Breast Cancer, Fertility and Pregnancye-syllabus.gotoper.com/_media/_pdf/SOBO2012_36_Hahn...risk of...
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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.