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Chemotherapy Adjuvant Treatment (ChAT) for Breast Cancer in Young Women.
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Transcript of Chemotherapy Adjuvant Treatment (ChAT) for Breast Cancer in Young Women.
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. Patient presentation
2. Normal ovarian function
3. Ovarian ablation or suppression
4. Chemotherapy
5. Trastuzumab
6. Pregnancy after breast cancer
7. Gonadotoxicity of chemotherapy
8. Endocrine effects of chemotherapy
9. 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. Now
b. When I tell her the risks of the therapy that she will receive
c. After she’s recovered from surgery
d. I won’t ask, but I will answer her questions about fertility
e. I won’t ask, and I’m not sure how to answer fertility questions
?
Raising the Topic of Fertility
Ellen Greenblatt MD FRCSC Clinical Director Reproductive Biology & IVF UnitsMount Sinai Hospital, Toronto
“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.”
The patient reveals that she might want to have a child in the future.
2. Normal Ovarian Function
1. Patient presentation
2. Normal ovarian function
3. Ovarian ablation or suppression
4. Chemotherapy
5. Trastuzumab
6. Pregnancy after breast cancer
7. Gonadotoxicity of chemotherapy
8. Endocrine effects of chemotherapy
9. Referral to a fertility specialist
Average maternal age at birth of first child:
– 1970 =– 2003 =
% of first-time mothers >30 yr:– 1983 = – 1999 =
% of first-time mothers 35–39 yr:– 1974 = – 1994 =
Statistics Canada. Births 2003CMAJ 2002Tough SC et al. Pediatrics 2002
?24.6 yr
28.0 yr
14%
32%
13%
25%
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 2005Baldwin WH et al. Popul Bull 1984
?
Definitions:– Infertility– Sterility
?
?Woman’s Age
at Marriage (yr) (no contraception)
Failure to Conceive (%)
20–24
25–29
30–34
35–39
40–44
6
9
15
30
64
Menken J et al. Science 1986
Fertility and Miscarriage Rates as a Function of Maternal Age
Heffner LJ. N Engl J Med 2004
Back to Basics: Menstrual Cycle
Cou
rtes
y of
Joh
n P
arris
h P
hD, U
nive
rsity
of W
isco
nsin
–Mad
ison
Byer C et al. Dimensions of human sexuality, 2002. © The McGraw-Hill Companies
Ovary
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 Aging
Ovarian Reserve
ovarian reserve with age
7-yr-old 20-yr-old 30-yr-old
Cortvrindt RG et al. Fertil Steril 2001
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. Patient presentation
2. Normal ovarian function
3. Ovarian ablation or suppression
4. Chemotherapy
5. Trastuzumab
6. Pregnancy after breast cancer
7. Gonadotoxicity of chemotherapy
8. Endocrine effects of chemotherapy
9. Referral to a fertility specialist
Oxford Overview: Effect of Ovarian Ablation or Suppression on Mortality
EBCTCG. Lancet 2005
60
50
40
30
20
10
0
0 5 10 15
Years
Bre
as
t c
an
ce
r m
ort
ali
ty (
%)
Control: 43.5%
Ovarian ablation or suppression: 40.3%
15-year gain: 3.2% (SE 2.0)Log rank 2p=0.004
34.9
32.2
18.4
16.6
Can Ovarian Ablation Replace Chemotherapy? ABCSG Trial 5
5-Yr Follow-up
Endocrine Therapy
(goserelin 3 yr + tam 5 yr )
Chemo-therapy(CMF 6 cycles)
n % n % p
n (assessable for final analysis) 511 523
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
Can Ovarian Ablation Replace Chemotherapy? ZEBRA Trial
Kaufmann M et al. Eur J Cancer 2003
Goserelin ( 2 yr) CMF (6 cycles)
nLocal
Events (%)Distant
Events (%) nLocal
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
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
No chemotherapy stratum
(randomize after surgery)
Primary surgery
Chemotherapy stratum
(randomize within 6 mo after chemotherapy completion)
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
OM
I
Z
E
B OFS + tam 5 yr
A Tam 5 yr
C OFS + exemestane 5 yr
www.ibcsg.org
Suppression of Ovarian Function Trial (SOFT)
OFS: triptorelin 5 yr OR surgical oophorectomy OR ovarian irradiation Patients may have received tam or an AI prior to randomization.
IBCSG 24-02 (BIG 2-02)Targeted accrual: 3000 women
Tamoxifen and Exemestane Trial (TEXT)IBCSG 25-02 (BIG 3-02)Targeted accrual: 1845 women
Primary
surgery
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
www.ibcsg.org
Premenopausal Endocrine Responsive Chemotherapy Trial (PERCHE)IBCSG 26-02 (BIG 4-02)Targeted accrual: 1750 women
Primary
Surgery
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
OM
I
Z
E
A OFS plus tam or exemestane 5 yr
B Chemotherapy + OFS + tam or exemestane 5 yr
www.ibcsg.orgOFS: triptorelin 5 yr OR surgical oophorectomy OR ovarian irradiation
Randomization prior to any adjuvant chemotherapy
ABCSG Trial 12
http://abcsg.cyberfox.at/abcsg/html_studien/mamma_offen.html
Austrian Breast Cancer and Colorectal Study GroupTargeted accrual: 1250 premenopausal women with ER- and/or PR-positive stage 1 or 2 disease
Surgery
Randomization
1:1 1:1
Goserelin 3.6 mg
q 28 d 3 yr
Anastrozole 1 mg/d 3 yr
Zoledronic acid 4 mg/d q 6 mo 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)
“What if I don’t want to have a baby? What other treatments are available?”
?
4. Chemotherapy
1. Patient presentation
2. Normal ovarian function
3. Ovarian ablation or suppression
4. Chemotherapy
5. Trastuzumab
6. Pregnancy after breast cancer
7. Gonadotoxicity of chemotherapy
8. Endocrine effects of chemotherapy
9. Referral to a fertility specialist
Efficacy of Chemotherapy in Premenopausal Women: Historical Context
Bonadonna G. Cancer Res 1992
1 3 5 7 9 11 13 15
50 –
100
To
tal
Su
rviv
al
(%)
Years
Log rank: p=0.02
Wilcoxon: p=0.02
CMF
Surgery alone
Efficacy of Adjuvant Chemotherapy in Node-Negative Women
NSABP B-23CMF vs. AC
Overall Survival, All Ages
Bonadonna G. Cancer Res 1992 Fisher B et al. J Clin Oncol 2001
BonadonnaCMF vs. Surgery
Total Survival, ER-Negative, All Ages
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. Patient presentation
2. Normal ovarian function
3. Ovarian ablation or suppression
4. Chemotherapy
5. Trastuzumab
6. Pregnancy after breast cancer
7. Gonadotoxicity of chemotherapy
8. Endocrine effects of chemotherapy
9. Referral to a fertility specialist
Correlates of HER2 Expression
Patient characteristic:– Young age
Disease characteristics:– Grade 3 tumours– Increased risk of
recurrence with HER2-positive 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 hormone-
receptor 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. Patient presentation
2. Normal ovarian function
3. Ovarian ablation or suppression
4. Chemotherapy
5. Trastuzumab
6. Pregnancy after breast cancer
7. Gonadotoxicity of chemotherapy
8. Endocrine effects of chemotherapy
9. 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 2004Kenney LB et al. Cancer 1996
?
EBCTCG. Lancet 2005
Why Wait to Conceive?Recurrence Rates
60
50
40
30
20
10
1 2 5
Years
Re
cu
rre
nc
e (
%)
3 4
0
60
50
40
30
20
10
1 2 5
Years
3 4
0R
ec
urr
en
ce
(%
)
5-year gain 9.9% (SE 1.3)
Log rank 2p<0.00001
Control 27.4%
Polychemotherapy17.5%
Control 55.2%
Polychemotherapy40.6%
5-year gain 14.6% (SE 2.3)
Log rank 2p<0.00001
0 0
Age <50 Yr, Node-Negative 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. Patient presentation
2. Normal ovarian function
3. Ovarian ablation or suppression
4. Chemotherapy
5. Trastuzumab
6. Pregnancy after breast cancer
7. Gonadotoxicity of chemotherapy
8. Endocrine effects of chemotherapy
9. Referral to a fertility specialist
Definitions:– Amenorrhea
• Primary• Secondary
– Chemotherapy-related amenorrhea• Transient• Permanent
?
Dow KH. Pocket guide to breast cancer, 2002Norwitz 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
Low/no risk:− Methotrexate− 5-fluorouracil
Unknown risk:– Taxanes– Trastuzumab– Synergies between agents
in combination regimens
Sonmezer M et al. Hum Reprod Update 2004
Risk of Amenorrhea Due to Chemotherapy (%)
CMF 42.6
AC 34
AC→PTX 84 / 61 / 50 / 57 1 / 12 / 24 / 36 mo
DD AC→PTX NR
FEC vinorelbine
Cumulative E <300 mg/m2
Cumulative E 300–450 mg/m2
Cumulative E >450 mg/m2
52
58
69
CEF 51
TAC 61.7
FEC→DTX 68.4
Disease-Free Survival According to Amenorrhea Status: IBCSG Trial VI
Pagani O et al. Eur J Cancer 1998
All patients: n=1196 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)
Borde F et al. SABCS 2003:138
The prognostic value of amenorrhea requires further study.
Probability of Menopause During the First Year after Diagnosis
Goodwin et al. J Clin Oncol 1999
+ Tamoxifen x CMF or CEF
“I’m going to start menopause? With all the side effects?”
?
8. Endocrine Effects of Chemotherapy
1. Patient presentation
2. Normal ovarian function
3. Ovarian ablation or suppression
4. Chemotherapy
5. Trastuzumab
6. Pregnancy after breast cancer
7. Gonadotoxicity of chemotherapy
8. Endocrine effects of chemotherapy
9. 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
Limited/no efficacy:– Evening primrose– Dong quai– Soy/isoflavone products– DHEA/wild yam– Vitamin E
Unknown efficacy:– Exercise– Behavioural therapy
Adapted from Chlebowski RT et al. Semin Oncol 2003Barton DL et al. J Clin Oncol 1998Pandya KJ et al. Ann Intern Med 2000
Friedlander M et al. Intern Med J 2003
?What are the potential sexual consequences of adjuvant therapy?
– Body image concerns – Decreased libido– Vaginal dryness/dyspareunia– Decreased sexual activity
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
Indirect effects:– Chemotherapy in
premenopausal women:• Effects of ovarian
suppression on BMD
– Hormonal treatments in pre- and post- menopausal women:• Bone loss from
estrogen-inhibiting effects
Fontages E et al. Joint Bone Spine 2004
“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. Patient presentation
2. Normal ovarian function
3. Ovarian ablation or suppression
4. Chemotherapy
5. Trastuzumab
6. Pregnancy after breast cancer
7. Gonadotoxicity of chemotherapy
8. Endocrine effects of chemotherapy
9. 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 2002Menken 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 2001Sonmezer 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 2001Sonmezer 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
Embryo Cryopreservation
Sonmezer M et al. Hum Reprod Update 2004Wright VC et al. MMWR Surveill Summ 2005
Cou
rtes
y of
Cen
ter
for
Rep
rodu
ctiv
e M
edic
ine,
Wes
t Virg
inia
Uni
vers
ity
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
Ovarian-stimulation medications
Semen assessment (per sample)
Intracytoplasmic sperm injection
Each IVF cycle
Embryo cryopreservation
Annual embryo storage fee
Embryo thawing and transfer
Approximately how much do assisted reproductive technologies cost?
?
Reproductive Biology Unit, Mount Sinai Hospital. Schedule of fees, 2005
$2000–$5000
$350
$1200
$5500
$650
$240
$1100
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
Ovarian tissue cryopreservation and transfer Oocyte cryopreservation Ovarian transplantation
Less-Proven Fertility Preservation Options
Lutchman Singh et al. Hum Reprod Update 2005Sonmezer M et al. Hum Reprod Update 2004
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
Future Research
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