Expert consensus on fertility preservation in patients with breast cancer occurring during pregnancy

Abstract

The prevalence of breast cancer currently ranks first among Chinese women with malignant tumors, occurring during premenopausal childbearing age in more than 60% of patients. With the increasing age of women at childbirth, the wide application of assisted reproductive technology (ART) and the rejuvenation of tumor patients, the prevalence of breast cancer occurring during pregnancy (PrBC) is gradually increasing. There are many domestic and foreign expert consensus articles and guidelines on fertility preservation for children and patients of childbearing age with malignant tumors, but there is a lack of expert consensus or guidelines on fertility preservation for patients with PrBC. Considering the uniqueness of PrBC patients, there is an urgent need for a standardized suggestion regarding their fertility preservation. The Committee of Fertility Protection and Preservation of China Association for the Promotion of Health Science and Technology together with the Chinese Society of Gynecological Endocrinology affiliated with the International Society of Gynecological Endocrinology (CSGE-ISGE) organized relevant experts from different disciplines to formulate this consensus to guide fertility preservation of PrBC patients.

摘要

目的

乳腺癌的患病率目前位居中国女性恶性肿瘤第一位, 60% 以上患者发生在绝经前的育龄期。随着女性生育年龄的推迟、辅助生殖技术的广泛应用及肿瘤患者的年轻化, 妊娠期乳腺癌（breast cancer occurs during pregnancy, PrBC）的患病率逐渐增加。关于生育力保护, 国内外已有不少儿童及育龄期恶性肿瘤患者的专家共识与指南, 但缺乏妊娠期恶性肿瘤患者生育力保护的专家共识或指南。考虑到PrBC 患者的特殊性, 其生育力保护亟需一个规范化的指导建议。中国人体健康科技促进会生育力保护与保存专业委员会联合国际妇科内分泌学会中国妇科内分泌学分会, 组织不同学科相关专家制定本共识, 为PrBC 患者的生育力保护提供指导。

Keywords:

• Breast cancer occurring during pregnancy
• fertility preservation
• surgery
• chemotherapy
• expert consensus

关键词:

• 妊娠期乳腺癌
• 生育力保护
• 手术
• 化疗
• 专家共识

Introduction

A multicenter study in the Breast Surgery Group of the Surgery Branch of the Chinese Medical Association showed that the median age of patients with pregnancy-associated breast cancer (PABC) was 32 years. The commonly used definition of PABC includes breast cancer diagnosed during pregnancy, named PrBC, and postpartum breast cancer (PPBC) diagnosed within 1 year after delivery [1–3]. The prevalence of PABC is 1/1000 to 1/3000 [4]; PABC accounts for 0.2%–3.8% of all breast cancer (BC) patients and 2.6%–7.0% of 45-year-old women with BC [2,5].

BC is one of the most common types of malignancies during pregnancy, with cervical cancer and BC accounting for 50% of all tumors during pregnancy [6], The prevalence of PrBC is about 1/3000, accounting for about 4% of BC patients under the age of 45 [6]. With the release of the ‘two-child policy’ and ‘three-child policy’, the increase in pregnancies and frequency of births and the postponement of childbearing, PrBC is more common in the hospital. However, PrBC patients also need counseling on fertility preservation (FP) methods once they have been diagnosed. The experts’ consensus focuses on the FP of PrBC patients.

Diagnosis

Medical history and physical examination

Physiological changes to the breast during pregnancy can affect the early detection of lesions. When screening for PrBC, clinicians should enquire about any abnormal symptoms, perform a pregnancy examination, record the family and patient’s personal medical history, etc., and pay special attention to whether the regional lymph nodes are enlarged or accompanied by abnormal manifestations.

Imaging examination

Breast ultrasound is recommended to evaluate the condition of the breast and local lymph nodes to determine the scope and degree of the BC. Ultrasound can be performed repeatedly, and tissue biopsy under ultrasound is also feasible. Almost 100% of abnormalities can be detected in PrBC patients using ultrasound examination [7].

The radiation dose from mammography is about 0.004 Gy, which is much lower than the fetal teratogenic radiation exposure threshold of 0.1 Gy [8]. Mammography during pregnancy is not contraindicated when it is necessary. Mammography can be performed safely with abdominal shielding, with an accuracy of up to 80% [7]. The sensitivity of X-ray diagnosis may be reduced during pregnancy due to the increase in breast density, therefore breast X-ray is not recommended as the first choice. The magnetic resonance imaging (MRI) scan of the breast is of little value in the diagnosis of BC, and contrast media that enhance MRI can cross the blood-placental barrier and may be teratogenic and are therefore not recommended.

Histopathological diagnosis

If the imaging evaluation of breast lesions is classified into Breast Imaging Reporting and Data System (BI-RADS) 4 or 5 during pregnancy, punch biopsy is recommended to confirm the histopathological diagnosis [2]. A hollow needle biopsy can provide sufficient tissue for hormone receptor, human epidermal growth factor receptor-2 (HER2) analysis and proliferation index evaluation, which is considered to be a more reliable method for the pathological diagnosis of BC. Regular follow-up and biopsy if necessary are recommended for BI-RADS 3 patients with a family history or high-risk factors of BC. For suspected abnormal axillary lymph nodes, hollow needle biopsy or fine-needle aspiration cytology (FNAC) can be performed [9].

Whole-body examination

Ultrasound and MRI should be the first choice for general examination, abdominal shielding should be used when radiation examination is involved, and the application of whole-body bone scan and PET-CT nuclear medical examination is strictly contraindicated. The patients should be informed of the risk of incomplete evaluation.

Treatment

BC can be diagnosed and treated in stages during pregnancy, with the involvement of a multidisciplinary team. PrBC requires an interdisciplinary team of obstetricians and gynecologists, reproductive specialists, breast surgeons, oncologists, imaging diagnostics, pediatricians, geneticists, psychologists, etc. to develop and implement individualized treatment plans according to disease progression, pregnancy status and patient’s wishes. The appropriate treatment method is selected according to tumor biology, tumor stage and pregnancy stage at the time of diagnosis. The principle of treatment is to start treatment as soon as possible to maximize the survival rate of the patient while minimizing harm to the fetus. The treatment of PrBC should refer to the general guidelines of young non-pregnant patients as far as possible, consider the safety of the treatment for the fetus, and carry out individualized treatment according to gestational age [10,11].

Indication of termination of pregnancy

For pregnancies of less than 13 weeks gestation, doctors should discuss the possibility of pregnancy termination with the patient and fully inform them about the balance between cancer treatment and fetal health. If the patient wishes to continue the pregnancy, tumor progression should be closely monitored. On the premise of ensuring maternal and fetal safety, effective treatment during pregnancy can benefit patients. Compared with postpartum reassessment and treatment, the overall survival rate of patients who received treatment during pregnancy was 78.7%, while that of patients without treatment was 44.7% [12]. Patients with a pregnancy of 13–28 weeks gestation can undergo surgery and chemotherapy after evaluation and choose natural delivery or cesarean section after more than 34 weeks of pregnancy. Doctors should pay attention to ensuring fetal lung maturation if the birth is premature in patients with a pregnancy of 28–34 weeks gestation, after the disease condition and fetal growth and development have been evaluated comprehensively in a multidisciplinary consultation. Doctors can choose to promote the maturation of fetal lungs, surgery, radiotherapy, and chemotherapy after birth when needed. If PrBC patients are diagnosed at ≥34 weeks of pregnancy, they should undergo comprehensive BC evaluation and standardized treatment after delivery. The possible risks and benefits of treatment options should be assessed when discussing termination of pregnancy. There is no evidence to suggest that termination of pregnancy improves prognosis [12]. Nevertheless, in the case of advanced disease stage (stage III or IV) or for high-grade or aggressive primary tumors diagnosed in the early first trimester, termination of pregnancy may be considered [12].

Treatment

Once diagnosed PrBC, they need to be referred to a tertiary medical institution for treatment and receive high-risk maternal management. Because chemotherapy and radiation may affect the fetus, PrBC treatment should consider both the efficacy of treatment and the safety of the fetus. The treatment plan is made according to the pregnancy stage of the patient at the time of diagnosis and the effect of chemotherapeutic drugs on the fetus at different gestational ages [13].

Sentinel lymph node biopsy

Sentinel lymph node biopsy (SLNB) has been widely used in the clinical setting. However, there is no scientific basis for the use of SLNB during pregnancy. The application of SLNB should be an individual decision and should not routinely be used in pregnant women at less than 30 weeks of pregnancy. If SLNB is needed, a 99mTc colloidal solution should be the first choice [14].

Surgery

BC surgery does not increase the risk of maternal death and fetal congenital defects; delayed BC surgery may increase the risk of tumor metastasis. Surgery is feasible and relatively safe at any stage of pregnancy. Surgery at more than 28 weeks of pregnancy results in a premature birth rate of 1.5–2.0%, and surgery at less than 13 weeks of pregnancy results in spontaneous abortion or low birth weight infant [15]. Therefore, it is recommended that breast surgery is performed at 13–27 weeks of pregnancy, if there is a need to perform the breast surgery, it should get timely support from the department of anesthesiology, obstetrics, neonatal pediatrics, neonatal intensive care unit and nursing department, and do a good job of individualized nursing after surgery. Under the premise of ensuring R0 resection (there are no cancer cells at the cutting edge), clinicians should choose the appropriate surgical method according to the clinical stage.

Chemotherapy

Chemotherapy in early pregnancy can easily lead to fetal malformation and preterm delivery, but can also increase the risk of placental complications such as preeclampsia and intrauterine fetal growth restriction [4]. Therefore, chemotherapy should be administered after 13 weeks gestation. Doctors should conduct a multidisciplinary consultation with the obstetrician to screen for fetal malformation, formulate the chemotherapy plan and choose the best time to begin chemotherapy. Chemotherapy should be stopped after 34 weeks of pregnancy or 3–4 weeks before the planned delivery date because chemotherapy can cause myelosuppression and may increase the risk of maternal and neonatal infection and bleeding [13].

Endocrine therapy and targeted therapy

Endocrine therapy and targeted therapy such as trastuzumab are contraindicated during pregnancy and should be postponed until after the birth because of the risk of deformity and oligohydramnios [16,17].

Radiotherapy

The radiation dose for BC mostly exceeds the radiation dose tolerated by the fetus, which increases the risk of intrauterine fetal growth restriction (FGR), cancer, delayed neurocognitive development, and even death. Therefore, it is recommended that radiotherapy be carried out after delivery, and that indications for radiotherapy are strictly followed [18].

Pregnancy outcome and prognosis

After the diagnosis of PrBC and before receiving anti-cancer therapy, the fetus should be accurately evaluated to rule out deformity. During treatment, the fetus and amniotic fluid should be evaluated by ultrasound at least every 3 weeks, intrauterine growth rate observed, and intrauterine safety evaluated so the trend of FGR can be detected in time [3]. Regular blood pressure and albuminuria tests should be performed to assess the patient’s health. Monitoring fetal development and determining the time of delivery is essential to reduce neonatal morbidity and mortality [19]. Studies have shown that there is no significant difference in disease-free survival (DFS) and overall survival (OS) between PrBC patients and non-pregnant BC patients if they receive standard local and systemic treatment [20,21].

Fertility preservation needs and strategies

Fertility preservation needs

The 5-year relative survival rate of BC patients has exceeded 80%, and 90% of the patients need fertility treatment in the future [22,23]. Although large-scale meta-analyses found that post-BC pregnancy had no negative effect on survival, women with pregnancy after BC had even higher survival rates than non-pregnant women after BC, and there may be a ‘healthy mother effect’, that is, patients who judge their prognosis to be good are more likely to choose pregnancy [21]. However, the pregnancy rate of BC patients after treatment is less than 5% [24]. The degree of ovarian function damage caused by chemotherapeutic drugs for BC is related to the age, type, dose and duration of chemotherapy. Among the commonly used chemotherapeutic drugs, alkylating agents are the most toxic to gonads, followed by platinum, taxanes, anthracycline, etc. Although menstruation can recover in some patients after chemotherapy, ovarian function is still impaired [25]. Although endocrine therapy has no reproductive toxicity, endocrine therapy lasts for 5–10 years, and the ovarian function of patients continues to decrease with age. Therefore, BC patients with fertility needs are advised to preserve their fertility before receiving anticancer therapy [26].

As the study of pregnancy safety after BC treatment involves ethical issues, it is difficult to conduct clinical randomized controlled trials, there are few reports, and the optimal time for pregnancy after a BC diagnosis is still inconclusive. It is generally recommended that estrogen receptor-negative BC patients should prepare for pregnancy 2–3 years after radiotherapy and chemotherapy according to their prognosis. Estrogen receptor-positive BC patients can discuss whether endocrine therapy should be interrupted after 2–3 years of endocrine therapy, but patients must be informed that there is little research evidence [27].

Strategies for fertility preservation

Embryos/oocytes cryopreservation

Embryo cryopreservation is recognized worldwide as an established FP method, which requires married women in China, and involves oocyte retrieval, in vitro fertilization (IVF), and embryo cryopreservation. The pregnancy rate and live birth rate depend on the age of the patient and the number of frozen embryos. Oocyte cryopreservation has no longer been considered an experimental technique since 2013 [28]. However, the number of oocytes is the key to the success of pregnancy, and it is generally believed that at least 15 oocytes are needed to achieve a 50% chances of a successful pregnancy. The chance of pregnancy depends strongly on the female age at the time of oocyte cryopreservation and on the same time on the number of oocyte as well [29]. Therefore, to ensure that an ideal number of oocytes are cryopreserved before chemotherapy, ovulation induction therapy is usually required for 10–12 days, 12–14 days for oocytes retrieval, and multiple cycles of ovulation induction if necessary [30].

To reduce the proliferation of BC cells induced by high estrogen levels caused by ovulation induction, gonadotropin is usually used to induce ovulation with the aromatase inhibitor letrozole. The study has shown that the tumor-related prognosis of BC patients receiving ovulation induction is similar to that of BC patients who do not receive ovulation induction [31]. However, at present, due to the small sample size and short follow-up period, more data and evidence are needed.

For PrBC patients, embryos/oocytes cryopreservation cannot be carried out during pregnancy, but only after delivery or termination of pregnancy, according to the individual conditions of the patients. Embryos/oocytes cryopreservation is not recommended for patients who have received adjuvant chemotherapy during pregnancy, because recent chemotherapy is more likely to damage growing follicles and lead to chromosome mutation [32].

Ovarian tissue cryopreservation and transplantation

Ovarian tissue cryopreservation (OTC) and transplantation (OTCT) have become one of the most promising FP methods because they cannot only preserve fertility, but also ovarian endocrine function. OTC is performed before radiotherapy and high-dose chemotherapy by laparoscopic minimally invasive surgery or open surgery in the treatment of primary disease. The amount of ovarian tissue retrieval is at least half of the unilateral ovary. After the ovarian tissue is transported to a centralized ovarian tissue cryobank, the ovarian tissue is prepared into cortical slices about 8 mm × 4 mm in size, and 1 mm in thickness, which is programmed to be frozen and cryopreserved until the primary disease is cured or completely relieved. The frozen ovarian tissue is then thawed and transplanted to the patients, which can restore not only the fertility of the patient, but also the endocrine function of the ovary [33]. The world’s first healthy baby was born using this technology in 2004 [34]. At present, more than 200 healthy babies have been born worldwide through this technology [35]. In 2018, the corresponding author of this consensus led the formulation of China’s first expert consensus on ovarian tissue cryopreservation and transplantation [33]. In 2019, the American Society of Reproductive Medicine announced that OTCT is no longer an experimental technique. It does not depend on the menstrual cycle and does not require ovulation [36]. OTCT technique is the only method to preserve fertility and ovarian endocrine function in patients with prepuberty, radiotherapy, and chemotherapy that cannot be delayed or who have recently been given chemotherapy [35].

OTC can be performed at the same time as cesarean section in patients with PrBC to avoid secondary surgery [37]. If the patient undergoes natural labor, laparoscopic ovarian tissue retrieval can also be performed after delivery to preserve future fertility. The surgery for ovarian tissue biopsy for OTC can be completed within 1–2 days, and anti-cancer treatment will not be delayed. After the retrieval of ovarian tissue, the immature follicles of both ovaries can be sucked under direct vision and combined with the immature cumulus-oocyte complexes (COCs) obtained in vitro from the cortical preparation process, which can maximize the fertility of patients after in vitro maturation (IVM) [38].

In the tumor-free survival period of BC patients, if there is a need for fertility but the ovarian function of the patients is altered or seriously decreased, autologous ovarian tissue transplantation (OTT) can be considered after multidisciplinary evaluation. Ovarian function can be recovered in an average of 2–4 months after OTT, with a success rate of 88%–95% [39]. The average lifespan of transplanted ovaries was 4–5 years, and about 55% of the patients had ovarian activity of more than 5 years [40]. Ten cases have been successfully transplanted in Beijing Obstetrics and Gynecology Hospital, Capital Medical University, and all ovarian function has returned to normal after OTT [41], One of the patients successfully became pregnant naturally and gave birth to a healthy baby girl [42], the first baby born in China through OTCT [43]. Internationally, the pregnancy rate and live birth rate after OTCT are up to 40%, and the natural pregnancy rate is more than 50% [44].

BC is a disease with a risk of recurrence. The age at diagnosis of BC is related to the risk of recurrence [45]. Patients with OTC are usually under 40 years old, and younger women with OTC have better fertility outcomes after OTT [46]. BC is the most common indication for OTCT. Of the 285 OTT patients in five major centers in Europe, 96 were BC, of which 7 patients relapsed (7%). The recurrence rate is similar to that of BC women without OTC [44]. Research shows that the local recurrence rate of ordinary BC patients under 40 years old after treatment is about 10%, and the 10-year recurrence rate is 4%–8.7% [47]. The recurrence in 7 patients with BC was not related to OTCT. The site of recurrence is far from the site of transplantation and close to the location of primary cancer [48]. In patients with BC, it should be considered that they are still tumor patients in the remission stage, and close follow-up of gynecological endocrine and reproductive outcomes should be carried out [49].

Gonadotropin-releasing hormone agonists

Most data show that gonadotropin-releasing hormone agonists (GnRHa) are insufficient to preserve the ovaries from chemotherapy, so international academic organizations do not recommend GnRHa as the only way to preserve fertility. And importantly, GnRHa cannot be used at all anyway during pregnancy. The ovarian protective effect of GnRHa needs to be confirmed by more studies, and the best suitable population for this treatment should be determined [50]. In a meta-analysis of 873 BC patients, patients were randomly assigned to receive GnRHa or not during chemotherapy. The results showed that regardless of the status of estrogen and progesterone receptors, there was no significant improvement in the DFS or OS rate of BC patients treated with GnRHa, and there was no evidence of FP of GnRHa [51].

Summary

With the progress of malignant tumor diagnosis and treatment technology, the 5-year survival rate of BC patients has exceeded 80%. More and more attention has been paid to the fertility problems and future quality of life of tumor survivors. With the increase in the incidence of PrBC patients, full attention should be paid to the preservation of fertility in this special population. Because of the importance of the timing of FP, it is strongly recommended that breast experts, obstetricians and gynecologists, oncologists, and reproductive experts should inform patients with PrBC to undergo counseling on fertility preservation as soon as possible. If PrBC patients continue the pregnancy, it is best to perform a cesarean section after 34 weeks of pregnancy to terminate the pregnancy and initiate postoperative anti-cancer treatment as soon as possible. Part of the ovarian tissue can be retrieved for cryopreservation at the same time during cesarean section to preserve the patient’s fertility and the recovery of ovarian endocrine function.

Other experts involved in the consensus

Binghe Xu (National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College);

Chenghong Yin (Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital);

Qinjie Tian (Peking Union Medical College Hospital, Peking Union Medical College/Chinese Academy of Medical Sciences);

Fei Ma (National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College);

Wei Zhang (Obstetrics and Gynecology Hospital of Fudan University);

Yi Fang (National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College);

Liangzhi Xu (West China Second University Hospital, Sichuan University);

Jun Zhai (The First Affiliated Hospital of Zhengzhou University);

Xiaowei Liu (Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital);

Yan Ruan (Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital);

Yinmei Dai (Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital);

Han Zhao (Center for Reproductive Medicine, Shandong University);

Liqiang Qin (National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College);

Qinying Cao (Shijiazhuang People’s Hospital);

Lei Chen (The Sixth Medical Center of PLA General Hospital);

Xiaodong Li (The First Hospital of Hebei Medical University);

Lihui Shi (Tongzhou Maternal and Child Health care Hospital of Beijing);

Yuhua Shi (Guangdong Provincial People’s Hospital, Guangdong Academy of Medical);

Lihong Zhu (Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital);

Shulan Lv (The first affiliated hospital of Xi’an Jiao tong University);

Lina Hu (The Second Affiliated Hospital of ChongQing Medical University);

Wei Huang (West China Second University Hospital, Sichuan University);

Xin Yang (Peking University People’s Hospital);

Wenpei Bai (Beijing Shijitan Hospital, Capital Medical University);

Meiqing Xie (Sun Yat-sen Memorial Hospital, Sun Yat-sen University);

Chanwei Jia (Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital);

Xu Chen (Tianjin Central Hospital of Gynecology and Obstetrics/The Obstetrics and Gynecology Hospital of Nankai University);

Wei Ma (Beijing Luhe Hospital, Capital Medical University);

Li Li (Guangzhou Women and Children’s Medical Center);

Jiaojiao Cheng (Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital);

Juan Du (Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital);

Muqing Gu (Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital);

Fengyu Jin (Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital);

Rui Ju (Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital);

Alfred O. Mueck (Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital; University Women’s Hospital and Research Centre for Women’s Health, Department of Women’s Health, University of Tuebingen);

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

Supported by Beijing Natural Science Foundation (No. 7202047); Capital’s Funds for Health Improvement and Research (2020-2-2112); Beijing Municipal Administration of Hospitals’ Ascent Plan (DFL20181401).