Breast Cancer, Fertility and PregnancyKarin Hahn MD, MSc, MPH, FRCPCAssociate Professor, The University of Western Ontario

Breast Cancer Diagnosed During Pregnancy

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

• Impact upon the incidence of PABC unclear.• 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.

– Recent data also suggests BRCA1 mutation may be associated with low oocyte reserve.

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, Oktay K et al. J Clin Oncol 2010;28:240

The Diagnosis of Breast Cancer During Pregnancy: Diagnostic Imaging

• Mammography: Estimated fetal radiation exposure 0.007-0.02 cGy (risk of fetal harm when exposure exceeds threshold dose of 10-20 cGy)

• Breast Ultrasound: MDACC review: breast and nodal basin ultrasound identified 100% of biopsy-proven cancers

• MRI of the breast: very little published data (controversy regarding the safety of gadolinium in pregnancy)

Montella KR et al. American College of Physicians 2000; Yang W et al. Radiology 2006;239:52.

Staging Investigations in the Pregnant Breast Cancer Patient

• Suspicious regional nodal disease: ultrasound and FNA

• CXR: Fetal radiation exposure <0.005 cGy• Liver ultrasound• Bone scan: challenging b/c of radioactivity

– Consider screening non-contrast MRI of the spine

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: cytology may be difficult to interpret due to proliferative changes of pregnancy

• Core biopsies: definitive histology, safe and only one case report of milk duct fistula

• Obtain ER/PR/HER 2/Neu statusNCCN Practice Guideline Invasive Breast Cancer V.1. 2010, 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 (-)– HER-2/neu expression: 29% to 58% for HER-

2/neu over-expression or amplification– Most commonly: Invasive ductal; poorly

differentiated; diagnosed at more advanced stages (node positive)

Tobon and Horowitz. Breast Dis 1993;6:127, Ishida et al. Jpn J Cancer Res 1992;83:1143, Middleton et al. Cancer 2003; 98:1055, Hahn et al Cancer 2006;107:1219, Ring et al. J Clin Oncol 2005;23:4192, Elledge et al. Cancer 1993;71:2499.

Treatment of Breast Cancer During Pregnancy: Termination of Pregnancy

• Termination of pregnancy does not improve survival.

• 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

(Duncan et al. Anesthesiology 1986;64:790)• 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. (Mazz and Kallen. Am J Obstet Gynecol 1989;161:1178)

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

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).

– 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 anaphylaxisMorita 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 biopsiesDominici LS et al. Breast Diseases 2010; 31:1

www.fda.gov

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: actual weight versus ideal body wt

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 21-28 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 after delivery.- Trastuzumab postpartum.- Tamoxifen after delivery.

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, 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, Kelly, H et al. Clin Breast Cancer 2006;7: 339.

Supportive Care Medications in Pregnant Breast Cancer Patients (FDA category)

• Antiemetics: – MDACC routinely uses dexamethasone (C) and

ondansetron (B).– promethazine and prochlorperazine (C)

• Filgrastim has been given to pregnant patients with chronic severe neutropenia (C).

• No published reports of using pegfilgrastim in pregnant breast cancer patients (C).

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

Prognosis of Pregnant Breast Cancer Patients

Study N Survival CommentsRibeiro 1986 121 Decreased Most treatment was after delivery

Tretli 1988 20 Decreased Treatment and delay not described

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 2010 75 Improved DFS, OS same Chemotherapy during pregnancy (MDACC)

Breast Cancer During Pregnancy: Labor and Delivery Results

• Earlier studies showed low birth weight and earlier deliveries

• More recent series have allowed women to go closer to term

• MDACC cohort has higher vaginal births than c-sections with similar neonatal outcomes

• Paucity of long term outcome data in children

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 WeightN = 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 weeks gestation) and early neonatal (<7 days) deaths

Hahn KME et al. Cancer 2006; 107:1219

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.

References for Tables1. Martin, JA, Kochanek KD, Strobino DM, et al. Annual Summary of

Vital Statistics– 2003. Pediatrics 2005;115:619-34.2. Cunningham FG, Gant NF, Leveno KJ, et al. Williams Obstetrics

21st Ed, McGraw-Hill, 2001.3. Agrawal V, David RJ, Harris VJ. Classification of acute respiratory

disorders of all newborns in a tertiary care center. J. Natl Med Assoc 2003;95:585-95

4. Wen SW, Liu S, Kramer MS, 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

Pregnancy After a Diagnosis of Breast Cancer

Pregnancy Following Breast Cancer Treatment

• Studies:– Often retrospective, cohort or case-control – not

randomized– Overall pregnancy after breast cancer treatment

does not appear to have worse prognosis– Some studies even show better prognosis– Risk of recurrence does not appear to be

influenced by hormone receptor status

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 Case series 1986 57 N.S.

Ariel et al3 Case series 1989 47 N.S.

Sutton et al4 Clinical trial registrants

1990 25 N.S.

Sankila et al5 Population based match survival

1994 91 N.S.

Von Schoultz et al6

Case comparison clinical trial registrants

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

Pregnancy Following Breast Cancer - Risk of Recurrence/Death

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; 53:4712Ribeiro et al Br J Surg 1986; 73:607 8Bonnier et al Int J Cancer 1997; 72:7203Ariel et al Int Surg 1989; 74:185 9Kroman et al BMJ 1997; 315:8514Sutton et al Cancer 1990; 65:847 10Gelber et al J Clin Oncol 2001; 19:16715Sankila et al Am J Obstet Gynecol 1994; 170:818 11Mueller et al Cancer 2003; 98:11316von Schoultz et al J Clin Oncol 1995; 13:430

Meta-analysis on Safety of Pregnancy After Breast Cancer Diagnosis

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

• 9 studies met the criteria for inclusion and had data appropriate for analysis

• OS was statistically higher among patients who became pregnant compared to controls: HR for death 0.51 (95% CI: 0.42-0.62)

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

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 recurrence

• Some physicians have recommended waiting 2 years after diagnosis.

• Women with a history of breast cancer must know their own estimated risk of recurrence

Breast Cancer Treatment and Fertility

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 1996-2000: Of 126, 280 cases of

breast cancer:< 20 yrs: 0%; 20-34 yrs: 2%; 35-44 yrs: 10.9 %

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

CRA Among Breast Cancer Patients

• Bines et al (JCO 14:1718-29, 1996) summarized the data available at that time:< 40 years of age: 21-71%*

> 40 years of age: 49-100%*

* Depending 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

Abusief ME et al. Cancer 2010;116:791

Study Design

• 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

Chemotherapy Regimens Included in this Retrospective Review

1) AC x 4 cycles2) 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 totalb) 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 AnalysisVariable Odds Ratio 95% CI P-valueTamoxifen Use 2.12 1.13-4.0 0.02Paclitaxel Use 1.59 0.80-3.2 0.19Trastuzumab Use 0.60 0.22-1.61 0.31Dose-dense Regimen 0.56 0.25-1.3 0.31Age at Diagnosis:

< 35 1.00 Referent35-39 10.1 1.28-79 0.0340-44 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 Dx (N=135) Age > 40 Years at Dx(N=296)

Variable OR 95% CI P OR 95% CI PTamoxifen 1.89 0.52-6.89 0.33 2.51 1.20-5.24 0.01Paclitaxel 3.54 0.60-20.8 0.16 1.66 0.77-3.58 0.20Trastuzumab 0.09 0.06-1.55 0.10 0.84 0.27-2.57 0.76Dose-dense Regimen

0.12 0.01-0.94 0.04 0.74 0.29-1.94 0.54

GnRH Agonists and Fertility Preservation

Published Randomized Clinical Trials of GnRH Agonists in Premenopausal Women with Early

Breast CancerAuthor Study Population Intervention N Primary

OutcomeP-value

Gerber B, et al(JCO 2011;29: 2334)

18-45 yoa,Anthracyclinecyclophosphamide +/- 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, Anthracyclinecyclophosphamide +/- 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 CancerAuthor Study Population Intervention N Primary

OutcomeP-value

Badawy A, et al (Fert Ster2009;91:694)

18-40 yoa,FAC chemotherapy, ? 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, Anthracyclinecyclophosphamide +/- taxane or CMF, Tamoxifen if hormone-sensitive tumour

Triptorelin 281 Incidence of early menopause within 1 year of completing chemotherapy

<0.001

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 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 IVF patients (45.08 v 33.46 days; P=.01).

• Peak estradiol levels ranged from 58.4 to 1,166 pg/mL

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

• RR ratio for recurrence after IVF was 0.56 (95% CI, 0.17 to 1.9)

• 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 treatment by 2-6 wks• Eliminates immediate need for a sperm donor or male

partner• Out-of-pocket costs similar to IVF; still considered

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

Ovarian Tissue Freezing

• Experimental

• Few pregnancies reported

• Restoration of endocrine function and embryo development in several studies

• Uncertain transplantation site

• Potential transmission of cancer cellsOktay K et al. Fertil Steril 2010;93:762, Anderson RA et al. Reproduction 2008;136:681

Other Roads to Parenthood

• Adoption• Surrogacy• Donor egg• Resources for patients and health care

professionals include:www.fertilehope.orgwww.livestrong.org

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

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.