Delivery of a healthy infant in a woman with breast cancer inadvertently treated with exemestane and goserelin during pregnancy: A case report

Introduction

Breast cancer is the commonest malignancy diagnosed in women of reproductive age. ¹ Exemestane, an aromatase inhibitor, and goserelin, a gonadotropin-releasing hormone (GnRH) agonist, may be used in combination to treat hormone receptor-positive breast cancer in premenopausal women. ² Both medications are contraindicated in pregnancy as their safety in the pregnant population is yet to be established. Clinical reports of pregnancy in women treated with exemestane and/or goserelin are rare. Here, we report a case of an unexpected pregnancy conceived whilst receiving exemestane and goserelin, both of which were inadvertently continued until 13 weeks gestation.

Case report

A 40-year-old pregnant woman presented to our high-risk antenatal clinic. She had had one previous pregnancy, with monochorionic diamniotic twins (2700 g/2500 g) delivered via forceps for prolonged second stage labour nine years prior. Her past medical history was significant for a bilateral mastectomy and sentinel lymph node biopsy for a T1N0M0 left breast cancer five years prior to the current pregnancy. Histology had revealed a grade 2 invasive ductal carcinoma which was oestrogen and progesterone receptor-positive, progesterone receptor-positive and human epidermal growth factor receptor 2 (HER2) negative. Genetic testing for BRCA1, BRCA2 and PALB2 mutations returned negative. She received postoperative adjuvant endocrine therapy with oral exemestane 25 mg daily and subcutaneous goserelin 3.6 mg every 28 days. She did not receive any other chemotherapy or radiotherapy. Amenorrhoea, along with vaginal dryness and hot flushes, occurred shortly after commencing endocrine therapy. She was not using any form of contraception.

In January 2024, over four years after induction of amenorrhoea, the woman noticed increasing abdominal distension and performed a urine pregnancy test which returned positive. Pelvic ultrasound demonstrated a live intrauterine pregnancy of approximately 13 weeks gestation. She had been inadvertently taking goserelin and exemestane from conception up until this point. A midtrimester structural ultrasound revealed a live fetus with no anatomical anomaly, and an anterior low-lying placenta. Routine laboratory investigations (full blood count, thyroid function, oral glucose tolerance test, antenatal serology and urinalysis) were unremarkable. The woman was referred to a maternal–fetal medicine specialist and was informed of the possible risks of goserelin and exemestane to the fetus, including pregnancy loss. She opted to maintain the pregnancy. Both goserelin and exemestane were ceased. Her pregnancy continued uneventfully with serial ultrasound surveillance confirming appropriate fetal growth and normal structural anatomy throughout.

The woman had an induction of labour at 40 + 1 weeks for advanced maternal age. At 8 cm cervical dilatation, a decision was made for an emergency caesarean section for presumed fetal distress, indicated by abnormal cardiotocography. A healthy 3580 g female infant was delivered via lower segment caesarean section with Apgar scores of 9 and 9. No abnormalities were observed at birth. The woman's postpartum course was complicated by postpartum haemorrhage secondary to uterine atony, with 1400 mL estimated blood loss, requiring medical intervention including tranexamic acid, syntocinon, carbetocin, ergometrine, carboprost and rectal misoprostol. Her haemoglobin was 90 g/L and she received an intravenous iron infusion prior to discharge home three days later.

Discussion

Combined use of exemestane plus goserelin is a well-established adjuvant endocrine therapy for premenopausal women with hormone receptor-positive breast cancer. ² Exemestane, a steroidal third-generation aromatase inhibitor, reduces concentrations of circulating oestrogen to inhibit oestrogen-dependent breast cancer cell growth. As it does not suppress ovarian oestrogen synthesis, it can only be used in premenopausal women together with ovarian suppression, such as goserelin, a GnRH agonist. ³ Both agents are contraindicated in pregnancy.

The safety of exemestane in pregnant women is not established. In animal studies, administration of exemestane to pregnant rats and rabbits was linked to increased pregnancy loss, embryo-fetal toxicity and difficult labour, but not structural fetal anomalies. ⁴ We found one previously reported case of a woman with metastatic breast cancer who conceived whilst taking exemestane and goserelin, in the context of poor compliance with the 28-day dosing frequency for goserelin. ⁵ Following multidisciplinary discussion, the pregnancy was terminated at 14 weeks.

Reports of pregnancy in women receiving goserelin are also rare. In one case, a 36-year-old woman fell pregnant around the time of her first dose of goserelin for recurrent breast cancer, and inadvertently continued it until 16 weeks' gestation. ⁶ In another, a 26-year-old woman receiving goserelin for fertility preservation whilst on cytotoxic chemotherapy, was found to be pregnant at 25 weeks. ⁷ A third case involved a 32-year-old woman who continued tamoxifen and goserelin for locally advanced breast cancer until 25 weeks' gestation. ⁸ None of these cases showed teratogenic effects, and the women delivered healthy infants.

The remarkable features of our case are inadvertent pregnancy occurring after over four years of amenorrhoea whilst on goserelin for ovarian suppression, and delivery of a healthy infant with no congenital fetal anomaly despite exposure to exemestane and goserelin until 13 weeks’ gestation. From this single case, we cannot conclude whether the woman's complicated labour was related to exemestane and goserelin exposure during early pregnancy, or coincidental, noting the presence of other obstetric risk factors such as advanced maternal age and previous prolonged second stage.

Contraceptive use significantly decreases from time of diagnosis to treatment follow-up in women with early breast cancer, which may be due partly to a misconception that cancer treatments cause permanent infertility.^9,10 Women of child-bearing age must be aware that inadequate ovarian suppression, ovulation and pregnancy can occur despite induction of amenorrhoea with a GnRH agonist. The mechanism of this remains poorly understood but, in this case, may be related to concomitant use of an aromatase inhibitor; by depleting levels of circulating oestrogens, aromatase inhibitors prevent negative feedback suppression in the hypothalamic-pituitary axis, thus stimulating gonadotropin secretion and ovarian folliculogenesis. ¹¹

As such, it is essential for women of reproductive potential receiving adjuvant endocrine therapy for breast cancer to be advised to use effective contraception.^12,13 Having a consultation with a gynaecologist after breast cancer diagnosis has been associated with a greater likelihood of contraceptive use. ⁹ Given that female hormones drive the pathogenesis of breast cancer, especially hormone receptor-positive disease, traditional oestrogen and/or progesterone-based contraception may increase recurrence, thus are contraindicated. Appropriate non-hormonal options include barrier methods (e.g. male condoms) and the copper intrauterine device, a long-acting reversible contraception.^14,15 Should they wish to try for a pregnancy, some women treated for early breast cancer may consider a temporary discontinuation of endocrine therapy, which did not increase short-term risk of recurrence or birth defects in one recent prospective trial. ¹⁶ In the event of an unplanned pregnancy during endocrine therapy, women should receive counselling about the possible implications for fetal wellbeing, to enable informed decision-making about their pregnancy. This case adds to the limited body of evidence regarding exemestane and goserelin exposure in pregnancy, and we observed no short-term effects on the fetus.