 25 30 35 40 45 50 55 60Months

95% CI

3.7, 7.02.0, 4.6

p value

0.0016

Median PFS

4.8 months2.4 months

Events

8799

0.0

No. at risk

TAnDEM: Progression-Free Survival

TAnDEM: Conclusions

The combination of A+H in first-line treatment of women with HER2-positive hormone-dependent MBC leads to significant improvements in :

PFS 4.8 vs. 2.4 months; p=0.0016

CBR 42.7% vs. 27.9%; p=0.026

ORR 20.3% vs. 6.8%; p=0.018

OS was longer in the A+H arm (28.5 vs. 23.9 months, p=0.325) despite crossover by patients in the A arm to receive H upon PD.

Endocrine Therapy in MBC

Summary

Many options available for metastatic breast cancer; hence individual patient and tumor characteristics are important in treatment decisions.

Clinical studies continue to clarify roles of endocrine therapy, chemotherapy, and biologic therapy, results are very promising.

For post-menopausal patients with hormone receptor-positive disease, several endocrine agents are available including AI’s (anastrozole, exemestane, and letrozole), SERM’s (tamoxifen) and the selective ER down-regulator, fulvestrant.

- Hormonal agents can be used sequentially in post-menopausal women

In pre-menopausal women (HR+ve tumour), tamoxifen or tamoxifen plus LHRHa may be a useful option

The potential effect of all of these endocrine, chemotherapeutic, and biologic treatments on quality of life is an important consideration.

Thank You

EGFR, HER2

Raf

MEK1/2

Ras

ERK 1/2

p90rskAKT

GRB2 SOS

PI3Kinase

Cbl

p110p85

p160ER CBPBasal

TranscriptionMachinery

ERE Target gene

PP

P

Rac1 cdc42

MLK3

MKK3/6MEKK1

P38

Inflammatory cytokinesTNF,IL-1

IGFR

Cytokinesstress

Many signal pathways target ER

Targets HER2 protein

High affinity and specificity

95% human, 5% murine

– Decreases potential for immunogenicity

– Increases potential for recruiting immune effector mechanisms

HER2 epitopes recognized by hypervariable murine

antibody fragment

Human IgG-1

Trastuzumab (Herceptin): Humanized Anti-HER2 Antibody

.

The HER Family

Adapted from Tzahar and Yarden. Biochim Biophys Acta. 1998;1377:M25.

The epidermal growth factor family of receptors comprises 4 transmembrane proteins, each with different properties but all involved

in the regulation of cell proliferation

Extracellular

Intracellular

Berger et al. Cancer Res. 1988;48:1238. Chazin et al. Oncogene. 1992;7:1859. Hynes and Stern. Biochim Biophys Acta. 1994;1198:165. O’Reilly et al. Br J Cancer. 1991;63:444. Paik et al. J Clin Oncol. 1990;8:103. Press et al. J Clin Oncol. 1997;15:2894. Slamon et al. Science. 1987;235:177. van de Vijver et al. N Engl J Med. 1988;319:1239.

Prognosis for HER2 Positive Patients

HER2 positivity is an independent predictor of poor prognosis

HER2 positivity also correlates with other clinical pathologic variables

– Short disease-free interval

– Tumor size

– Positive nodal status

– Ductal rather than lobular histology

– High S-phase fraction

– High nuclear grade

– Mutated p53

– Decreased estrogen and progesterone receptor expression

Slamon et al. N Engl J Med. 2001;344:783.

Trastuzumab Combination (with CT) Pivotal Trial: Time to Progression

H + CT 235 152 63 15

CT 234 103 25 6

1.0

0.8

0.6

0.4

0.2

0.0

p < 0.001Median follow-up: 35 mo

Herceptin + CT (n = 235)CT alone (n = 234)

0 5 10 15 20 25 30

Pro

gre

ssio

n-f

ree

surv

ival

MonthsNo. at risk:

Median TTP was significantly longer for the Herceptin + CT arms (7.4 months) than for the CT arms (4.6 months; p < 0.001).

Health & Medicine

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