Download Patient Presentation

Chemotherapy Adjuvant
Treatment (ChAT)
for Breast Cancer in Young Women
Learning Objectives
 At the conclusion of the session, participants should be
able to
– Describe the physiologic decline in fertility that occurs with
aging
– Raise the issue of fertility with all premenopausal women who
require chemotherapy
– Discuss the possible effects of treatment on fertility
– Recognize endocrine effects of chemotherapy
– Identify women who are appropriate candidates for ovarian
ablation or suppression
– Refer appropriate women to a fertility specialist to explore
options for fertility preservation
1. Patient Presentation
1.
2.
3.
4.
5.
6.
7.
8.
9.
Patient presentation
Normal ovarian function
Ovarian ablation or suppression
Chemotherapy
Trastuzumab
Pregnancy after breast cancer
Gonadotoxicity of chemotherapy
Endocrine effects of chemotherapy
Referral to a fertility specialist
Patient Presentation




36-yr-old woman
Recent diagnosis of left-sided breast cancer
Lumpectomy and sentinel lymph node sampling
Pathology:
–
–
–
–
–
–
1.7 cm invasive ductal carcinoma
Grade 2/3
No lymphovascular invasion
ER/PR: positive
HER2: nonamplified
Sentinel lymph nodes: negative (0/2)
?
When will you ask your patient about her future plans to
have children?
a.
b.
c.
d.
e.
Now
When I tell her the risks of the therapy that she will receive
After she’s recovered from surgery
I won’t ask, but I will answer her questions about fertility
I won’t ask, and I’m not sure how to answer fertility questions
Raising the Topic of Fertility
“The issue of fertility preservation for
a young woman with breast cancer
should be mentioned right at the
beginning of discussion related to
treatment and its possible results,
such as early menopause.”
Ellen Greenblatt MD FRCSC
Clinical Director
Reproductive Biology & IVF Units
Mount Sinai Hospital, Toronto
 The patient reveals that she might want to have a
child in the future.
2. Normal Ovarian Function
1.
2.
3.
4.
5.
6.
7.
8.
9.
Patient presentation
Normal ovarian function
Ovarian ablation or suppression
Chemotherapy
Trastuzumab
Pregnancy after breast cancer
Gonadotoxicity of chemotherapy
Endocrine effects of chemotherapy
Referral to a fertility specialist
?
 Average maternal age at birth
of first child:
– 1970 = 24.6 yr
– 2003 = 28.0 yr
 % of first-time mothers >30 yr:
– 1983 = 14%
– 1999 = 32%
 % of first-time mothers 35–39 yr:
– 1974 = 13%
– 1994 = 25%
Statistics Canada. Births 2003
CMAJ 2002
Tough SC et al. Pediatrics 2002
?
Why has the average age of first-time mothers
increased?
–
–
–
–
–
Increased participation in higher education
Delay due to career
Delayed marriage
Poor awareness of impact of age on fertility
Unrealistic expectations of assisted reproductive
technology
Hammarberg K et al. Aust Fam Physician 2005
Baldwin WH et al. Popul Bull 1984
?
 Definitions:
– Infertility
– Sterility
?
Woman’s Age
at Marriage (yr)
Failure to
Conceive (%)
(no contraception)
20–24
6
25–29
9
30–34
15
35–39
30
40–44
64
Menken J et al. Science 1986
Fertility and Miscarriage Rates as a
Function of Maternal Age
Heffner LJ. N Engl J Med 2004
Courtesy of John Parrish PhD, University of Wisconsin–Madison
Back to Basics: Menstrual Cycle
Ovary
Byer C et al. Dimensions of human sexuality, 2002. © The McGraw-Hill Companies
Ovarian Aging
 Embryo at 8 wk = 600,000 oocytes
 20 wk = 7 million oocytes
 Birth = 1 million oocytes
 Puberty = 250,000 primordial follicles
 Age 37 yr = 25,000 primordial follicles
 Menopause = 1000 follicles
Bukman A et al. Hum Reprod Update 2001
Ovarian Reserve
 ovarian reserve with age
7-yr-old
Cortvrindt RG et al. Fertil Steril 2001
20-yr-old
30-yr-old
Like Mother, Like Daughter?
 Age of menopause
largely due to
interaction of multiple
genes
de Bruin et al. Hum Reprod 2001
?
“What kind of cancer
treatment will give me
the best chance of
having a baby later?”
3. Ovarian Ablation or Suppression
1.
2.
3.
4.
5.
6.
7.
8.
9.
Patient presentation
Normal ovarian function
Ovarian ablation or suppression
Chemotherapy
Trastuzumab
Pregnancy after breast cancer
Gonadotoxicity of chemotherapy
Endocrine effects of chemotherapy
Referral to a fertility specialist
Oxford Overview: Effect of Ovarian
Ablation or Suppression on Mortality
60
Breast cancer mortality (%)
50
Control: 43.5%
40
Ovarian ablation or
suppression: 40.3%
34.9
30
32.2
18.4
20
15-year gain: 3.2% (SE 2.0)
Log rank 2p=0.004
16.6
10
0
0
5
10
Years
EBCTCG. Lancet 2005
15
Can Ovarian Ablation Replace
Chemotherapy? ABCSG Trial 5
Endocrine
Therapy
5-Yr Follow-up
(goserelin  3 yr
+ tam  5 yr )
n
Chemotherapy
(CMF  6 cycles)
%
n
%
p
n (assessable for final analysis)
511
Breast cancer–specific deaths
41
8
51
10
0.0900
Relapses
88
17
109
21
0.0176
Local recurrences
24
5
42
8
0.0029
Cancer of opposite breast
3
1
12
3
0.0001
Jakesz R et al. J Clin Oncol 2002
523
Can Ovarian Ablation Replace
Chemotherapy? ZEBRA Trial
Goserelin ( 2 yr)
n
Local
Events (%)
Distant
Events (%)
CMF (6 cycles)
n
Local
Events (%)
Distant
Events (%)
ER
positive
591
47.5
42.8
598
45.0
40.6
ER
negative
144
61.8
56.3
160
41.3
38.8
ER ?
62
48.4
N/A
59
39.0
N/A
Total
797
50.2
45.3
817
43.8
40.0
Event: disease recurrence, second primary, or death before recurrence
Kaufmann M et al. Eur J Cancer 2003
Efficacy of Ovarian Ablation or
Suppression
 Adjuvant setting, hormone receptor–positive
disease:
– OA/OS monotherapy increases DFS and overall
survival compared to observation, regardless of
nodal status.
– OA/OS + tamoxifen are roughly equal to adjuvant
CMF.
– Failure to develop chemotherapy-related
amenorrhea appears to increase recurrence risk.
Prowell TM et al. Oncologist 2004
Suppression of Ovarian Function
Trial (SOFT)
IBCSG 24-02 (BIG 2-02)
Targeted accrual: 3000 women
No chemotherapy stratum
(randomize after surgery)
Primary
surgery
Chemotherapy stratum
(randomize within 6 mo
after chemotherapy
completion)
www.ibcsg.org
Stratify:
 Institution
 Prior chemotherapy
(no, yes)
 Number of positive
nodes (0, ≥1)
 Intended initial method
of OFS, if assigned by
randomization
R
A
N
D
O
M
I
Z
E
A
Tam  5 yr
B
OFS + tam  5 yr
C
OFS + exemestane
 5 yr
OFS: triptorelin  5 yr OR surgical oophorectomy OR ovarian irradiation
Patients may have received tam or an AI prior to randomization.
Tamoxifen and Exemestane Trial
(TEXT)
IBCSG 25-02 (BIG 3-02)
Targeted accrual: 1845 women
Primary
surgery
www.ibcsg.org
Stratify:
 Institution
 Chemotherapy (no, yes)
 Number of positive nodes
(0, ≥1)
R
A
N
D
O
M
I
Z
E
A ( chemotherapy)
Triptorelin  5 yr + tam  5 yr
B ( chemotherapy)
Triptorelin  5 yr +
exemestane  5 yr
Premenopausal Endocrine Responsive
Chemotherapy Trial (PERCHE)
IBCSG 26-02 (BIG 4-02)
Targeted accrual: 1750 women
Primary
Surgery
www.ibcsg.org
Stratify:
 Institution
 Number of positive nodes (0, ≥1)
 Intended initial method of OFS
 Intended chemotherapy, if assigned
by randomization (not containing
anthracycline or taxane; containing
anthracycline or taxane)
 Intended endocrine agent (selected
by subsequent randomization in the
TEXT trial (recommended option);
tam; exemestane
R
A
N
D
O
M
I
Z
E
A OFS plus tam or
exemestane  5 yr
B Chemotherapy + OFS +
tam or exemestane  5 yr
OFS: triptorelin  5 yr OR surgical oophorectomy OR ovarian irradiation
Randomization prior to any adjuvant chemotherapy
ABCSG Trial 12
Austrian Breast Cancer and Colorectal Study Group
Targeted accrual: 1250 premenopausal women with ER- and/or PR-positive
stage 1 or 2 disease
Anastrozole 1 mg/d  3 yr
Zoledronic acid 4 mg/d q 6 mo  3 yr
Surgery
Randomization
1:1 1:1
Goserelin 3.6 mg
q 28 d  3 yr
Anastrozole 1 mg/d  3 yr
(Control)
Tam 20 mg/d  3 yr
Zoledronic acid 4 mg/d q 6 mo  3 yr
Tam 20 mg/d  3 yr
(Control)
http://abcsg.cyberfox.at/abcsg/html_studien/mamma_offen.html
?
“What if I don’t want to have a baby? What other
treatments are available?”
4. Chemotherapy
1.
2.
3.
4.
5.
6.
7.
8.
9.
Patient presentation
Normal ovarian function
Ovarian ablation or suppression
Chemotherapy
Trastuzumab
Pregnancy after breast cancer
Gonadotoxicity of chemotherapy
Endocrine effects of chemotherapy
Referral to a fertility specialist
Efficacy of Chemotherapy in Premenopausal
Women: Historical Context
100
Log rank: p=0.02
Total Survival (%)
Wilcoxon: p=0.02
CMF
50 –
Surgery alone
1
3
5
7
Years
Bonadonna G. Cancer Res 1992
9
11
13
15
Efficacy of Adjuvant Chemotherapy
in Node-Negative Women
Bonadonna
CMF vs. Surgery
Total Survival, ER-Negative, All Ages
Bonadonna G. Cancer Res 1992
NSABP B-23
CMF vs. AC
Overall Survival, All Ages
Fisher B et al. J Clin Oncol 2001
www.adjuvantonline.com:
Estimate of Recurrence Risk
www.adjuvantonline.com:
Survival Estimate
Efficacy of Chemotherapy
 The supplementary slides contain information
on the most common breast cancer regimens.
 Consider using those slides as a stimulus for a
structured learning project (Maintenance of
Certification Section 4 credits).
?
“I know a woman who had breast cancer, and she
was lucky to get this drug — I think it starts with H
— and it basically saved her life. Could I get it?”
5. Trastuzumab
1.
2.
3.
4.
5.
6.
7.
8.
9.
Patient presentation
Normal ovarian function
Ovarian ablation or suppression
Chemotherapy
Trastuzumab
Pregnancy after breast cancer
Gonadotoxicity of chemotherapy
Endocrine effects of chemotherapy
Referral to a fertility specialist
Correlates of HER2 Expression
 Patient characteristic:
– Young age
 Disease characteristics:
– Grade 3 tumours
– Increased risk of
recurrence with HER2positive tumours ≤2 cm
(RR=13.68; CI, 1.06–175.76)
Blackwell KL et al. Clin Cancer Res 2004
Konecny GE et al. Clin Cancer Res 2004
Swede H et al. Breast J 2003
 Biomarkers:
– Negative hormonereceptor status
– Increased levels of
VEGF
– Increased markers of
fibrin degradation
– Decreased levels of
hypoxia
HER2 as a Predictive Marker
 Recommendations of the 2000 ASCO Tumor
Markers Expert Panel:
– High levels of HER2 expression, as determined by
IHC, may identify patients who are particularly likely
to benefit from anthracycline-based adjuvant
therapy.
– Low levels of HER2 expression should not be used
to exclude patients from anthracycline treatment.
– A definitive recommendation regarding the use of
HER2 to predict benefit from adjuvant CMF
chemotherapy could not be made.
Bast RC Jr et al. J Clin Oncol 2001
HERA Trial: Disease-Free Survival
Piccart-Gebhart MJ et al. N Engl J Med 2005
NSABP B-31/NCCTG N9831 Trials: Survival
Romond EH et al. N Engl J Med 2005
?
“So if I do have chemo,
what are my chances of
having a healthy baby?”
6. Pregnancy after Breast Cancer
1.
2.
3.
4.
5.
6.
7.
8.
9.
Patient presentation
Normal ovarian function
Ovarian ablation or suppression
Chemotherapy
Trastuzumab
Pregnancy after breast cancer
Gonadotoxicity of chemotherapy
Endocrine effects of chemotherapy
Referral to a fertility specialist
?
Does cancer treatment increase the risk of
abnormalities in children born to survivors?
– No evidence that it increases the risk of
chromosomal abnormalities in the next generation.
Winther JF et al. Am J Hum Genet 2004
Kenney LB et al. Cancer 1996
Why Wait to Conceive?
Recurrence Rates
60
60
Control 55.2%
5-year gain 9.9% (SE 1.3)
Log rank 2p<0.00001
50
40
30
Control 27.4%
20
Polychemotherapy
17.5%
Recurrence (%)
Recurrence (%)
50
30
20
5-year gain 14.6% (SE 2.3)
10
10
0
0
0
1
2
3
4
5
Years
Age <50 Yr, Node-Negative
EBCTCG. Lancet 2005
Polychemotherapy
40.6%
40
Log rank 2p<0.00001
0
1
2
3
4
5
Years
Age <50 Yr, Node-Positive
?
Does pregnancy after breast cancer affect
survival?
– Little data available
– No evidence that pregnancy after breast cancer
decreases long-term survival
• Healthy mother bias
Partridge A et al. Oncology (Williston Park) 2005
?
“Will my chance of getting pregnant be the same
no matter which kind of chemo we pick?”
7. Gonadotoxicity of Chemotherapy
1.
2.
3.
4.
5.
6.
7.
8.
9.
Patient presentation
Normal ovarian function
Ovarian ablation or suppression
Chemotherapy
Trastuzumab
Pregnancy after breast cancer
Gonadotoxicity of chemotherapy
Endocrine effects of chemotherapy
Referral to a fertility specialist
?
 Definitions:
– Amenorrhea
• Primary
• Secondary
– Chemotherapy-related amenorrhea
• Transient
• Permanent
Dow KH. Pocket guide to breast cancer, 2002
Norwitz E et al. Obstetrics & gynecology at a glance, 2001
?
Besides chemotherapy, what else can cause
prolonged amenorrhea?
–
–
–
–
Pregnancy
Weight extremes
Depression
Endocrine disorders
Warren MP et al. Minerva Ginecol 2004
?
 Definitions:
– Menopause
– Perimenopause (climacteric transition)
Factors Affecting Gonadotoxicity of
Chemotherapy
 Agent
 Cumulative dose
 Synergy between agents
 (Age)
Goodwin PJ et al. J Clin Oncol 1999
Gonadotoxicity of Agents
 High risk:
− Cyclophosphamide
 Intermediate risk:
− Cisplatin
− Doxorubicin/epirubicin
Sonmezer M et al. Hum Reprod Update 2004
 Low/no risk:
− Methotrexate
− 5-fluorouracil
 Unknown risk:
– Taxanes
– Trastuzumab
– Synergies between agents
in combination regimens
Risk of Amenorrhea Due to
Chemotherapy (%)
CMF
AC
AC→PTX
42.6
34
84 / 61 / 50 / 57
DD AC→PTX
FEC  vinorelbine
NR
Cumulative E <300 mg/m2
Cumulative E 300–450 mg/m2
Cumulative E >450 mg/m2
CEF
TAC
FEC→DTX
52
58
69
51
61.7
68.4
1 / 12 / 24 / 36 mo
Disease-Free Survival According to
Amenorrhea Status: IBCSG Trial VI
All patients: n=1196
Pagani O et al. Eur J Cancer 1998
ER/PR positive patients: n=964
Disease-Free and Overall Survival
According to Amenorrhea Status
 Eight FASG trials
 n=1253
 Premenopausal, node-positive women
 9-yr DFS: 65% if amenorrheic vs. 40% if not
(p<0.001)
 9-yr OS: 75% if amenorrheic vs. 54% if not
(p<0.001)
The prognostic value of amenorrhea requires further study.
Borde F et al. SABCS 2003:138
Probability of Menopause During the
First Year after Diagnosis
+ Tamoxifen
x CMF or CEF
Goodwin et al. J Clin Oncol 1999
?
“I’m going to start menopause? With all the side
effects?”
8. Endocrine Effects of Chemotherapy
1.
2.
3.
4.
5.
6.
7.
8.
9.
Patient presentation
Normal ovarian function
Ovarian ablation or suppression
Chemotherapy
Trastuzumab
Pregnancy after breast cancer
Gonadotoxicity of chemotherapy
Endocrine effects of chemotherapy
Referral to a fertility specialist
Interventions for Hot Flashes in
Women with Breast Cancer
 High efficacy/potential adverse
breast cancer influence:
– Estrogens/progesterones
 Moderate efficacy/controversial
breast cancer influence:
– Black cohosh
 Moderate efficacy/no known
breast cancer influence:
–
–
–
–
–
Venlafaxine
Fluoxetine
Paroxetine
Gabapentin
Clonidine
Adapted from Chlebowski RT et al. Semin Oncol 2003
Barton DL et al. J Clin Oncol 1998
Pandya KJ et al. Ann Intern Med 2000
 Limited/no efficacy:
–
–
–
–
–
Evening primrose
Dong quai
Soy/isoflavone products
DHEA/wild yam
Vitamin E
 Unknown efficacy:
– Exercise
– Behavioural therapy
?
What are the potential sexual consequences of
adjuvant therapy?
–
–
–
–
Body image concerns
Decreased libido
Vaginal dryness/dyspareunia
Decreased sexual activity
Friedlander M et al. Intern Med J 2003
Effects of Breast Cancer Treatment
on Bone
 Direct effects:
– Chemotherapy:
• Decreased bone
formation (not proven in
humans)
– High-dose
glucocorticoids:
• Dose-dependent
inhibition of bone
formation
• Increased osteoclastic
resorption
Fontages E et al. Joint Bone Spine 2004
 Indirect effects:
– Chemotherapy in
premenopausal women:
• Effects of ovarian
suppression on BMD
– Hormonal treatments in
pre- and postmenopausal women:
• Bone loss from
estrogen-inhibiting
effects
?
“I want the best cancer
treatment, but I want the
best chance to have a
baby too. Is there anything
else I can do?”
9. Referral to a Fertility Specialist
1.
2.
3.
4.
5.
6.
7.
8.
9.
Patient presentation
Normal ovarian function
Ovarian ablation or suppression
Chemotherapy
Trastuzumab
Pregnancy after breast cancer
Gonadotoxicity of chemotherapy
Endocrine effects of chemotherapy
Referral to a fertility specialist
?
Besides chemotherapy-related amenorrhea, what
factors may affect fertility?
–
–
–
–
Advanced maternal age
Pre-existing ovulatory problems
Tubal and mechanical factors
Male factors
Makar RS et al. Am J Clin Pathol 2002
Menken J et al. Science 1986
?
What factors determine the suitability of a woman
with breast cancer for fertility preservation?
–
–
–
–
–
–
Age of patient
Risk of permanent sterility
Urgency of treatment
Long-term prognosis
Theoretical concerns about controlled ovarian hyperstimulation
Willingness to accept other options
• Future egg donation
• Adoption
Seymour JF. Reprod Fertil Dev 2001
Sonmezer M et al. Hum Reprod Update 2004
?
What topics do you want your local fertility expert
to address with patients you refer?
?
What topics does a fertility specialist hope you
have addressed with your patients before referral?
– Long-term prognosis
– Age-related decline in fertility
– Risk of premature ovarian failure
Seymour JF. Reprod Fertil Dev 2001
Sonmezer M et al. Hum Reprod Update 2004
Before cancer treatment:
– Controlled ovarian
hyperstimulation
– Egg harvest and IVF
– Embryo cryopreservation
After cancer treatment:
– Embryo transfer
(ideally after 2–5 yr)
25% live-birth rate
Sonmezer M et al. Hum Reprod Update 2004
Wright VC et al. MMWR Surveill Summ 2005
Courtesy of Center for Reproductive Medicine, West Virginia University
Embryo Cryopreservation
Timing Issues
 Day of menstrual cycle at referral determines
delay before treatment
 Expedited fertility consultations available
 Oncologist: order HBV, HCV, CMV, VDRL, and
HIV tests on woman and sperm donor
?
Approximately how much do assisted
reproductive technologies cost?
Ovarian-stimulation medications
$2000–$5000
Semen assessment (per sample)
$350
Intracytoplasmic sperm injection
$1200
Each IVF cycle
$5500
Embryo cryopreservation
$650
Annual embryo storage fee
$240
Embryo thawing and transfer
$1100
Reproductive Biology Unit, Mount Sinai Hospital. Schedule of fees, 2005
?
What are the ethical issues associated with
embryo cryopreservation?
– Estimates of prognosis
– Estimates of risk of premature ovarian failure
– Orphaned embryos
• Destruction of embryos
– Little long-term data
– Funding
Seymour JF. Reprod Fertil Dev 2001
Less-Proven Fertility Preservation
Options
 Ovarian tissue cryopreservation and transfer
 Oocyte cryopreservation
 Ovarian transplantation
Lutchman Singh et al. Hum Reprod Update 2005
Sonmezer M et al. Hum Reprod Update 2004
Future Research
 Growth of oocytes from stem cells
– Hubner K et al. Science 2003
 Development of renewable supply of ovarian
stem cells
– Johnson J et al. Cell 2005
 In vitro follicle maturation from cryopreserved
ovarian tissue
– Kagawa N et al. J Reprod Dev 2005
 Gonadal protection
– Recchia F et al. Anticancer Drugs 2002
Key Messages
 Raise the issue of fertility with all premenopausal
women who require chemotherapy.
 Discuss the possible effects of treatment on
fertility and menopause.
 Refer appropriate women to a fertility specialist
to explore options for fertility preservation.
 Identify women who are appropriate candidates
for ovarian suppression or ablation and inform
them about this option.
Chemotherapy Adjuvant
Treatment (ChAT)
for Breast Cancer in Young Women