Aromatase Inhibitors and Their Toxicities

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Aromatase Inhibitors and Their Toxicities

• Lessons learned from the adjuvant trials.

Normand Blais, MD Hématologist and medical
Oncologist Breast and thoracic oncology
units Hôpital Notre-Dame CAGPO Annual General
Meeting - Saturday October 21st 2006
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Outline

• Aromatase inhibitor physiology
• Patient benefit assessement
• Updated efficacy data
• Hormonal therapy toxicities
• Gynecologic
• Bone health
• Cardiovascular
• Thromboembolic disease

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What do hormones have to do with breast cancer?
Hormones 101

ESTROGEN MATTERS Dr Normand Blais

Estrogens and Progesterone
Before menopause
Ovarian aromatase
Gonadotrophins (FSH LH)
LH-RH (hypothalamus)
Breast
Pituitary gland
Adrenals
Before aftermenopause
Androgens Estrogens
ACTH
Progesterone
Peripheral aromatase
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Hormones 101
tumour growth
ANDROGENS
ESTROGENS
(Estradiol, estrone)
(Testosterone, androstenedione, 16-OH-testosteron
e)
Aromatase Inhibitors
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Peripheral Aromatase Inhibition Postmenopausal
Women
Inhibition ()
Residual ()
Letrozole Exemestane Anastrozole Formestane
(i.m.) Aminoglutethimide
98.9 97.9 96.7 91.9 90.6
1.1 2.1 3.3 8.1 9.4
Geisler et al, Eur J Cancer 199632A789-92. Geisl
er et al, Brit J Cancer 1996741286-91. Geisler
et al, Clin Cancer Res 19984208993.
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Who should be treated ?
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Adjuvant online55 ans, er, 1.2 cm, grade 2 (10
yrs)
Adjuvant! Online V 8.0, accessed 10/2006
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Adjuvant online 70 ans, er, 1.2 cm, grade 2
(10 yrs)
Adjuvant! Online V 8.0, accessed 10/2006
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Oncotype DXTM multi-gene prognostic assay
Paik et al, NEJM 12/2004
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Paik, ASCO 2005
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Paik, ASCO 2005
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Mammaprint 70 gene model (Amsterdam) vs
Adjuvant! (DFS)
Buyse et al, JNCI 09/2006
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Summary of the adjuvant trials
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Recurrence rate of breast cancer according to
estrogen receptor status
0,3
ER (n 2 257)
ER (n 1305)
0,2
Recurrence rate
0,1
0
0
1
2
3
4
5
6
7
8
9
10
11
12
Years
Saphner et al. J Clin Oncol. 1996142738.
16
Recurrence and mortality rate from breast cancer
with and without 5 years of tamoxifen therapy
Early Breast Cancer Trialists' Collaborative
Group (EBCTCG), The Lancet, Mai 2005
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Benefits and risks of TAM
Fisher, JNCI 11/2005
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Overview of Ongoing Trials with AIs
A
Anastrozole
ATAC
A T
T
Letrozole
T
L
BIG 1-98
Exemestane
L
T
T
L
Tamoxifen
IES
T
T
E
Placebo
ARNO/ABCSG
T
A
T
NCIC MA-17
T
P
P
T
L
L
TEAM
T
E
EXEM 027
E
Years 10 15
P
MA27
A
E
Years
5
2
0
7
10
Adjuvant
Extended Adjuvant
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Recurrence rate/year()
16
12
8
Node ve
4
Node -ve
0
0
2
4
6
8
10
Time (years)
Tamoxifen
Arimidex, Tamoxifen Alone or in Combination
(ATAC)
Anastrozole
Upfront Adjuvant
Tamoxifen
Breast International Group (BIG) 1-98
Letrozole
Saphner T et al. J Clin Oncol 1996142738-2746
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Cumulative IncidenceBreast Cancer Relapse
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5-year diff (L-T) -3.2 (S.E. 1.1) Cum inc
P0.005
13.4
15
T
Proportion Relapse ()
7.9
L
10
10.2
5
6.0
0
0
2
3
4
5
1
Years from Randomization
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ATAC versus BIG 1-98 Efficacy Endpoints
ATAC HR 68 m2
BIG 1-98 51 m1

0.82
DFS
0.91
0.97
OS

0.87
Systemic DFS
0.83
0.83
DFS (w/o 2nd malignancy)
0.81
0.84
Time to distant recurrence
0.74
0.78
Time to recurrence
1.0
0.5
0.75
1.33
2.0
Hazard Ratio (LetrozoleTamoxifen)
Favours L
Favours T
1 Coates AB, et al. ESMO 2006 2 ATAC Trialists
Group. Lancet. 200536560-62
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Recurrence rate/year()
16
12
8
Node ve
4
Node -ve
0
0
2
4
6
8
10
Time (years)
Tamoxifen
Italian Tamoxifen Anastrozole (ITA) Austrian
Breast Colorectal Cancer Study Group (ABCSG)
8 / Arimidex-Nolvadex (ARNO) 95
Anastrozole
Tamoxifen
Switching
Tamoxifen
International Exemestane Study (IES)
Exemestane
Tamoxifen
Saphner T et al. J Clin Oncol 1996142738-2746
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IES Schema
RANDOMIZATION
Postmenopausal women Early ER breast
cancer Disease free after adjuvant tamoxifen 20
mg po qd 23 years
3-2 yearsExemestane25 mg po qd
3-2 yearsTamoxifen 20 mg po qd
5 years total therapy
Coombes RC et al. N Engl J Med 2004
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Does Exemestane Improve Disease Free Survival?
Intent to Treat
Exemestane
End of treatment
354 events 2352 at risk
Tamoxifen
454 events 2372 at risk
HR 0.76 95 CI (0.66 0.88) P-value 0.0001
2.5 years 3.2 (1.6 4.9)
5 years 3.4 (0.1 6.8)
absolute difference (95 CI)
Coombes, ASCO 2006.
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Does Exemestane Improve Overall Survival?
Intent to Treat
Exemestane
End of treatment
222 events 2352 at risk
Tamoxifen
261 events 2372 at risk
HR 0.85 95 CI (0.71 1.02) P-value 0.08
2.5 years 0.8 (-0.4 1.9)
5 years 1.2 (-1.5 3.9)
absolute difference (95 CI)
Coombes, ASCO 2006.
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Does Exemestane Improve Overall Survival?
ER/Unknown
Exemestane
210 events 2296 at risk
End of treatment
HR 0.83 95 CI (0.69 1.00) P-value 0.05
2.5 years 0.7 (-0.4 1.9)
5 years 1.6 (-1.2 4.3)
absolute difference (95 CI)
Coombes, ASCO 2006.
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ABCSG 8/ ARNO 95 Combined Analysis Trial
Structure
TAM 3 years n1,606
Total patients N3,224 ABCSG 8 n2,262 ARNO
95 n962
Primary surgery /- RTx
TAM 2 years
ANA 3 years n1,618
Jakesz R at al. San Antonio Breast Cancer
Symposium 2004.
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Event-free survival
EFS ()
100
ANA
95
90
TAM
85
80
ANA vs TAM p0.0009 HR 0.60 95 CI 0.44-0.81
75
0
0
1
2
3
4
5
EFS time in years
At risk
1606
343
176
1217
858
TAM
593
874
ANA
1618
1243
623
375
178
Zero point 2 years after surgery
Jakesz R at al. San Antonio Breast Cancer
Symposium 2004.
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Recurrence rate/year()
16
12
8
Node ve
4
Node -ve
0
0
2
4
6
8
10
Time (years)
Tamoxifen
MA-17
Extend
Tamoxifen
Letrozole
Tamoxifen
ABCSG 6
Tamoxifen
Anastrozole
Saphner T et al. J Clin Oncol 1996142738-2746
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MA.17 Trial Design
Randomization (Disease-free)
Letrozole 2.5 mg qd
Tamoxifen
Placebo qd
?5 years early adjuvant
5 years extended adjuvant
Primary end point DFS Secondary end points
OS/safety/QOL
n 2575 (efficacy) 2154 (safety) in the
letrozole arm. n 2582 (efficacy) 2145
(safety) in the placebo arm.
Goss PE et al. N Engl J Med 2003
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DFS (HR) 0.58, p lt.001
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OS (HR) 0.82, p .3
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Duration of letrozole treatment and outcomes in
the placebo-controlled NCIC CTG MA.17 extended
adjuvant therapy trial
Ingle et al, Breast Cancer Res Treat, 10/2006
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Burstein model (DFCI)

• Limitations
• Maximal  carry-over effect  assumed for TAM and
  AIs
• Based on DFS from ATAC, IES, BIG and ITA.
• And TTR from MA-17,ABCSG
• Linear recurrence rate over time
•  Sensitivity analysis  based on5 years of AIs
  after 2-3 years of TAM

Punglia et al, JCO 08/2005
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N-
N
Based on IES
N
Based on ITA
Punglia et al, JCO 08/2005
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Cuzick model

• Limitations
• Uses post-hoc TTR data from ATAC
• Makes data more comparable to EBCTCG
• Maximal  carry-over effect  assumed for TAM and
  AIs

Cuzick et al, abr 658, ASCO 2005
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Toxicities and AIs and Tamoxifen
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ATAC adverse events ()
plt 0,0001 lt 0,0001 lt 0,0001 0,02 0,03
0,0004 lt 0,0001 lt 0,0001
T 40,9 10,2 13,2 0,8 2,8 4,5
29,4 7,7
A 35,7 5,4 3,5 0,2 2,0 2,8
35,6 11,0
Hot flushes Vaginal bleeding Vaginal
discharge Endometrial cancer CVAs DVT-PE Joint
pain Fractures
Patients with ³ 1 fracture before recurrence,
including patients having stopped therapy.
ATAC Trialists Group. Lancet 200536560-62.
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Adverse events - BIG 1-98
1
CVAS
1
1.5
DVT-PE
3.5
Letrozole
4.1
Cardiac events
3.8
Tamoxifen
Fractures
5.7
4
3.3
Vaginal bleeding
6.6
6.4
Muscular pain
6.1
20.3
Joint pain
12.3
43.5
Hypercholesterolemia
19.1
33.5
Hot flushes
38
13.9
Night sweats
16.2
0
10
20
30
40
50
de pts
Fasting not mandated before blood sampling
Thurlimann B. ASCO 2005
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Adverse events IES
Adapted from Coombes et al. SABCS 2004.
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Adverse events MA-17
Letrozole Placebo p Hot flushes 58 54 0,003 Join
t pain 25 21 lt 0,0001 Muscular pain 15 12 0,04 Ost
eoporosis 8 6 0,003 Hypercholesterolemia 16 16 0,7
9 CVA 6 6 0,76 Fractures 5,3 4,6 0,25 Vaginal
bleeding 6 8 0,005
Adapted Goss. ASCO, 2004.
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Gyne symptoms - ATAC
Duffy, ESMO 2006
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Osteoporosis - ATAC

• Risk varies according to baseline BMD
• Bisphosphonates security ?
• ONJ

Coleman et al, ASCO 2006
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Osteonecrosis of the jaw
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ONJ - BON

• Estimated risk of ONJ for IV (Web based survey,
  Durie et al., NEJM 2005)
• Up to 7 in MM
• And 4,4 in breast cancer
• Prospective Greek study (Bamias et al, JCO 2005)
• Incidence 9.9 (MM), 2.9 (BrCa),6.5 (PrCa)
• Zoledr. HR of 1 at 1 yr ? 21 at 3 yrs
• Pamidr. HR of 0 at 2 yrs ? 7 at 4 yrs
• 70 related to recent dental procedures
• Median exposure of 35 infusions (13-68)

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Effect of letrozole vs tamoxifen on total serum
cholesterol
Cholesterol values remained stable in the
letrozole arm and decreased in the tamoxifen arm
by approximately 12
To convert mmol/L to mg/dL, multiply by 39
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Variation () of cholesterol after 5 yrs of
tamoxifen (MA-17)
Letrozole
8
Placebo
7
14,6
13,4
13,6
12,5
11,1
10,2
8,4
10,5
6
5
Total Cholesterol
(mmol/L)
4
3
NS
2
1
0
6 ms
12 ms
24 ms
36 ms
Start of study
Valeurs au fil du temps
Wasan KM, Goss P et al. Annals of Oncology 2005
16(5)707-715
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Cardiac toxicity

• Hortobagyi ESMO 2006
• There appears to be a 10 to 20 increase in
  cardiovascular events associated with IAs
• Risk 0,65 ?
• AINS / COX-2 inhibitor effect ?
• arthralgias

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In conclusion

• Many new options for the treatment of ER/PR
  breast cancer AFTER menopause.
• Best strategy to be defined by comparative trials
• Next results in 2008 (BIG 1-98)
• Different toxicity profiles of TAM and 3 new AIs
• Individualization of therapy !!