Frozen in time, thawed to life – A case of fertility preservation in a patient with breast carcinoma

Breast cancer is the most common malignancy accounting for almost 1 in 4 women, with a 6% incidence among women less than 40 years and a 5-year survival rate of over 85%.[12] Cancer has a huge impact on the quality of life of survivors with diminished fertility due to disease perse and gonadotoxicity of chemoradiotherapy. Reproductive functions after cancer survival are an important issue. We report a case of 26-year-old woman with carcinoma of the breast, who underwent fertility preservation of embryos followed by frozen embryo transfer 5 years later that resulted in a live birth. A 26-year old unmarried woman noticed a swelling in the left breast in March 2012. Fine needle aspiration cytology of the swelling suggested fibroadenoma. The subsequent lumpectomy revealed infiltrating ductal carcinoma on histopathology. The tumor was estrogen receptor and, progesterone receptor-positive, and Her-2-neu negative. Complete surgery (modified radical mastectomy) upstaged her disease to T2N0M0, and chemo-radiation was planned. She received whole breast radiotherapy of 50 Gy in 25 fractions followed by a boost dose of 16 Gy eight fractions; during the course of radiotherapy she got married. While fertility preservation was suggested initially in the form of oocyte cryopreservation, she was indecisive and went for cancer treatment outright. She came back with her husband after completion of radiotherapy with concerns of future pregnancy and now considering her marital status, embryo cryopreservation was suggested. However, the prognosis was guarded for fear of gonadal damage with completed radiation therapy. Fertility preservation was thus planned as an emergency after radiotherapy, but before chemotherapy. We assessed her ovarian reserve by antral follicle count and serum antimullerian hormone which was 10 (8-15) and 2.4 ng/mL (2-4 ng/mL), respectively. Husband's semen analysis was within normal limits. Random-start controlled ovarian stimulation was undertaken while she was on the seventh day of periods. Stimulation was initiated with letrozole 5 mg once daily along with recombinant follicle stimulating hormone (FSH), 300 IU/day. The antagonist was started when the lead follicle was 14 mm and continued along with letrozole and r-FSH until the trigger. Leuprolide trigger was given when there were three follicles measuring =17 mm, and oocyte retrieval was done 34 hours later. Letrozole was continued until serum estradiol levels fell below 50 pg/mL. Six mature oocytes were retrieved and inseminated with the husband spermatozoa resulting in five embryos that were frozen. The embryos were vitrified using ethylene glycol based media (Medicult, Cooper Surgical Fertility and Genomic Solutions, Denmark). The patient subsequently completed cyclophosphamide, epirubicin, and 5-fluorouracil-based chemotherapy and was continued on adjuvant tamoxifen for the subsequent 5 years. After 5 years of disease-free status, she came to us seeking pregnancy through her frozen embryos. Endometrial preparation for the frozen embryo transfer cycle was achieved using letrozole 2.5 mg once daily, and when the lining reached 8.2 mm triple layer pattern, micronized progesterone 100 mg intramuscular was started. The embryo thawing was done using sucrose based warming medium (Vitrolife, Sweden). Three embryos were thawed out, of which two survived and were transferred. Serum β-hCG was 1542 mIU/mL on day 16 of embryo transfer with a viable pregnancy at six weeks scan. The antenatal period was uneventful, and the patient delivered a 3.4 kg boy by emergency Cesarean section at 39 weeks due to nonprogress of labor. The baby was large for date and had no gross congenital anomaly. Mother and baby were discharged in stable condition on postoperative day 4. The ever-rising number of cancer patients in the young age group has necessitated more demand for oncofertility services. Cancer treatment by radiotherapy and chemotherapy can have a detrimental effect on the fertility of young cancer survivors. Fertility preservation helps cancer survivors have their biological children, and should be offered in situations where the 5-year survival is more than 50%. Radiotherapy-induced gonadotoxicity depends on the age of the patient, total dose, type of radiotherapy, and fractionation. The sterilizing dose of radiotherapy steadily decreases with increasing age.[3] While radiotherapy is more gonadotoxic than chemotherapy, 33 shots of radiotherapy to our patient still permitted successful cryopreservation of embryos, as ovaries were distant from the radiation field. Besides gonadotoxicity, deleterious effects of radiotherapy on the uterus also account for the lowered pregnancy, despite successful embryo cryopreservation. Chemotherapy also causes gonadotoxicity with a risk of premature ovarian insufficiency in 10-30% and infertility in 16%.[4] Cyclophosphamide which is an integral part of most chemotherapeutic regimens in breast cancer treatment is a high-risk agent causing gonadotoxicity.[5] Of the many challenges in fertility preservation, ovarian stimulation is precarious as the hiatus to starting chemotherapy or radiotherapy may be small and therefore stimulation has to be initiated irrespective of their day of the cycle. The concept of 'random-start stimulation' obviates these problems as was possible in our patient who was in the late follicular phase of her cycle to initiate stimulation.[6] As our patient had estrogen-responsive cancer, we did a letrozole-based antagonist protocol to maintain low estradiol levels throughout the cycle.[7] To prevent hyperstimulation, we instituted an antagonist protocol followed by agonist trigger, as the patient was awaiting chemotherapy. Our patient came back to us seeking pregnancy after a disease-free survival of 5 years after completion of treatment, which was as per the Society of Obstetricians and Gynecologists of Canada 2002 guidelines.[8] Recently, a case of successful fertility preservation in breast cancer survivor was reported from Japan[9] and in an anaplastic astrocytoma survivor from U.S.A.[10] A case of live birth following in vitro maturation of oocytes has been reported in breast cancer survivor from France.[11] Ongoing pregnancies have been reported from India in women who are Hodgkin's lymphoma and ovarian cancer survivors. However, so far no live birth has been reported in breast cancer survivors from India. Unfortunately, about 50% of women with cancer remain uninformed about the chances for infertility due to cancer treatment[1213] and even fewer are referred to fertility specialists.[14] Moreover, in a developing country like India, the awareness is even less. Sperm, oocyte, and embryo (if partner available) cryopreservation are the standard practices for fertility preservation.[15] However, oocyte and embryo cryopreservation takes at least 2 to 3 weeks. The technique of ovarian tissue cryopreservation is rapidly advancing and may be preferred when the delay for cancer treatment is not tolerable or increased estradiol because ovarian stimulation may cause adverse effects on cancer.[14] The evidence to recommend gonadotropin releasing hormone (GnRH) agonist before chemotherapy is conflicting but may be offered when proven methods are not feasible.[15] The successful reproductive outcomes in these cancer survivors are dependent on a liaison between the oncologist and reproductive specialist. We hope that this case report will throw light on oncologists' perspective of fertility preservation along with optimistic feelings regarding reproduction in cancer survivors. Fertility preservation in young cancer patients is a feasible option but requires a multidisciplinary approach. The possibility of infertility with cancer treatment during reproductive years and fertility preservation options should be discussed with the patients/parents, and referral to reproductive specialists should be done at the earliest. Widespread awareness is required regarding oncofertility among physicians and patients in a developing country like India.[16] Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

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