Conception after cancer: Family planning in breast cancer patients

Although breast cancer is mostly seen in older women, 23% of patients are under 50 at diagnosis, with 6% under 40, and issues surrounding fertility and family planning are major issues in survivorship care for many of these women. Conversations surrounding this typically begin shortly after diagnosis and before therapy for the breast cancer, and extend and recur for many years after treatment. 

Patients may ask if they are able to become pregnant or may erroneously assume they are infertile and do not need to use contraception, or they may worry about the risks prior chemotherapy pose to a future pregnancy, or that a future pregnancy could trigger a cancer recurrence. It is essential that oncologists are able to discuss these concerns with them and this article seeks to address these concerns, which are also highlighted by a series of case studies. 

Am I still able to have children?

Women in their late 30s/early 40s are likely to be already experiencing declining fertility, and the physical, psychological and economic impact of a breast cancer diagnosis requires a lot of women to ‘pause’ many aspects of their lives, including considering/attempting to conceive. This may need to be further delayed in those receiving adjuvant endocrine therapy. This means that a woman aged 32 when diagnosed with a high-risk hormone-positive cancer may be up to 43 years old at completion of current standard-of-care treatment, and may be outside her natural ‘fertility window’. 

The effects of age can be further compounded by premature ovarian failure, which occurs more commonly as a toxicity of chemotherapy in those with lower baseline ovarian reserve. This is not universal (as seen particularly in patient 2 in our case studies) and may occur in as few as 10% of women (those under 40, treated with doxorubicin/cyclophosphamide), or as many as 80-90% (those over 40, treated with fluorouracil/epirubicin/cyclophosphamide [FEC] or cyclophosphamide/methotrexate/fluorouracil [CMF] based regimens).¹

Irish patients, in keeping with ESMO and ASCO guidelines, are able to access fertility preservation prior to starting chemotherapy, typically via oocyte or embryo cryopreservation. With the rare exception of patients who present in visceral crisis, patients are usually able to complete this in a short number of weeks, with no significant delay in commencement of chemotherapy. Live birth rates are estimated at approximately 30-40% with frozen embryo transfers,^2,3 or 2-6% per frozen oocyte.² Conventional oocyte/embryo cryopreservation protocols require ovarian stimulation which raise serum oestrogen levels, and so modified protocols are used in those with breast cancer.2

Gonadotropin-releasing hormone analogues such as goserelin (Zoladex) may be additionally used to limit ovarian toxicity. This helps maintain ovulation and menstruation,⁴ and reduces rates of premature ovarian failure by 50% in early breast cancer patients.⁵ Although increases in pregnancies and live births has not been demonstrated convincingly in all meta-analyses,⁴ comparisons have been limited by incomplete data in some studies on how many women wished to conceive. 

A combination of many factors, including reductions in biological fertility, concerns about recurrence risk and foetal health, and other social/economic influences, results in only 5-10% of women having a live birth within 10 years of a cancer diagnosis,⁶ 60% fewer than seen in age-matched controls,⁷ although pregnancy after breast cancer can and does occur. Three case studies reflecting our local experience of this are presented here. 

Is it safe for the baby? 

Pregnancy during active treatment such as chemotherapy, HER2-directed therapy, and endocrine therapy is not deemed to be safe. While patients may be aware of the foetal risks of chemotherapy, they are also educated about the teratogenic effects of tamoxifen, associated with an almost 20% risk of major congenital abnormalities,⁸ and of the risks of trastuzumab, including severe oligohydramnios and a neonatal death rate of > 20%, especially when given after the first term.⁹ As a consequence, they are advised to postpone pregnancy for a minimum of three months after completing therapy.

Pregnancy after completion of treatment is a different scenario. A large meta-analysis including more than eight million women reported on pregnancy outcomes in women with a history of breast cancer.⁷ While women with a history of breast cancer have slightly higher-risk pregnancies, with higher rates of Caesarean section (OR, 1.14; 95% CI, 1.04 to 1.25), and more low birth weight (OR, 1.50; 95% CI, 1.31 to 1.73), preterm (OR, 1.45; 95% CI, 1.11 to 1.88) or small for gestational age babies (OR, 1.16; 95% CI, 1.01 to 1.33), the risk of congenital abnormalities was not significantly increased, and some risks (low birth weight/small for gestational age) were only significantly higher in those who received chemotherapy, suggesting that foetal safety should not be a major barrier to those who wish to attempt pregnancy.

Is it safe for the woman?

Breast cancer in younger women often presents later, and may be associated with more aggressive biology and high-risk features, such as oestrogen/progesterone receptor–negative or HER2-enriched subtypes, grade 3 histology, and vascular/lymphatic invasion. Women under 40 have a nine-fold risk of recurrent disease compared to those over 60,⁶ and recurrence may occur either in the first few years after treatment (particularly for hormone-negative disease), or after many years of surveillance (particularly hormone-positive disease). As 20% of breast cancers in very young women (under 30) occur in those who have been pregnant within the last year⁶ (‘pregnancy-associated breast cancers’), patients may worry about hormones in pregnancy inducing a recurrence, however many of these women have very high-risk disease, and were therefore at a higher risk of recurrence regardless of pregnancy. In patient 1 in our case studies, given her diagnosis immediately postpartum, it is tempting to attribute this to her pregnancy, however her baseline risk of recurrence was at least 5-10%, and therefore the association with pregnancy in her case is not necessarily causal.

Reassuringly, in Lambertini’s meta-analysis containing studies involving eight million women⁷ it was suggested that those who do conceive actually have superior disease-free survival (HR 0.66; 95% CI 0.49-0.89 in all patients) and overall survival (HR 0.56; 95% CI 0.45-0.68) than those who do not, while in those with hormone-sensitive disease no increased recurrence risk was seen (HR 1.10; 95% CI 0.73-1.66). This data comes with the caveat that those at a higher baseline recurrence risk may have made different decisions about family planning. 

For many women, deferring pregnancy until completion of all treatment (which may take up to 10 years for some hormone-positive women) is not a realistic option, and some may opt to interrupt endocrine therapy to allow for a planned pregnancy, as seen in two of our case studies, with differing outcomes. While the impact of this on recurrence risk is as-yet unknown, the POSITIVE trial (ClinicalTrials.gov Identifier: NCT02308085) has enrolled 518 women, including patients at Irish centres, to help answer this question. This trial allowed endocrine therapy interruption of up to two years in those who had completed between 18 months and 30 months of endocrine therapy, and will report on pregnancy rates and outcomes, foetal outcomes, and cancer recurrences, with first data expected next year. 

Until further evidence is available, early discontinuation of endocrine therapy requires a careful, informed discussion about recurrence risks, involving both the patient and her family, and other members of the multidisciplinary team, including breast surgery and (where relevant) gynaecology/reproductive endocrinology. 

In those who do wish to conceive, but who are not successful with spontaneous conception, approaches such as IVF may be considered. Given that widespread access to assisted fertility is relatively recent, the long-term safety of this is lacking, however Swedish registry studies enrolling 26,114 women (diagnosed 1980-2014) found no recurrences in the 37 patients who had had IVF.¹⁰ While this requires an individualised, multidisciplinary approach, IVF is not strictly contraindicated in breast cancer patients and, as seen in our case study of patient 3, can be very successful.

Conclusions

Patients who have a history of cancer are relatively unlikely to become pregnant compared to their peers and this is multifactorial, reflecting toxicity from chemotherapy, long endocrine therapy durations, and patient choice. In those who wish to proceed with pregnancy, doing so after completing all treatment is safe for the mother, and relatively safe for baby. For those who have not yet completed all treatment, data from POSITIVE study will shed light on the oncological safety of adjuvant endocrine treatment interruptions.

References

1. Partridge AH, Burstein HJ, Winer EP. Side effects of chemotherapy and combined chemohormonal therapy in women with early-stage breast cancer. J Natl Cancer Inst Monogr 2001; 30: 135-42
2. Salama M, Anazodo A, Woodruff TK. Preserving fertility in female patients with hematological malignancies: a multidisciplinary oncofertility approach. Ann Oncol 2019; 30: 1760-1775
3. Cobo A, García-Velasco J, Domingo J, et al. Elective and onco-fertility preservation: factors related to IVF outcomes. Hum Reprod 2018; 33(12): 2222-2231
4. Chen H, Xiao L, Li J, et al. Adjuvant gonadotropin-releasing hormone analogues for the prevention of chemotherapy-induced premature ovarian failure in premenopausal women. Cochrane Database Syst Rev 2019; 3(3): CD008018
5. Lambertini M, Moore HCF, Leonard RCF, et al. Gonadotropin-releasing hormone agonists during chemotherapy for preservation of ovarian function and fertility in premenopausal patients with early breast cancer: A systematic review and meta-analysis of individual patient-level data. J Clin Oncol 2018; 36: 1981-1990
6. Cathcart-Rake EJ, Ruddy KJ, Bleyer A, et al. Breast cancer in adolescent and young adult women under the age of 40 years. JCO Oncology Practice 2021; 17(6): 305-313
7. Lambertini M, Blondeaux E, Bruzzone M, et al. Pregnancy after breast cancer: A systematic review and meta-analysis. J Clin Oncol 2021; 39: 3293-3305
8. Buonomo B, Brunello A, Noli S, et al. Tamoxifen exposure during pregnancy: A systematic review and three more cases. Breast Care 2020; 15: 148-156
9. Sarno MA, Mancari R, Azim HA, et al. Are monoclonal antibodies a safe treatment for cancer during pregnancy? Immunotherapy 2013; 5: 733-741
10. Rosenberg E, Fredriksson A, Einbeigi Z, et al. No increased risk of relapse of breast cancer for women who give birth after assisted conception. Hum Reprod Open 2019; 2019(4): hoz039