Karin Hahn MD, MSc , MPH, FRCPC Associate Professor ...e-syllabus.gotoper.com/_media/_pdf/SOBO14_Module9_1500_Hahn...Karin Hahn MD, MSc2, MPH, FRCPC Associate Professor, Schulich School

Karin Hahn MD, MSc2, MPH, FRCPC

Associate Professor, Schulich School of Medicine

and Dentistry, Western University, London, Ontario

Epidemiology

Approximately 3 in 10,000 deliveries are to women with breast cancer

Prevalence of pregnancy at diagnosis of breast cancer approximately 1.5%

In women < 30 years of age, the prevalence of pregnancy-associated breast cancer has been reported to be 9.7% and 25.6% (MSKCC and MDACC respectively)

Sanders CM, Baum M. J R Soc Med 1993;86:162; Anderson JM. BMJ

1979;1:1124; Anderson BO et al. Ann Surg Oncol 1996;3:204; Noyes RD et al.

Cancer 1982;49:1302

Pregnancy-associated Breast

Cancer (PABC) Breast cancer diagnosed during pregnancy or during

the 12 months following delivery.

Breast cancer diagnosed in the 12 months following

delivery is managed per standard guidelines.

Except: No breastfeeding if treatment includes

chemotherapy, trastuzumab and/or anti-estrogen

therapy.

BRCA1 and BRCA2 Mutations

and PABC

Multiple cohort studies: Women with germline BRCA1 mutations more

likely to have PABC than BRCA2 carriers.

Women with BRCA2 mutations may have increased risk of breast cancer after pregnancy.

Unclear whether association between mutations and PABC is causal or coincidental.

PABC does not appear to adversely affect survival among BRCA 1/2 survivors.

Johannsson O et al. Lancet 1998;352:1359; Tryggvadottir L et al. Breast Cancer Res

2003; 5: R121; Cullinane CA et al. Intl J Cancer 2005; 117: 988; Valentini A et al.

Breast Cancer Res Treat 2013;142:177

The Diagnosis of Breast Cancer During

Pregnancy: Diagnostic Imaging

Breast Ultrasound: studies report 100%

sensitivity and 100% negative predictive value

for PABC.

Mammography: Estimated radiation dose to

uterus 0.03 µGy (no risk of fetal harm when

exposure < the 50 mGy threshold dose).

MRI of the breast: very little published data

and controversy regarding the safety of

gadolinium in pregnancy (crosses placenta).

• Vashi R et al. Am J Roentgenol 2013;200:321

Additional Staging Investigations in

the Pregnant Breast Cancer Patient

Suspicious regional nodal disease: US and FNA

CXR: Fetal radiation exposure <0.005 cGy

Liver ultrasound

Bone scan: challenging because of radioactivity

Consider screening non-contrast MRI of the spine

if node positive disease or locally-advanced breast

cancer. Also, if complaining of persistent back pain

consider MRI.

• Hahn KME et al. Cancer 2006;107:1219; Baker J et al. Clin

Nuc Med 1987;12:519

Breast Cancer During Pregnancy:

Pathologic Diagnosis

FNA of the breast mass: cytology may be difficult to

interpret due to proliferative changes of pregnancy.

FNA of a suspicious lymph node: can diagnose

invasive breast cancer

Core biopsies: definitive histology, usually safe

although rare case reports of milk duct fistula in

pregnant or lactating women.

Obtain ER, PR and HER 2/neu status of tumor

NCCN Practice Guideline Invasive Breast Cancer V.3. 2013; Hahn

KME et al. Cancer 2006;107:1219; Schackmuth EM. Am J

Roentgenol 1993;161:961

Pathologic Features of Breast Cancer

Diagnosed During Pregnancy

Case series and case-control studies of pregnant

women with breast cancer:

Majority of tumors ER and PR negative

HER-2/neu expression: ranges from 29% to 58%

for HER-2/neu over-expression or amplification

Most commonly cancers are:

Invasive ductal carcinoma

Poorly differentiated

Diagnosed at more advanced stages (node positive)

Tobon H, Horowitz LF. Breast Dis 1993;6:127; Ishida T et al. Jpn J Cancer Res

1992;83:1143; Middleton L et al. Cancer 2003; 98:1055; Hahn KME et al.

Cancer 2006;107:1219; Ring AE et al. J Clin Oncol 2005;23:4192, Elledge R et

al. Cancer 1993;71:2499; Azim HA Jr et al. Acta Oncol 2012;51:653; Amant F et

al. J Clin Oncol 2013;31:2532

Treatment of Breast Cancer During

Pregnancy: Termination of Pregnancy

Termination of pregnancy does not improve survival in most case-control studies.

The decision to continue or terminate the pregnancy must be made by a woman who has been fully informed of the evidence with regard to pregnancy termination.

Reasons to consider termination of pregnancy: Known or suspected fetal teratogenesis

Health of the mother

Chervenak FA et al. Cancer 2004; 100:215; Oduncu FS et al. J Cancer Res Clin

Oncol 2003:129:133; Holleb AI, Farros JF. Surg Gynecol Obstet 1962;115:65;

Nugent P, O’Connel TX. Arch Surg 1985;120:1221; Clark RM, Chua T. Clin

Oncol 1989;1:11; Deemarsky LJ, Beishtadt EL. Breast 1981;7:17

Surgery in the Pregnant Patient Possibly an increased rate of spontaneous abortions with

general anesthesia:

primarily those having obstetric or gynecologic procedures

Possibly an increase in low and very low birth weight infants as well as IUGR

thought to be secondary to the underlying problem that resulted in surgery.

Mastectomy with ALND can be performed with minimal risk to the developing fetus or the continuation of pregnancy

Duncan PG et al. Anesthesiology 1986;64:790, Mazze RI, Kallen B. Am J Obstet Gynecol

1989;161:1178

Breast Conserving Surgery in the

Pregnant Woman with Breast Cancer

Radiation therapy required to complete breast

conservation:

Radiation exposure to the fetus increases as

pregnancy proceeds secondary to greater

proximity of the fetus to the radiation field (breast or

chest wall).

Usually delayed until after delivery.

Kuerer HM et al. Surgery 2002;131:108; Annane K et al. Fetal Diagn.Ther.

2005;20:442.

Sentinel Lymph Node Biopsy in the

Pregnant Woman with Breast Cancer

Technetium-99m: fetal radiation exposure estimated to be below the 5 cGy limit recommended by the National Commission on Radiation Protection

Isosulfan blue dye:

Pregnancy Category C: animal reproduction studies have not been conducted

should be given to a pregnant woman only if clearly needed. Although recent data from the Mayo Clinic suggests low level of fetal exposure.

risk of anaphylaxis

Morita ET et al. Surg Clin North Am 2000;80:1721; Keleher A et al. Breast J.

2004;10:492; Keleher A et al. J Am Coll Surg 2001;194:54; Pruthi S et al. Am J Surg

2011;201:70

Pregnant Breast Cancer Patients:

MDACC Surgery Experience

Of 67 pregnant breast cancer patients:

30 had preoperative chemotherapy: 10 had breast

conserving surgery (BCS) and 20 had mastectomy

37 had surgery first: 9 had BCS and 28 had

mastectomy

No difference in surgical complications between

mastectomy and lumpectomy patients

No significant complications from core biopsies

Dominici LS et al. Breast Diseases 2010; 31:1

Systemic Therapy in the Pregnant

Breast Cancer Patient Retrospective case series: often non-uniform

treatments

Anthracyline-based therapies have the most supporting evidence regarding safety:

AC, FAC, FEC when given in 2nd and 3rd trimesters

Limited dose-dense anthracycline safety and tolerance data

Dosing: should we use actual body weight versus ideal body weight?

www.fda.gov

Supportive Care Medications in Pregnant

Breast Cancer Patients (FDA category)

Antiemetics:

MDACC approach routinely uses dexamethasone (C)

and ondansetron (B).

promethazine and prochlorperazine (C)

Filgrastim has been given to pregnant patients with

chronic severe neutropenia (C).

Few published reports of using pegfilgrastim in pregnant

breast cancer patients (C).

Sangalli MR et al. Aust NZ J Obstet Gynaecol 2001;41:470; Cardonick E et al.

Ann Oncol 2012;23:3016

Treatment of the Pregnant Breast

Cancer Patient: Systemic Therapy

1st Trimester (139 cases): 17% fetal malformation

2nd and 3rd trimester (150 cases): 1.3 – 3.8% fetal

malformation

Similar to the rate than in the general population.

Doll DC et al. Semin Oncol 1989;16:337.

Chemotherapeutic Treatment of Pregnant

Breast Cancer Patients (MDACC) After the 1st trimester: adjuvant or neoadjuvant FAC every 21

days:

5-fluorouracil: 500 mg/m2 IV on days 1 and 4

Doxorubicin: 50 mg/m2 IV continuous infusion over 72h

Cyclophosphamide: 500 mg/m2 IV on day 1 only

No chemotherapy after 35 weeks gestation

Additional systemic therapies if appropriate:

- Paclitaxel or docetaxel postpartum.

- Trastuzumab postpartum.

- Tamoxifen postpartum. Hahn KM et al. Cancer 2006;107:1219.

Non-anthracycline Based Therapies in

Pregnant Breast Cancer Patients

Methotrexate contraindicated

Docetaxel and paclitaxel: multiple case reports in breast and gynecologic cancers

Trastuzumab: oligohydraminios- FDA pregnancy category D.

Lapatinib: FDA pregnancy category D

Tamoxifen: FDA pregnancy category D- case reports of fetal malformations

De Santis M et al. Eur J Cancer Care 2000;9:235; Zagouri F et al. Clin Breast

Cancer 2013;13:16; Gonzalez-Angulo AM et al. Clin Breast Cancer 2004;5:317;

Watson WJ. Obstet Gynecol 2005;105:642; Waterston AM, J Clin Oncol

2006;21:321; Fanale MA et al. Clin Br Cancer 2005;6:354

Prognosis of Pregnant Breast Cancer Patients

Study N Survival Comments Ishida 1992 72 No difference When matched for age, stage

Zemlickis 1992 118 No difference When matched for stage

Ezzat 1996 28 No difference Chemotherapy during

pregnancy

Bonnier 1997 154 Decreased Chemotherapy/Rx not

described

Beadle 2008 51 No difference Chemotherapy during

pregnancy

Murphy 2009 99 No difference Chemotherapy during

pregnancy

Litton 2013 75 Improved DFS and OS Chemotherapy during

pregnancy (MDACC)

Amant 2013 311 No difference in DFS

or OS

Variety of chemotherapy

regimens; registry data

Breast Cancer During Pregnancy:

Labor and Delivery Results

Some studies have shown low birth weight and

earlier deliveries

More recent series have allowed women to go

closer to term if possible

MDACC cohort had higher number of vaginal births

than C-sections with similar neonatal outcomes

Paucity of long term outcome data in children

Loibl S et al. Lancet Oncol 2012;13:887; Ebert U et al. Pharmacol

Ther 1997;74:207, Zemlickis D et al. Am J Obstet Gynecol

1992;166:781

MDACC Cohort: Delivery Outcomes in Children with

Chemotherapy Exposure in Utero vs General

Population Outcomes (n) Percent (x/n) Reported Norms of General Population

Perinatal Mortality Rate* 0% 0/55 6.9 deaths per 1000 live births + fetal deaths.1

Type of Delivery

The C-section rate was 27.6% among the U.S.

population in 2003.1

Vaginal 57% (31/54)

C-section 39% (21/54)

Still pregnant

4% (2/54)

Mean Range

Gestational age at delivery

(n = 52)

37 weeks 29-42 weeks

47% of live births in US

are gestational age 37-39 weeks.2

Birth Weight

N = 47

2927 grams 1389-3977

grams

3117-3956 grams

(50th-95th percentiles at 37 weeks gestation).2

*Perinatal Mortality Rate includes both late fetal (at least 28 wks gestation) and early neonatal (<7d) deaths

Hahn KME et al. Cancer 2006; 107:1219

References for Preceding Tables 1. Martin, JA et al. Annual Summary of Vital Statistics– 2003.

Pediatrics 2005;115:619-34.

2. Cunningham FG et al. Williams Obstetrics 21st Ed, McGraw-Hill, 2001.

3. Agrawal V et al. Classification of acute respiratory disorders of all newborns in a tertiary care center. J. Natl Med Assoc 2003;95:585-95

4. Wen SW et al. Comparison of Maternal and Infant Outcomes between Vacuum Extraction and Forceps Deliveries. 2001;153:103-7

5. Moore KL, Persaud TVN. The Developing Human. Clinically Oriented Embryology. 7th Ed, Saunders 2003

MDACC Cohort: Post-Neonatal Outcomes in Children

with Chemotherapy Exposure In Utero*

Outcome Percent (x/n)

“Normal Development” compared to siblings or other

children, per child’s family**

97% (38/39)

Reported to have no health problems 43% (18/40)

Allergies/Eczema 20% (8/40)

Upper respiratory infections: ear, sinus, bronchiolitis 13% (5/40)

Require special attention in school*** 11% (2/18)

Asthma/Breathing difficulties 10% (4/40)

Attention Deficit Disorder 5% (2/40)

Hypercholesterolemia with obesity 3% (1/40)

“Eye problems,” NOS 3% (1/40)

Heart murmur (resolved by age 1 year) and “lazy eye” 3% (1/40)

•*Age at follow-up = 2 to 157 months.

•** The one child with Down’s Syndrome was considered to be developmentally delayed.

•*** The child with Down’s Syndrome and one of the 2 children with ADD require special attention in

school.

Observational Study: Breast Cancer

Diagnosed and Treated During Pregnancy

Registry for breast cancer patients diagnosed during

pregnancy: 7 European countries

Of the 447 patients with early breast cancer

registered from April, 2003 to December 2011, 413

were treated with chemotherapy while pregnant.

Birthweight was lower for those exposed to

chemotherapy in utero despite gestational age.

No statistical difference in premature deliveries or

malformations or newborn complications

Loibl S et al. Lancet Oncol 2012;13:887

Conclusions: Breast Cancer

Diagnosed During Pregnancy Women diagnosed during pregnancy can be

considered for surgery at any time and chemotherapy after the first trimester

Anthracycline-based chemotherapy regimens have the most safety data to date, however, other agents such as docetaxel and paclitaxel have been described

Radiation, tamoxifen and trastuzumab should be administered after delivery

Further long term follow up of the children exposed to chemotherapy in utero is warranted

Pregnancy After a Diagnosis

of Breast Cancer

Pregnancy Following Breast

Cancer Treatment

Studies:

Often retrospective, cohort or case-control

Overall pregnancy after breast cancer treatment

does not appear to have worse prognosis

Some studies even show better prognosis:

“Healthy Mother” effect

Risk of recurrence does not appear to be

influenced by hormone receptor status of the

tumor.

Pregnancy Following Breast Cancer - Risk of Recurrence/Death Reference

Study

Year

# Preg

Pts

Risk of Recurrence/ Death for Preg vs

Non-Preg

Harvey et al`

Case series 1981 41 N.S.

Ribeiro et al2


Ariel et al3


Sutton et al4

Clinical trial registrants

1990 25 N.S.

Sankila et al5

Population based match survival

1994 91 N.S.

Von Schoultz et al

6 Case comparison clinical trial registrants

1995 50 [(RR .42 (.16-1.12)]

Pregnancy Following Breast Cancer -

Risk of Recurrence/Death - continued Reference

Study

Year

# Preg

Pts

Risk of Recurrence/ Death for Preg vs

Non-Preg

Malamos et al7

Case control retrospective

1996 21 N.S.

Bonnier et al8

Retrospective multi-institutional

1997 92 (1.89 + .24 recur (2.26 + .27 death)

Kroman et al9

Multiple registries/ comparative

1997 173 N.S.

Gelber et al10

Case comparison 2001 137 RR .44 (.21 - .96)

Mueller et al11

Cohort population based cancer registry

2003 438 RR .54 (.41 - .71)

1Harvey et al Surg Gynecol Obstet 1981; 153:723 7Malamos et al Oncology 1996; 53:471 2Ribeiro et al Br J Surg 1986; 73:607 8Bonnier et al Int J Cancer 1997; 72:720 3Ariel et al Int Surg 1989; 74:185 9Kroman et al BMJ 1997; 315:851 4Sutton et al Cancer 1990; 65:847 10Gelber et al J Clin Oncol 2001; 19:1671 5Sankila et al Am J Obstet Gynecol 1994; 170:818 11Mueller et al Cancer 2003; 98:1131 6von Schoultz et al J Clin Oncol 1995; 13:430

Pregnancy Following Breast Cancer - Risk of

Recurrence/Death - continued

Reference Study Year #Preg Pts Risk of Recurrence/Death for Preg vs Non-preg

Azim Jr HA et al Multicenter, retrospective cohort study

2012 333 (197 with ER+ BrCa)

DFS: N.S. OS: improved for pregnant BrCa pts HR = 0.72 (0.54-0.97)

Litton JK et al Case control single institution

2013 75 DFS and OS: improved for pregnant BrCa pts

Azim Jr HA et al. J Clin Oncol 2012;31:73

Litton JK et al. Oncologist 2013;18:369

Impact of Pregnancy on Breast Cancer Survival in

Women who Carry a BRCA1 or BRCA2 Mutation

From an international multicenter cohort study of 12,084

women with one of these mutations, 128 case subjects

were diagnosed with breast cancer during pregnancy or

became pregnant after a diagnosis of breast cancer.

Age-matched to 269 mutation carriers who did not

become pregnant (controls).

The 15-year survival rate was 91.5% among the cases

and 88.6% among the controls (adjusted HR 0.76; 95%

CI 0.31-1.91, p = 0.56)

Valentini A, et al. Breast Cancer Res Treat 2013, Oct

18;142:177

Meta-analyses on Safety of Pregnancy After Breast

Cancer Diagnosis Valachis A et al.(Obstet Gynecol Surv 2010;65:786)

Assessed the effect of pregnancy at least 10 months from diagnosis on overall survival (OS) among premenopausal breast cancer patients < 45 yoa

Of the 9 studies met the inclusion criteria and had data appropriate for analysis, OS was statistically better among BrCa survivors who became pregnant compared to controls: HR for death 0.51 (95% CI: 0.42-0.62)

Luo M et al. (Int J Gynecol Cancer 2014;24:1366) Of the 5 studies analyzed, women who had undergone

surgery for breast cancer and subsequently became pregnant had a better OS than those who did not (PRR 0.78; 95% CI 0.64-0.95)

Recommendations to Women Considering

Pregnancy After a Diagnosis of Breast Cancer

Women with larger tumors and/or positive lymph

nodes have a higher risk of breast cancer

recurrence

Some physicians have recommended waiting 2

years after diagnosis perhaps because the more

aggressive cancers have tended to recur more

quickly.

Women with a history of breast cancer must be

aware of their own estimated risk of recurrence.

Amenorrhea Among Breast Cancer

Patients Only 5% of women < 45 years of age have

undergone natural menopause

Average age of menopause in US: 50-52 yrs

SEER 2006-2010: Percentage of cases of breast

cancer:< 20 yrs: 0%; 20-34 yrs: 1.8%; 35-44 yrs:

9.6%

Chemotherapy-related amenorrhea (CRA): varies in definition- anywhere from 3 to 12 months without a menstrual period

http://seer.cancer.gov

CRA Among Breast Cancer Patients J. Bines et al (J Clin Oncol 1996;14:1718)

summarized the data available at that time:

< 40 years of age: 21-71%*

> 40 years of age: 49-100%*

* Depended upon regimen and duration of therapy

Risk of Menopause During the First Year

After Breast Cancer Diagnosis 183 premenopausal women with locoregional

breast cancer (T1-3, N0-1, M0) who had undergone surgical treatment; enrolled at 1 year after dx; Adjuvant therapy was recorded.

Goodwin PJ et al. J Clin Oncol. 1999;17:120

Effects of Paclitaxel, Dose Density, and Trastuzumab on Treatment-related Amenorrhea in Premenopausal Women with Breast Cancer

Retrospective review of 431 premenopausal

women with early breast cancer treated at DFCI

and MGH from 1997-2005.

Premenopausal: menses in the 6 months prior to

first visit

Postmenopausal: no menses in the 6 months

prior to first visit (natural, surgical, medical,

pharmacologic or radiation-induced)

Type of chemo and use of tamoxifen recorded

Abusief ME et al. Cancer 2010;116:791

Chemotherapy Regimens Included in this

Retrospective Review

1) AC x 4 cycles

2) AC x 4 cycles followed by paclitaxel 175 mg/m2 x 4

cycles (AC-T)

3) AC followed or preceded by:

a) weekly paclitaxel with weekly trastuzumab x 12 doses,

then trastuzumab up to 52 weeks total

b) weekly paclitaxel x 12 doses, then trastuzumab for up to

52 weeks.

(AC-T + trastuzumab)

Likelihood of Persistent Treatment-related Amenorrhea by

Treatment History: Multivariate Analysis

Variable Odds Ratio 95% CI P-value

Tamoxifen Use 2.12 1.13-4.0 0.02

Paclitaxel Use 1.59 0.80-3.2 0.19

Trastuzumab Use 0.60 0.22-1.61 0.31

Dose-dense Regimen 0.56 0.25-1.3 0.31

Age at Diagnosis:

< 35 1.00 Referent

35-39 10.1 1.28-79 0.03

40-44 39.5 5.25-297.4 0.0004

> 45 558.7 70.6 to

>999

<0.0001

Treatment-associated Likelihood of Amenorrhea by

Age at Breast Cancer Diagnosis

Age < 40 Years at Diagnosis

(N=135)

Age > 40 Years at

Diagnosis (N=296)

Variable OR 95% CI P OR 95% CI P

Tamoxifen 1.89 0.52-6.89 0.33 2.51 1.20-5.24 0.01

Paclitaxel 3.54 0.60-20.8 0.16 1.66 0.77-3.58 0.20

Trastuzumab 0.09 0.06-1.55 0.10 0.84 0.27-2.57 0.76

Dose-dense

Regimen

0.12 0.01-0.94 0.04 0.74 0.29-1.94 0.54

ASCO Guideline Update 2013

Loren AW, et al.

www.asco.org

Key Recommendations Discuss fertility preservation with all patients of

reproductive age if infertility is a potential risk of therapy.

Refer patients who express an interest in fertility preservation (and patients who are ambivalent) to reproductive specialists.

Address fertility preservation as early as possible, before treatment starts.

Document fertility preservation discussions in the medical record.

Key Recommendations Answer basic questions about whether fertility

preservation may have an impact upon successful cancer treatment.

Refer patients to psychosocial providers if they experience distress about potential infertility.

Encourage patients to participate in registries and clinical trials.

Key Recommendations: Adult Females (non-gynecologic malignancies)

Present both embryo and oocyte cryopreservation as established fertility preservation methods.

Inform patients that there is insufficient evidence regarding the effectiveness of ovarian suppression (gonadotropin-releasing hormone analogs) as a fertility preservation method, and these agents should not be relied on to preserve fertility.

Inform patients that other methods (eg. Ovarian tissue cryopreservation, which does not require sexual maturity, for the purpose of future transplantation ) are still experimental.

Pituitary gonadotropin

secretion is dependent on the

intermittent, pulsating secretion

of GnRH by the hypothalamic

neurons. Continuous

stimulation of the pituitary by

GnRH or the long-acting GnRH

agonists results in

desensitization of gonadotropin

secretion and subsequent

gonadal suppression. (Kimmick

GG and Muss HB, Oncology,

1995)

Published Randomized Clinical Trials of GnRH

Agonists in Premenopausal Women with Early

Breast Cancer Author Study Population Intervention N Primary

Outcome

P-value

Gerber B, et al

(JCO 2011;29:

2334)

18-45 yoa,

Anthracycline

cyclophosphamide

+/- taxane,

Hormone-

insensitive cancer

Goserelin 60 Reappearance

of normal

ovarian function

6 months after

completion of

chemotherapy

0.284

Munster PN,

et al

(JCO 2012;30:

533)

< 45 yoa,

Anthracycline

cyclophosphamide

+/- taxane,

Tamoxifen if

hormone-sensitive

tumour

Triptorelin 49* Restoration of

menses during

FUp of at least 2

years after

completion of

chemotherapy

0.36

* Stopped early because of futility.

Published Randomized Clinical Trials of GnRH Agonists in

Premenopausal Women with Early Breast Cancer

Author Study Population Intervention N Primary

Outcome

P-value

Badawy A, et al

(Fert Ster

2009;91:694)

18-40 yoa,

FAC,

? Hormone-

insensitive tumours

Goserelin 80 Resumption of

spontaneous

menstruation

and ovulation

<0.001

Del Mastro L,

et al

(JAMA

2011;306:269);

Updated ASCO

Breast 2014

18-45 yoa,

Anthracycline

cyclophosphamide

+/- taxane or CMF,

Tamoxifen if

hormone-sensitive

tumour; 80% had

ER+ tumours

Triptorelin

281 Incidence of

early

menopause

within 1 year of

completing

chemotherapy

(8.9 vs 25.9%

favoring

Triptorelin)

<0.001

Not Yet Published Randomized Clinical Trials of GnRH

Agonists in Premenopausal Women with Early Breast

Cancer

Author Study Population Intervention N Primary

Outcome

P-

value

Moore HCF

et al. ASCO

General

Meeting 2014

18-49 yoa, ER/PR

negative tumors

who are to receive

cyclophosphamide-

based chemo;

(3- 4 months vs 6-8

months

anthracycline-based

OR 3-4 months vs

6-8 months non-

anthracycline-based

chemo)

Goserelin 135

evaluable

for

ovarian

failure

Resumption

of

spontaneous

menstruation

and ovulation

<0.001

Prevention of Early Menopause Study<br />(POEMS)-S0230<br /> Phase III trial of LHRH analog during chemotherapy to reduce ovarian failure in early stage, hormone receptor-

negative breast cancer: an international Intergroup trial of SWOG, IBCSG, ECOG, and CALGB (Alliance)

Presented By Halle Moore at 2014 ASCO Annual Meeting

Published Randomized Clinical Trials of GnRH Agonists in

Premenopausal Women with Early Breast Cancer

Author Study

Population

Intervention N Primary

Outcome

P-value

Badawy A, et al

(Fert Ster

2009;91:694)

18-40 yoa,

FAC,

? Hormone-

insensitive

tumours

Goserelin 80 Resumption of

spontaneous

menstruation

and ovulation

<0.001

Del Mastro L,

et al

(JAMA

2011;306:269)

18-45 yoa,

Anthracycline

cyclophosphamid

e +/- taxane or

CMF, Tamoxifen if

hormone-

sensitive tumour

Triptorelin 281 Incidence of

early

menopause

within 1 year of

completing

chemotherapy

<0.001

POEMS Objectives and Endpoints


Patient Eligibility


POEMS Consort Diagram


Patients


Endocrine Toxicity


POEMS Ovarian Failure


POEMS Secondary Ovarian Outcomes


POEMS Pregnancy


POEMS


In Vitro Fertilization (IVF) IVF with embryo freezing

Can delay chemo 2-6 weeks

Best results for future pregnancies

High out of pocket cost (www.fertilehope.org)

Needs sperm donation

Safety of Fertility Preservation by Ovarian Stimulation

With Letrozole and Gonadotropins in Patients With Breast

Cancer: A Prospective Controlled Study

215 breast cancer pts prospectively evaluated for fertility preservation before adjuvant chemotherapy. 79 chose conservative ovarian stimulation (COS)

with letrozole and gonadotropins for embryo or oocyte cryopreservation

136 patients underwent no fertility-preserving procedure and served as controls.

Azim AA et al. J Clin Oncol 2008; 26:2630

Results: No Difference in Survival with Short-

term Follow-up

Time between surgery and chemotherapy was longer for COS patients (45.08 v 33.46 days; P= 0.01).

Peak estradiol levels ranged from 58.4 -1,166 pg/mL in COS patients

Median follow-up after chemotherapy was 23.4 months in the COS group and 33.05 months in the control group.

HR for recurrence after COS was 0.56 (95% CI, 0.17-1.9)

Relapse-free survival was not compromised compared with controls (P=.36).

Azim AA et al. J Clin Oncol 2008;26:2630

Oocyte Freezing

Over 1500 pregnancies from frozen oocytes in the world

Oocyte preservation: compared to slow-freezing,

vitrification appears to result in higher oocyte survival rate,

higher fertilization rate, as well as improved embryo quality

and embryo cleavage rate

Could delay start of systemic cancer therapy by 2-6 wks

Eliminates immediate need for a sperm donor or male

partner

Out-of-pocket costs similar to IVF

Oktay K et al. Fertil Steril 2006;86:70; Cobo A, Diaz C. Fertil Steril 2011;96:277;

Borini A, Bianchi V. Clin Obstet Gynecol 2010;53:763; Huang JY et al. Am J Surg

2010:200;177; Rudick B et al. Fertil Steril 2010;94:2642

Ovarian Tissue Freezing

Experimental

Few pregnancies reported (19; www.asco.org)

Restoration of endocrine function and embryo

development in several studies

Uncertain transplantation site

Potential transmission of cancer cells

Oktay K et al. Fertil Steril 2010;93:762, Anderson RA et al. Reproduction 2008;136:681

Other Roads to Parenthood Adoption

Surrogacy

Donor egg

Online resources for patients and health care

professionals include:

www.fertilehope.org: Fertile Hope is a LIVESTRONG

initiative dedicated to providing reproductive

information, support and hope to cancer patients and

survivors whose medical treatment present the risk of

infertility.

http://www.fertilehope.org/

Conclusions: Pregnancy After a

Breast Cancer Diagnosis

Women who become pregnant after breast

cancer treatment do not appear to have

increased risk of recurrence

Fertility preservation should be discussed with

all premenopausal breast cancer recognizing

the potential challenges of the available

options.

Ovarian function and fertility preservation

options continue to be investigated.

Documents

Karin Hahn MD, MSc , MPH, FRCPC Associate Professor ...e-syllabus.gotoper.com/_media/_pdf/SOBO14_Module9_1500_Hahn...Karin Hahn MD, MSc2, MPH, FRCPC Associate Professor, Schulich School