Breast Cancer Research and Treatment

, Volume 129, Issue 2, pp 309–317

Pregnancy after breast cancer: if you wish, ma’am

Authors

    • Institute of Oncology of Southern Switzerland (IOSI) and International Breast Cancer Study Group (IBCSG)
  • Ann Partridge
    • Dana-Farber Cancer Institute
  • Larissa Korde
    • Division of Medical OncologyUniversity of Washington
  • Sunil Badve
    • Pathology and Lab MedicineIndiana University
  • John Bartlett
    • Endocrine Cancer Group, Edinburgh Cancer Research Centre
  • Kathy Albain
    • Chicago Stritch School of MedicineLoyola University
  • Richard Gelber
    • IBCSG Statistical Center, Dana-Farber Cancer Institute, Frontier Science and Technology Research Foundation, Harvard School of Public Health and Harvard Medical School
  • Aron Goldhirsch
    • Swiss Center for Breast Health
    • European Institute of Oncology
Review

DOI: 10.1007/s10549-011-1643-7

Cite this article as:
Pagani, O., Partridge, A., Korde, L. et al. Breast Cancer Res Treat (2011) 129: 309. doi:10.1007/s10549-011-1643-7

Abstract

A growing number of young breast cancer survivors consider reproductive health issues, including subsequent fertility and pregnancy, of great importance, but many questions regarding safety remain unanswered. We conducted a comprehensive literature search and review of published articles, control-matched, population-based, and co-operative group reports that addressed various aspects of pregnancy after breast cancer (patients’ expectations, fertility damage, assessment and preservation, maternal and fetal outcome, breast feeding). Overall, available data support pregnancy and breast feeding after breast cancer as safe and feasible for women at low risk of recurrence. This retrospective and population-based evidence is, however, frequently incomplete; usually not representative of the entire population, it can be biased by patients’ related effects or underpowered and is often not controlled for biological factors and risk determinants in the statistical model used. Before making any definitive assumption on this delicate and fundamental aspect of a woman’s life after breast cancer, we should demonstrate without any reasonable doubt that the scattered information available today is scientifically sound. The Breast International Group and North American Breast Cancer Group are planning a global prospective study in young women with endocrine responsive, early breast cancer who desire pregnancy, to assess both patients’ and pregnancy outcomes. The trial will include an observational phase investigating the feasibility and impact of a temporary treatment interruption to allow conception and an experimental phase investigating the optimal duration of the subsequent endocrine treatment after delivery or the last failed attempt to get pregnant.

Keywords

Breast cancerPregnancyFertilityBreast feeding

Introduction

Approximately, 25% of breast cancer patients are diagnosed <50 years of age and about 6% <40 years with a trend of increased incidence in younger Caucasian women in recent decades [1].

The worse prognosis repeatedly reported in young women [24] can be partly explained by either aggressive biologic characteristics or late diagnosis and distinctive molecular features in younger patients have also been proposed [5]. However, about 30–35% of women with breast cancer <50 years have T1N0 disease at diagnosis [6]. In one single institution study on 2,970 patients <35 years of age, the outcome of women with the Luminal A subtype (ER or PgR > 0, Ki-67 < 14% and HER2 0 to ++) was similar to that of older women [7].

Furthermore, the constant decrease in breast cancer death rates among Caucasian women since 1990 is larger in younger age groups (3.8% per year among women <50 and 2.2% per year among those ≥50) [8]. These numbers are likely to further improve with the widespread use of targeted therapies [9, 10]. Reproductive issues, including fertility, pregnancy, contraception and menopause, are therefore of great importance for this growing number of young breast cancer survivors.

In this article, the Endocrine Working Group of the Breast International Group (BIG)–North American Breast Cancer Group (NABCG) discusses the complex issue of fertility and pregnancy in women with a history of breast cancer, by summarizing the concerns and available data using a question and answer format.

Materials and methods

We searched Medline on the following terms: pregnancy and breast feeding after breast cancer, treatment-induced amenorrhea and premature menopause, fertility assessment, and preservation. Further references were obtained from reports retrieved in the initial search.

Do young women with breast cancer have a desire for pregnancy?

Pregnancy rates in women >30 years of age have been increasing worldwide since 1991 [11, 12] for a variety of different (i.e., cultural, educational, professional) reasons. In the U.S., the proportion of first-time mothers who were >30 years increased from 4.1 to 21.2% since the early 1990s [13]. Consequently, an increasing number of women face breast cancer before the completion of their reproductive plans.

Retrospective data clearly show that many “young” breast cancer patients have significant concerns at diagnosis about treatment-related infertility [14, 15] and report difficulty obtaining information from treating physicians [16, 17]. The results of a survey of the Breast International Group (BIG) to assess the attitude of very young patients (<35 years) with early breast cancer, toward the risk of treatment-related loss of fertility, are going to be published. Prospective data are being collected through a joint international initiative (Helping Ourselves, Helping Others HOHO: The Young Women’s Breast Cancer Study). Preliminary results from over 200 patients confirm that over 50% of women ≤40 years at diagnosis are concerned about future fertility and a significant proportion wish to consider pregnancy after breast cancer treatment.

What evidence exists on the impact of pregnancy after breast cancer on disease-related outcomes?

Historically, pregnancy after breast cancer has been considered potentially detrimental. Tissue exposure to very high levels of ovarian estrogens and progestins, pituitary prolactin, and placental lactogens during pregnancy was the primary justification for the past recommendation not to become pregnant after breast cancer [18].

However, the best available modern evidence suggests that pregnancy after breast cancer does not increase a woman’s risk of recurrence, and in fact may even confer a protective effect [1921]. In several population-based retrospective studies, where patients are matched for age, disease stage, and year of diagnosis, relative risk of death was lower for women who conceived after breast cancer than for those who did not. In two of these studies, overall survival results were statistically significantly in favor of the cohort that became pregnant [22, 23]. A recent meta-analysis of 14 such studies, involving 1,244 cases and 18,145 controls, showed a 41% reduced risk of death in women who became pregnant following breast cancer compared to women who did not [21]. One potential explanation for such a survival benefit is a selection bias called the “healthy mother” effect, i.e., women with breast cancer who subsequently conceive are a self-selecting healthier group with better prognosis [23]. In vitro preclinical data also suggest that apoptosis is induced in endocrine-responsive breast tumor cells by high estrogen, progesterone, and human chorionic gonadotrophin levels similar to those observed during pregnancy [24, 25]. In addition, the fetal antigen hypothesis suggests that the mother’s immunity is boosted against breast cancer cells during pregnancy [26]. Prospective controlled data are needed to determine the true effect of pregnancy on breast cancer outcomes.

Recent data are also reassuring concerning the safety of pregnancies for BRCA1 and BRCA2 carriers [27]: pregnancy should therefore not be discouraged in this population after comprehensive genetic counseling and adequate psychological support.

Despite this growing and encouraging body of evidence, the number of women who become pregnant and give birth to a live infant after breast cancer is low (3–15%, depending on the age of women considered). Several different factors may contribute to this low rate (i.e., treatment-induced infertility, competing risks, fear of recurrence, insufficient counseling, and patient’s preference). Providing evidence-based information and psychosocial support to breast cancer survivors who wish to become pregnant is an important area in need of improvement [2830].

Do adjuvant treatments jeopardize ovarian function?

The data regarding incidence of chemotherapy-induced amenorrhea (CIA) show substantial inconsistencies: the definition of amenorrhea is not uniform across studies, the time point at which it was assessed ranges widely, and the cut points to define age groups are not consistent [31]. On the other hand, the decline in the quality and quantity of ovarian follicles, i.e., ovarian aging, is known to accelerate around age 35, when the number of oocytes drops to approximately 25,000 (having been approximately 300,000 at puberty) [32].

Overall, the risk of ovarian failure after chemotherapy is likely to be underestimated, as studies have only looked at amenorrhea incidence as a surrogate for fertility [33].

The most commonly used adjuvant chemotherapy regimens include agents with a well-recognized negative impact on fertility; rates of permanent amenorrhea depend on the agents and cumulative doses administered as well as the woman’s age at the time of treatment (Table 1). Alkylating agents in particular are quite toxic to the primordial follicles which represent the ovarian reserve [31, 33]. Overall, amenorrhea rates become pronounced in patients’ ≥40 years of age [34] but many studies do not stratify by age. In addition, the very limited data on women under 35 show extremely low rates of CIA (0–10% in most studies) [35]. Although the diagnosis of breast cancer is rare in this age group, definitive data would be extremely useful as these women are most likely to have not completed child-bearing.
Table 1

Incidence of chemotherapy-induced amenorrhea (CIA) according to regimen and age

Regimen

Time of assessment

Incidence (%)

By age at diagnosis

Incidence (%)

CMF

At CT end

50

≤35

0

 

3–6 Months after CT end

42–46

<40

18–35

 

12 Months after CT end

45–69

≥40

68–93

 

24–36 Months after CT end

55–74

  

AC

At CT end

75–85

20–34

0

 

12 Months after CT end

34–68

35–40

2–21

 

24–36 Months after CT end

38–48

≥40

31–81

FAC

3–36 Months after CT end

52–72

  

CEF

At CT end

93

25–39

 

3 Months after CT end

51–64

 At CT end

32

 

12 Months after CT end

45–55

 6 months after CT end

55

   

 >12 months after CT end

22–46

   

≥40

   

 At CT end

73–98

   

 6 months after CT end

80–84

   

 >12 months after CT end

82–90

AC→taxane

  

≤40

15–61

   

>40

85

AC→paclitaxel

At CT end

90

<35

3–10

 

12 Months after CT end

70–83

35–39

16–37

 

36 Months after CT end

78

≥40

42–75

AC→docetaxel

At CT end

90

  
 

12 Months after CT end

70–83

  
 

36 Months after CT end

78

  

FEC→docetaxel

  

<40

28.60

   

≥40

79.50

CT Chemotherapy, CMF cyclophosphamide, methotrexate, fluorouracil, AC doxorubicin, cyclophosphamide, FAC fluorouracil, doxorubicin, cyclophosphamide, CEF cyclophosphamide, epirubicin fluorouracil

Transient menstrual irregularity or amenorrhea is common during chemotherapy, but a proportion of patients will resume menstruation within 6–12 months of treatment completion [35], which is the time required for damaged developing follicles to be replaced by new follicles from the remaining primordial follicle pool. In addition, fertility is often compromised even if women continue or resume menses [36], and they can undergo early menopause due to the loss of a significant proportion of their primordial follicle pool [37].

The impact of tamoxifen on ovarian function is less well understood, since the number of young patients who have not also received adjuvant chemotherapy is very small. The relative contribution of tamoxifen to treatment-induced amenorrhea is debated: some studies demonstrate an increased incidence with the addition of tamoxifen, others report no impact, with tamoxifen having apparently less effect on amenorrhea in younger women [31, 38].

Standard radiation therapy for breast cancer is not associated with significant ovarian toxicity, although internal scatter radiation can reach the pelvis and ovaries.

Do adjuvant therapies damage the fetus?

One of patients’ major concerns is the potential teratogenic impact of breast cancer treatments on a future pregnancy. Few data are available on birth outcomes in breast cancer survivors: overall, no excess risk for offspring health from that of the normal population is reported. In all articles, including 5,752 patients from breast cancer cooperative group trials and population-based case–control studies, the induced abortion rate is quite high (20–44%), probably reflecting the uncertainties of patients and physicians about the safety of pregnancy after breast cancer [3942].

Two recent large population-based cohort studies are reassuring regarding the risks of adverse birth outcome for breast cancer survivors [43, 44]. However, in a Swedish cohort, an increased risk of delivery complications, cesarean section, very preterm birth (<32 weeks) and low birth weight (<1500 g) were reported in women with a history of breast cancer compared to healthy controls. These findings have potential implications for pregnancy surveillance and management in this population [44].

What are the available options for fertility preservation?

Several options are currently available to preserve fertility [45]: the most effective and established is embryo cryopreservation which requires delaying adjuvant systemic therapy for up to 6 weeks for a patient to undergo ovarian stimulation. Early referral to reproductive specialists before breast surgery seems to increase the likelihood of obtaining a sufficient quantity of oocytes without a delay in breast cancer treatment [46].

Cryopreservation of mature oocytes is considered experimental, although more than 500 live births have been reported with this method [47] and technical improvements may increase success rates [48]. While oocyte collection can also be performed without ovarian stimulation, the embryo yield is extremely low. For women with hormone-sensitive tumors, alternative hormonal stimulation strategies such as letrozole or tamoxifen have been developed to reduce the potential risk of estrogen exposure [49]. New methods, such as in vitro follicle maturation and ovarian tissue cryopreservation and transplantation, are under active investigation [50, 51].

Is there a protective role of GnRH analogs against chemotherapy-induced gonadal damage?

In premenopausal women, GnRH analogs induce a temporary and reversible medical hypoestrogenism by decreasing pituitary FSH and LH. Potential mechanisms of fertility protection include ovarian suppression, preservation of follicles that have already initiated growth, interruption of FSH-initiated follicular recruitment, and reduction of blood flow to the ovary.

Most human studies of GnRH analogs to date have been small, uncontrolled, and/or retrospective, comparing patients of disparate ages, tumor types, and chemotherapy regimens [52, 53]. These methodological limitations have hampered definitive and safe conclusions regarding the widespread use of GnRH analogs [54].

A randomized controlled study in 80 young women with breast cancer has recently demonstrated a significant ovarian protection in those patients who received chemotherapy and the GnRH agonist goserelin as compared with those who received chemotherapy alone, using end-points of cycle regularity and serum gonadotropin levels [55]. The study has some limitations: the short duration of follow-up (8 months), and the lack of information on any additional adjuvant hormonal treatment do not allow identifying those women in whom ovarian function may have resumed later on.

Several prospective, randomized studies are under way: the results of the ZORO trial (Zoladex Rescue of Ovarian Function) in young women with hormone-insensitive breast cancer receiving anthracycline-containing chemotherapy do not show a statistically significant difference in ovarian function preservation between the patients receiving goserelin (70%) and patients undergoing observation alone (56.7%) (P = 0.28) [56]. The PROMISE trial, run by the Gruppo Italiano Mammella, completed accrual of 280 patients in 2008, but the results of this study have not yet been published.

Another prospective, randomized study, chaired by the Southwest Oncology Group (SWOG 0230) on behalf of the North American Breast Cancer Group and the International Breast Cancer Study Group, is currently recruiting premenopausal women with hormone-receptor-negative breast cancer, and will evaluate the ovarian failure rate at 2 years after adjuvant chemotherapy. The Ovarian Protection Trial in Premenopausal Breast Cancer Patients (OPTION), led by the Anglo Celtic Cooperative Oncology Group, is assessing menstruation at 12 months after treatment.

Considering the limited and conflicting evidence available, the routine use of GnRH analogs for ovarian protection is not presently recommended outside the context of a clinical trial.

The American Society of Clinical Oncology has published evidence-based guidelines for fertility preservation in patients with cancer [45]. They strongly recommend that “oncologists discuss at the earliest opportunity the possibility of infertility as a risk of cancer treatment, recognizing that in many cases, adequate data are not available to provide accurate predictions for any one individual. If patients are at risk for infertility and interested in considering options for fertility preservation, referral to appropriate specialists as early as possible is recommended”.

Can we reliably measure fertility?

The accurate assessment of fertility after anti-tumor treatments is limited by the lack of reliable and reproducible surrogate measures. The presence or absence of menstrual periods does not precisely reflect ovarian reserve: women with decreased ovarian reserve often have shorter, more regular cycles due to accelerated follicle development.

Hormonal levels (e.g., FSH, LH, estradiol, inhibin B, anti-mullerian hormone = AMH) could be better tools to measure a woman’s fertility. The most promising is AMH, as it reflects earlier stages of follicle development, which could more closely approximate the number of ovarian primordial follicles, and does not vary substantially during the menstrual cycle [5759]. AMH is increasingly regarded as a measure of follicular reserve in older women, and as a potential tool to prospectively assess fertility pre- and post-chemotherapy. The widespread use of hormone levels has been precluded by cost and the lack of sensitivity and reproducibility of available assays. In addition, single measurements reflect ovarian function only at that specific time point and therefore do not predict the potential for ovarian recovery. The evaluation of antral follicle count and ovarian volume by transvaginal ultrasound may be an alternative predictor of ovarian function [60, 61]. However, hormonal treatments for breast cancer interfere with many of these indicators. In addition, even when women are not receiving hormonal therapy, no particular laboratory test or imaging modality is a perfect reflection of a woman’s ability to become pregnant in the future.

How long should a woman wait to think about pregnancy after breast cancer diagnosis and/or treatment?

The available data suggest that early pregnancy (even within 2 years from diagnosis or treatment) is unlikely to affect prognosis for women at low risk of recurrence, with no specific information according to hormone receptor status [22, 29]. Nevertheless, in common clinical practice, it is generally suggested to wait at least 2 years from diagnosis before attempting conception, mainly to allow early recurrences to manifest. Other factors such as risk at diagnosis, adjuvant treatment length, residual fertility, and age should be taken into consideration when counseling young patients about interval time between diagnosis and pregnancy [43, 45].

Taking into account the time of oocyte maturation, it is reasonable to advise waiting at least 6 months from the end of chemotherapy. For endocrine treatments, data are less conclusive: both tamoxifen and aromatase inhibitors (AIs) have been used during assisted reproduction to improve oocyte yield. Practical advice is to wait at least 2 months and up to 3–6 months after withdrawal from endocrine therapy before attempting conception [19].

Is breast-feeding possible and safe after breast cancer?

Several personal and socio-cultural factors influence women’s decisions regarding initiation and duration of breastfeeding. Women previously treated for breast cancer face a unique physical and emotional condition that might impact their decisions and ability to breastfeed [62].

No prospective or retrospective data, specifically comparing women who nursed and women who bottle fed their babies after breast cancer, have been reported. The limited evidence available reports successful lactation in approximately 30% of women and no detrimental effect on survival [41]. Apart from safety concerns, feasibility of nursing remains an important issue in women with unilateral mastectomy or reduced milk production from the operated and irradiated breast. The reported series after breast conservation and radiotherapy show an acceptable self-reported breastfeeding success [41, 62], consistent with the historical data in young women treated with chest radiation for Hodgkin lymphoma [63]. Young women should be reassured about the nutritional adequacy of milk production by a single breast [64], which is exclusively chosen by several mothers and children.

Recent qualitative investigations in limited samples of breast cancer survivors reported both the high motivation and satisfactory outcomes in breastfeeding, despite the difficulties of lactating mostly or entirely with one breast [62, 65, 66]. Women should not be discouraged by their physicians from breastfeeding after breast cancer [67] but need adequate counseling and practical information and should not receive any additional therapy given the risk of drug transmission through the breast milk [62, 68].

What additional data are needed to support young women in their pregnancy decisions after breast cancer?

Personalized care of young women with breast cancer represents a challenge for healthcare providers who need to address a composite personal, familial, and disease scenario. A survey of the Young Survival Coalition underscores the perception of “age discrimination or bias” related to the rarity of the disease at this age [69] mandating an upfront and multidisciplinary global planning.

The information available about safety of pregnancy after breast cancer does not provide definitive and unquestionable evidence. Data collected and published from retrospective and population-based studies have several limitations and are frequently incomplete; they are usually not representative of the entire population, can be biased by the “healthy mother” effect or underpowered and often do not control for biological factors and risk determinants in the statistical model used. In particular breast cancer outcome is not analyzed according to hormone receptor status. The availability of reliable, actual figures from dedicated, prospective, international registers will help the scientific community to better understand this multifaceted picture but will not fill in the gap of the many unanswered questions in this field of breast cancer medicine (Table 2).
Table 2

Pregnancy after breast cancer: question and answer summary

Question

Answer

Ref.

Do young women with breast cancer have a desire for pregnancy?

Young patients are concerned about their future fertility, report difficulty obtaining information from treating physicians and wish to consider pregnancy after treatment

[1417]

What’s the impact of subsequent pregnancy on disease-related outcomes?

According to the best available, retrospective evidence pregnancy does not increase a woman’s risk of recurrence, and it may even confer a protective effect

[1923, 27]

Do adjuvant treatments affect ovarian function?

The most common adjuvant chemotherapies have a negative impact on fertility: rates of permanent amenorrhea depend on agents, cumulative doses and woman’s age at the time of treatment

[31, 33, 34]

The impact of tamoxifen on ovarian function is less well understood

[31, 38]

Can we reliably measure fertility?

Presence or absence of menstrual periods does not precisely mimic ovarian reserve. No reliable and reproducible surrogate measures (i.e., laboratory tests or imaging modalities) are still available

[5660]

What are the available options for fertility preservation?

Several options are available: the most effective and established is embryo cryopreservation after short term ovarian stimulation, followed by embryo cryopreservation

[45]

Is there a protective role of GnRH analogs?

Several prospective, randomized studies are under way: no definitive conclusions are available

[51, 53]

How long should a woman wait to think about pregnancy?

The limited available data show that early pregnancy (within 2 years from diagnosis or treatment) is unlikely to affect prognosis. In common clinical practice, it is still suggested to wait at least 2 years from diagnosis

[22, 29]

Do adjuvant therapies damage the fetus?

Few data are available on birth outcome in breast cancer survivors but offspring health does not seem to be compromised

[3944]

Is breast-feeding possible and safe after breast cancer?

The limited evidence available reports lactation as feasible, adequate and safe

[41, 6167]

One approach to improving our understanding is to maximize and standardize the data collected in currently accruing adjuvant trials but a definitive assessment of pregnancy incidence and outcomes among breast cancer survivors will be possible only through a global initiative involving both the scientific and the advocacy communities. The potential relationship between the biological and genetic risk of disease and successful conception/pregnancy requires comprehensive, prospective assessment focused specifically on the issues unique to young cancer survivors, such as fertility resumption and/or preservation, pregnancy/birth outcomes, and patient’s outcomes.

The Breast International Group and North American Breast Cancer Group (BIG–NABCG) is launching an ambitious project to prospectively study the different clinical and biological features contributing to the “puzzle” of safe and successful pregnancy after breast cancer. The project, directed to young women with endocrine responsive, early breast cancer and desire of pregnancy, who are disease free after 2 years of adjuvant endocrine therapy, aims to assess patients and offspring outcomes, focusing on pregnancy (i.e., abortion, miscarriage, ectopic, stillbirth, or live birth rates), birth (i.e., preterm birth, low birth weight, birth defect rates), and breast cancer (i.e., local and distant recurrence rate, survival) endpoints.

The proposed trial includes an observational phase which investigates the feasibility and impact of a temporary treatment interruption to allow conception. The experimental phase will then investigate the optimal duration of subsequent endocrine treatment after delivery or the last failed attempt to get pregnant.

Ovarian function suppression has been associated with improved outcome in premenopausal women with hormone-sensitive breast cancer [70, 71], and studies indicate a better disease-free and overall survival for women who develop CIA [31, 72, 73]. Thus, there is some concern that interrupting endocrine therapy and recovering menses may increase the risk of breast cancer recurrence. The proposed global prospective trial provides the unique opportunity to test endocrine treatment interruption to allow pregnancy in women with low-risk endocrine responsive breast cancer in a controlled fashion. The information gained will hopefully allow young women with breast cancer to safely plan and pursue a pregnancy without waiting for many years required for the completion of adjuvant treatment.

Acknowledgments

The authors express their gratitude to Mrs Kris Vantongelen for coordinating the work of the Breast International Group and North American Breast Cancer Group Endocrine Working Group. The Breast International Group and the North American Breast Cancer Group Collaboration is supported by a grant of The Breast Cancer Research Foundation.

Conflict of interest

None.

Copyright information

© Springer Science+Business Media, LLC. 2011