Endocrine Therapy In Advanced Breast Cancer
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Transcript of 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-/post- menopausal
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
Estrogenbiosynthesis
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
Estrogenbiosynthesis
Tumor cell
Nucleus
Inhibition of cell
proliferation
Estrogenbiosynthesis
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)
Median follow-up 22.1 months
0 6 12 18 24 30 36 42
Fulvestrant 250 mgAnastrozole 1 mg
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
Robertson JFR et al. Cancer 2003; 98: 229–238
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
Median follow-up 27.0 months
Fulvestrant 250 mgAnastrozole 1 mg
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
Robertson JFR et al. Cancer 2003; 98: 229–238
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
Robertson JFR et al. Cancer 2003; 98: 229–238
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)
Gradishar W et al. SABCS 2006
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
Gradishar W et al. SABCS 2006
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)
Gradishar W et al. SABCS 2006
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%
Gradishar W et al. SABCS 2006
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
Gradishar W et al. SABCS 2006
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).