Transcript Challenges in the Treatment of Breast Cancer: Overcoming

Clinical Updates
Optimizing Endocrine Therapy for Early Breast Cancer
A Case Based Approach to
Hormone Therapy
Hope S. Rugo, MD
Professor of Medicine
Director, Breast Oncology and Clinical Trials Education
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, CA
Case 1
• A healthy 48 year old woman discovers a mass in
the central right breast while showering. A
mammogram 6 months before showed dense
breasts without focal mass.
– Exam: 2 cm central breast mass, no palpable axillary nodes
– Ultrasound: 1.8 cm ill-defined hypoechoic mass
• Ultrasound guided core biopsy reveals a grade II invasive
ductal carcinoma with lymphovascular invasion
Case I (cont.)
• Lumpectomy and sentinel lymph node biopsy reveals a 2.1
cm grade II invasive ductal cancer that is ER+, PR+ and
HER2 1+ (negative) by IHC, one sentinel lymph node is
positive for 0.8 cm of invasive cancer
– Completion axillary lymph node dissection reveals 1 additional
positive node for a total of 2/15 positive nodes
• She is well with no medical problems and is seeing you to
discuss adjuvant therapy
– She is premenopausal, although she notes skipped menses every
few months for the last year
Question
•
The patient receives adjuvant chemotherapy and
has completed radiation. Her last menstrual
period was the month before starting
chemotherapy.
•
You recommend:
1.
An aromatase inhibitor (AI) for 5 years
2.
Tamoxifen for 2-3 years followed by an AI for a total duration
of 5 years
3.
Tamoxifen for 5 years followed by discussion of extended
adjuvant hormone therapy with an AI
4.
Ovarian suppression or ablation with tamoxifen
5.
Ovarian suppression or ablation with an AI
Important Points to Consider
• How to choose the best hormone therapy for your
patient?
– When is a woman in menopause?
– When are AIs safe to give to perimenopausal women?
– Should ovarian suppression be used routinely?
What Hormone Therapy?
• Premenopausal at treatment start
– Amenorrheic after chemotherapy does not mean
menopause
– Safest approach upfront is tamoxifen
• Options include
– Tamoxifen for 5 years followed by an AI
– Tamoxifen for 2-3 years to guarantee menopause, then
AI to complete 5 years of therapy
– Tamoxifen with ovarian suppression if ovaries recover
Estradiol, FSH and Amenorrhea
Following Chemotherapy for Breast Cancer
• Braverman et al, 2002
– 16 women with amenorrhea
• 10 with E2 > 40pg, 8 were amenorrheic > 6 months
• 5 with E2 > 40pg but FSH > 40
– Ovarian function may persist for months, and possibly years after
chemotherapy induced amenorrhea
• Amenorrhea is not menopause
• AIs stimulate ovarian function!
– Beware of AIs in young women with chemotherapy induced
amenorrhea
AIs Stimulate Gonadotropin Production in Women
Whose Ovaries are Still Active; Resulting in Ovarian
Stimulation and Follicle Growth
De Ziegler et al, J Steroid Biochem and Biol, 2005
Chemotherapy-induced Amenorrhea
Royal Marsden Experience - Case Series
45 women with CIA* on AIs
(16 upfront, 20 switching, 9 extended)
• Median age: 47 (range 39-52)
• 33 biochemically confirmed ovarian suppression before therapy
• 12 (27%) recovered ovarian function
–
menses [10],
–
pregnancy without menses [1],
–
biochemical assay without menses [1]
• Median duration of amenorrhea before recovering ovarian function
12 months (range 4-59)
* Chemotherapy-Induced Amenorrhea
Smith I et al, JCO 2006
Criteria for Determining Menopause
(NCCN v.2.2008)
• Prior bilateral oophorectomy
• Age > 60 y
• Age < 60 y and amenorrheic for 12 or more months in the absence
of CT, Tam, toremifene or ovarian suppression and FSH and
estradiol in the post-menopausal range
• If taking tamoxifen or toremifene, and age < 60 y, then FSH and
plasma estradiol level in post-menopausal ranges
• It is not possible to assign menopausal status in women receiving
LHRH agonist or antagonist
• In women pre-menopausal (by hormonal status and/or with
menses) at the beginning of adjuvant therapy CT-induced
amenorrhea is not a reliable indicator of menopausal status
IES - Intergroup Exemestane Study Cumulative HR
Overall Survival
ITT
ER+/Unknown
Exemestane
0.14
0.12
0.12
0.10
0.08
0.06
0.04
0.02
0.10
End of
treatment
Cumulative Rate
0.14
End of
treatment
Cumulative Rate
Tamoxifen
0.08
0.06
0.04
0.02
0.00
0
1
2
3
4
5
0.00
0
1
Time since randomization (years)
2
3
4
5
Time since randomization (years)
Annual Hazard Rate, % (95% CI)
ITT
1
2
3
4
5
Exemestane
0.8 (0.5, 1.2)
1.8 (1.3, 2.5)
2.2 (1.6, 2.9)
3.6 (2.8, 4.5)
2.3 (1.6, 3.4)
Tamoxifen
1.0 (0.7, 1.5)
2.4 (1.8, 3.1)
2.5 (2.0, 3.3)
3.2 (2.5, 4.1)
2.9 (2.1, 4.1)
Jassem, J. et al Anticancer Drugs. 2008 Feb;19 Suppl 1:S3-7.
IES - Intergroup Exemestane Study
Consistency of OS Across Subgroups
Favors Tamoxifen
Favors Exemestane
ER+/Unknown
HR (95% CI)
Nodes negative (2384)
Nodes positive (2038)
0.84 (0.61, 1.18)
0.75 (0.60, 0.95)
No previous CT (3103)
Previous CT (1499)
0.85 (0.67, 1.07)
0.81 (0.60, 1.09)
ER positive (4042)
ER unknown (560)
0.84 (0.69, 1.02)
0.83 (0.52, 1.32)
Prior tam ≤2.5 yrs (2764)
Prior tam >2.5 yrs (1838)
0.83 (0.65, 1.05)
0.84 (0.63, 1.13)
Age <60 yrs (1480)
Age 60-69 yrs (1969)
Age >70 yrs (1153)
1.01 (0.70, 1.47)
0.70 (0.52, 0.95)
0.90 (0.67, 1.22)
OS (Adjusted)*
0.83 (0.69, 0.99)
p=0.04
0.5
0.6
0.8
1.0
1.2
1.5
Hazard ratio (95% CI)
CT=chemotherapy
*Adjusted for Nodal Status, Chemotherapy Use & HRT Use
Coombes RC et al. Lancet 2007; 369: 559-70.
Results of Switch Trials
HR DFS
IES
0.76
n=4,274
ARNO
0.62
n=979
ABCSG
0.61
n=2579
ITA
0.42
n=448
exemestane
1.0
anastrozole
tamoxifen
AIs
better
TAM
better
Boccardo, F et al Ann Oncol. 2006 Jun;17 Suppl 7:vii10-4,
Jakesz, R. et al Lancet. 2005 Aug 6-12;366(9484):455-62.
ABCSG12
ANA Does Not Improve DFS vs TAM in 1800
Premenopausal Women with Early Stage Disease
100
Disease-free survival, %
90
80
70
60
Overall: 4-year DFS = 92.4%; 4-year OS = 97.7%
30% with node positive disease
50
40
30
20
ANA
TAM
10
0
No. of
events
72
65
Hazard ratio (95% CI)
vs TAM
1.096 (0.78 to 1.53)
P value
.593
0
12
24
36
48
60
Time since randomization, months
72
84
TAM
900
834
718
552
411
243
129
50
ANA
903
844
725
540
411
255
139
51
No. at risk
Median follow-up = 48 months.
Gnant et al, NEJM 2009
MA.17: Summary of Efficacy
DFS
Distant DFS
OS
Node+
HR 0.61*
HR 0.53*
HR 0.61*
patients
(95% CI, 0.45-0.84)
(95% CI, 0.36-0.78)
(95% CI, 0.38-0.98)
All patients
HR 0.58; P<0.001
HR 0.60; P<0.002
HR 0.82+; P=0.3
Node–
HR 0.45*
HR 0.63
HR 1.52
patients
(95% CI, 0.27-0.75)
(95% CI, 0.31-1.27)
(95% CI, 0.76-3.06)
 Extended adjuvant letrozole significantly decreased overall risk of recurrence by 42%
(4.2% absolute reduction) and risk of developing distant metastases by 40% compared
with placebo.
*Statistically significant benefit of letrozole.
+Absolute increase of 0.4% for letrozole.
HR = hazard ratio; CI = confidence interval.
Goss et al. J Natl Cancer Inst. 2005;97:1262.
Peri-menopausal Women
Assessment and Therapy
Yes
Test
Tamoxifen
Exemestane
Post-menopause
No
Tamoxifen
2-3 years
2-3 years
Switch to AI in peri-menopausal patients is an option
but only if
close monitoring of ovarian function is performed
Adjuvant Endocrine Therapy Trials
In Hormone-responsive Pre-menopausal
Breast Cancer Patients
Study
Design
Patient Population
Questions
TAM 5y
vs
TAM 5 y + OFS
vs
EXE 5 y + OFS
2,700 pre-menopausal women
with endocrine responsive
disease treated with no
adjuvant chemo or remain premenopausal after chemo
Does OS add to TAM (or EXE) in
pre-menopausal women not
treated with chemotherapy?
Does OFS add to chemo in premenopausal women?
TEXT
(IBCSG 25-02)
OFS = TAM 5 y
vs
OFS + EXE 5 y
2,025 pre-menopausal women
with endocrine responsive
disease and candidates for
OFS, and who may or may not
receive chemo
Is an AI superior to TAM in premenopausal women treated with
OFS?
ABC SG 12
OFS + TAM
vs
OFS + ANA
1,750 pre-menopausal women
with endocrine responsive
disease
Is an AI superior to TAM in premenopausal women treated with
OFS?
Study
SOFT
(IBCSG 24-02)
OFS=Ovarian Function Suppression
ZOL Significantly Improves DFS Compared With
Endocrine Therapy Alone
100
Disease-free survival, %
90
80
70
60
50
40
30
20
ZOL
No ZOL
10
No. of
events
54
83
Hazard ratio (95% CI)
vs No ZOL
0.64 (0.46, 0.91)
P value
.012
0
0
No. at risk
No ZOL 904
ZOL 899
12
832
846
24
36
48
60
Time since randomization, months
713
730
537
555
407
414
241
257
72
145
123
84
47
54
Median follow-up = 48 months.
Gnant et al, NEJM 2009
What Would I Do?
• Hormonal therapy
– This patient is likely to recover some degree of ovarian
function
• I would use tamoxifen upfront followed by an AI when clearly
menopausal, similar to the sequencing used in the IES trial
– Duration of therapy
• Based on MA.17, I would consider extending the duration of AI
therapy to 5 years if given following a course of tamoxifen
• This patient would also be eligible for ongoing trials evaluating
duration of AI therapy
– Consider bisphosphonate trials……
Case 2
• A 62 year old healthy postmenopausal woman
is diagnosed with:
–
–
–
–
1.5 cm infiltrating ductal carcinoma
Grade II, KI-67 20%
ER-positive (50%)/PR-negative (5%)
HER-2 negative by FISH
• She undergoes lumpectomy and sentinel lymph
node biopsy
– Margins of resection are negative
– One sentinel node is positive for carcinoma
– Completion axillary dissection reveals a total of 4
out of 20 nodes positive
Question
She is treated with an anthracycline and taxane
chemotherapy regimen and radiation
You then recommend:
– 5 years of tamoxifen
– 5 years of an aromatase inhibitor
– 2 years of tamoxifen followed by 3 years of an
aromatase inhibitor
– 2 years of an aromatase inhibitor followed by 3 years
of tamoxifen
– 5 years of tamoxifen followed by 5 years of an
aromatase inhibitor
– Use of CYP2D6 testing to help in the decision of
what hormonal therapy to use
Breast Cancer Adjuvant Therapy
Replacing 5 Years of Tamoxifen
as the Gold Standard
Three Strategies
AIs as
Initial Therapy
AIs After
2-3 Yrs of TAM
TAM X 5 Yrs
TAM X 5 Yrs
AIs After
5 Years of TAM
AI X 5 Yrs
TAM X 5 Yrs
AI X 5 Yrs
TAM X 2-3 AI X 2-3
PLAC X 5 Yrs
Relative Reductions in DFS Event
As Reported in Eight AI Adjuvant Trials
Anastrozole
Letrozole
Exemestane
70
60
ITA
52 m
58%
MA.17
30 m
Percent
50
40
IES
56 m
30
20
ATAC
100 m
10
15%
BIG
76 m
TEAM
2.75 y
24%
42%
ABCSG/
ARNO
72 m
ABCSG-6
60 m
36%
B-33
30 m
32%
18%
12%
11%
0
Up-Front
ATAC trialists’ group. Lancet Oncol 2008
Mouridsen H, et al. SABCS 2008
Jones S, et al: SABCS 2008
After 2-3 yrs
of TAM
Boccardo et al. ASCO 2005
Coombes RC et al. ASCO 2006
Jakesz et al. SABCS 2008
After 5 yrs
of TAM
Goss et al. JNCI 2005
Jakesz et al. ASCO 2005
Mamounas et al. JCO 2008
BIG 1-98 Trial
S
U
R
G
E
R
Y
Tamoxifen
N=911
Letrozole
N=917
Tamoxifen
N=1548
Letrozole
N=1546
N=1828
Enrolled
1998-2000
R
0
Tam
Let
N=1548
Let
Tam
N=1540
2
Years
5
N=8010
N=6182
Enrolled
1999-2003
619 patients crossed
over from tamoxifen
only to letrozole arm
Previous analyses show 5 yrs of upfront letrozole significantly
prolongs DFS and time to distant recurrence vs upfront tamoxifen
DFS=disease-free survival.
Mouridsen. SABCS. 2008 (abstr 13); BIG 1-98 Collaborative Group. N Engl J Med. 2005;353:2747; Coates. J Clin Oncol.
2007;25:486.
BIG 1-98: Sequential Therapy TTR
Tam
Let
Letrozole
1
5
9.1
10
4.1
5
7.3
2.5
0
0
Tam vs Let
Breast Cancer Recurrence (%)
Let
Breast Cancer Recurrence (%)
Overall
2
0
1
2
3
4
5
Years From Randomization
Let
Tam
Letrozole
1
5
1
0
7.3
5
2.5
7.3
2.5
0
0
TTR=time to recurrence.
1
2
3
4
5
6
Years From Randomization
Tam
Let
Letrozole
14.7
15
Node+
10
12.
4
4.9
7.9
4.7
5
1.3
0.9
0
0
6
Overall
2
0
By Nodal Status*
2
0
Breast Cancer Recurrence (%)
Let vs Let
Breast Cancer Recurrence (%)
Tam
Node–
*42% of
population is
node+; 58%
is node–.
3.5
1
2
3
4
5
6
Years From Randomization
By Nodal Status*
2
0
Let
Tam
Letrozole
15
12.5
Node+
1
0
12.4
4.7
5
3.9
3.9
1.5
0.9
0
0
Node–
3.5
2
3
4
5
1
6
Years From Randomization
Mouridsen. SABCS. 2008 (abstr 13).
More Than Half of Breast Cancer
Recurrences and Deaths Occur Post-Tamoxifen
Recurrences
15%
100
17%
9%
100
85.2
62.7
54.9
40
Tamoxifen
Control
55%
% of patients
68%
73.7
20
91.4
80
68.2
60
18%
80.9
76.1
80
% of patients
Breast Cancer Deaths
87.8
73.0
73.2
60
64.0
73%
64%
40
Tamoxifen
Control
20
0
0
0
5
10
Years
15
0
5
10
15
Years
Adapted with permission.
Early Breast Cancer Trialists’ Collaborative Group Meeting, 2000.
NSABP B-42
Trial Evaluating Adjuvant AI Duration
Postmenopausal, Disease-free, Stage I, II, or III invasive BC
at diagnosis ER-positive and/or PgR-positive
AI X 5 yrs
TAM X 2-3 yrs
AI X 3-2 yrs
Planned Accrual:
3,840
Letrozole X 5 yrs
Placebo X 5 yrs
Other Duration Trials:
NCIC MA.17R
Sole – intermittent dosing
Decreased Tamoxifen Metabolism
Non-compliance
X
Enzymatic Repression
Inhibitory Influences
Adapted from: Stearns, V et al. J Natl Cancer Inst. 2003 Dec 3;95(23):1758-64.
CYP2D6 Genotype and Endoxifen
180
P<0.001, r2=0.24
160
Plasma
Endoxifen
(nM)
140
120
100
80
60
40
20
0
Wt/Wt
Wt/*4
*4/*4
CYP2D6*4
(most common genetic variant associated with the CYP2D6 poor metabolizer state)
Jin Y et al: J Natl Cancer Inst 97:30, 2005
RFS According to CYP2D6 (*4)
Metabolizer Status in Women Receiving TAM as Adjuvant Therapy
100
n=171
EM (n=115)
80
60
IM (n=40)
%
40
2-year RFS
EM 98%
IM 92%
PM 68%
20
PM (n=16)
Log rank
Multivariate HR
(PM+IM/EM)=1.74
P=0.017
P=0.009
0
0
2
4
6
8
10
12
Years after randomization
E: Extensive
P: Poor
I: Intermediate
M: Metabolizer
Goetz M et al. Breast Cancer Res Treat 101:113-121, 2007
Incidence of Moderate or Severe
Hot Flashes and CYP2D6 Status
Genotype
% of Patients With Moderate or
Severe Hot Flashes
CYP2D6 *4/*4
0%
CYP2D6 *4/WT or Wt/WT
20%
Goetz et al J Clin Oncol. 2005;23(36):9312-8.
Breast Cancer and
Relevant Inhibitors of CYP2D6
Strong Inhibitors
Moderate Inhibitors
Non or weak Inhibitors
Generic / Brand Names
Generic / Brand Names
Generic / Brand Names
Fluoxetine Prozac®
Diphenhydramine Benadryl®
Venlavaxine Effexor®
Paroxetine Paxil®
Thioridazine Mellaril®
Qunidine Cardioquin®
Duloxetine Cymbalta®
Bupropion Wellbutrin®
Cimetidine Tagamet®
Amiodarone Cordarone®
Citalopram Celexa®
Escitalopram Lexapro®
Sertraline Zoloft® (moderate?)
Adapted from: http://medicine.iupui.edu/clinpharm/ddis
What Would I Do in This Case?
• She has a high risk cancer and is clearly postmenopausal
• I would start with an aromatase inhibitor
• If she has significant side effects, consider changing to
tamoxifen after two or three years
• The optimal duration of hormonal therapy has not yet been
defined, however:
– Several trials are evaluating the impact of longer duration AI
therapy
– When this patient is five years out from start of hormone therapy,
additional data should be available
– For patients on therapy now, consider tolerance of hormone
therapy, co-morbidiity and risk of relapse in your recommendation
regarding treatment duration
Conclusion
• The future for hormone receptor positive breast cancer
is very exciting and will help us to understand the
pathways responsible for resistance to hormone
therapy – and then use appropriate targeted agents to
prevent recurrence and improve the treatment of
advanced disease.