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