Childbirth after perioperative systemic therapy in patients with breast cancer: a retrospective single institutional study in Japan

Abstract

Background

The number of breast cancer patients of childbearing age has been increasing. Therefore, we investigated the characteristics and the childbearing status of the patients who received systemic therapy for breast cancer during their childbearing age to better understand the clinical impact of childbirth.

Methods

Female patients with breast cancer younger than 40 years old who underwent surgery and received perioperative systemic therapy from 2007 to 2014 were included in this study. We compared the characteristics of patients with and without childbirth after treatment.

Result

Of 590 patients, 26 delivered a child, and 355 did not bear a child during the median observation period of 8.1 years, whilst 209 had unknown childbirth data. The childbirth group had a lower mean age at surgery (32.2 vs. 35.1, P < 0.001). The proportion of patients who desired childbirth and used assisted reproductive technology was significantly higher in the childbirth group (65.4 vs. 23.9% and 45.2 vs. 5.1%, respectively, P < 0.001). The patients in the childbirth group had significantly less advanced disease (P = 0.002). In the childbirth group, the age at childbirth was significantly older in patients who received combined endocrine therapy and chemotherapy (40.8 years) than in patients who received either alone (endocrine therapy: 36.9 years, chemotherapy: 36.7 years, P = 0.04). However, survival was not different between those with and without childbirth.

Conclusion

It is critical to recognize the desire for childbirth in patients with breast cancer who are receiving systemic therapy and to provide them with necessary fertility information before treatment to support their decision-making.

Introduction

According to the population-based cancer registry 2019 in Japan (1), the prevalence of breast cancer ranked first among all malignancies in females, with approximately 3700 patients (3.7%) under 40 years old and approximately 18 000 patients (18.2%) aged between 40 and 49 years. The age of childbirth in Japanese women has been rising due to women’s social progress and assisted reproductive technology (ART) development. The maternal age at childbirth in 1985 was 6.5% for 35–39 years old and 0.6% for 40 years old or older. In 2018, it became 23.0% for 35–39 years old and 5.8% for 40 years old or older (2). Meanwhile, breast cancer cases during their reproductive ages have been increasing.

Chemotherapy (CT) for breast cancer increases the risk of treatment-associated amenorrhea leading to infertility (3,4). Moreover, endocrine therapy (ET) is contraindicated during pregnancy because of teratogenicity (5), and thus, the pregnancy should be prevented during long-term ET for 5–10 years. As the drug therapies for breast cancer commonly affect subsequent pregnancy and childbirth, the American Society of Clinical Oncology (ASCO) guidelines 2018 (6) and the Clinical Practice Guidelines 2017 of the Japan Society of Clinical Oncology (7) recommend giving information on the risk of infertility associated with treatment and on fertility preservation methods before the initiation of the treatment to patients who want to bear a child. However, few reports on pregnancy and childbirth after systemic therapy for breast cancer were documented in Japan. Moreover, although the safety of pregnancy after systemic therapy for breast cancer has been reported in a few studies, specific information, including the period from treatment completion to childbirth, has been rarely reported.

Therefore, this study was conducted to clarify the clinical and maternal characteristics and childbearing status of the patients with breast cancer who received systemic therapy during their reproductive years.

Patients and methods

This study recruited female patients who underwent surgery for breast cancer at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research in Tokyo from 2007 to 2014. We excluded patients with bilateral breast cancer (synchronous and metachronous breast cancer) and age 40 years or older and who are in stage IV and not receiving neoadjuvant or adjuvant systemic therapy. Patients without ovary (bilateral oophorectomy) and uterus (hysterectomy) before breast cancer were excluded.

According to their childbirth status after treatment, patients were divided into the childbirth and non-childbirth group. The childbirth group did not include surrogate mothers and adoptive parents. A gestational breast cancer patient was included in this study.

Patient characteristics, survival and recurrence were retrospectively reviewed in the medical record. Patients’ desire to bear a child before treatment was determined based on the medical records.

Endpoints were defined as the local recurrence, distant recurrence and development of contralateral breast cancer. If patients had metastasis after primary surgery, they were censored for the analyses on local recurrence and contralateral breast cancer. The observation period was from 1 January 2007 to 31 December 2019.

Statistical analysis

A comparison between the two groups was performed by the t-test for continuous variables and chi-square test for categorical variables. Moreover, the analysis of variance was used to compare the means of the different groups. The Kaplan–Meier method was used to measure the survival rate. The log-rank test was used to analyse the difference in survival. The Cox proportional hazards model was used for adjustment by confounding factors. Conditional landmark analysis in which the landmark time was set at 5 years after surgery was performed to remove the guarantee-time bias (8). All statistical analyses were conducted using the Statistical Package for Social Sciences version 20 (IBM, Chicago, IL, USA), and two-sided P < 0.05 was considered statistically significant.

Ethical approval

This study was approved by the Ethical Review Board (ERB) of the Cancer Institute Hospital (CIH) of Japanese Foundation for Cancer Research (No. 2020–1070). Patients’ informed consent was waived by the ERB of the CIH. This study was conducted following the ethical principles established by the Helsinki Declaration, updated in 2008.

Results

Among 8407 female breast cancer patients who underwent surgery, 590 received systemic therapy and they were recruited to the study according to the criteria (Fig. 1). A retrospective search of the medical record revealed that 26 patients had the records of childbirth at a median observation period of 10.1 years (range: 7.0–12.2), and 355 patients had the records of not having childbirth at a median observation period of 8.1 years (0.4–12.7. The median observation period for the whole population was 8.1 years (0.4–12.7). The information on childbirth was unavailable in the remaining 209 patients. Table 1 shows the background characteristics between the childbirth group and the non-childbirth group. One patient was pregnant at diagnosis in the childbirth group.

Among 26 patients in the childbirth group,12 patients had ART: 6 had in vitro fertilization, and 6 had unknown details, but no further details could be collected. We have made a comparison between with and without ART in the childbirth group (Supplementary table 1).

The mean age at surgery was 32.2 and 35.1 years in the childbirth and non-childbirth groups, respectively. Therefore, patients were significantly younger at the surgery in the childbirth group (P < 0.001). However, no difference between the two groups was observed in marital and childbirth status before breast cancer diagnosis. The rate of patients who desired pregnancy or who used ART was significantly higher in the childbirth group than in the non-childbirth group (P < 0.001). Moreover, among 102 patients who desired to become pregnant, 17 (16.7%) patients gave birth within the study period.

Patients in the non-childbirth group were significantly more severe with a higher positive rate of lymph node metastasis than in the childbirth group. Furthermore, the hormone receptor (HR)–positive cancer rate was significantly higher in the non-childbirth group than in the childbirth group (P = 0.014).

Despite no difference in the type of breast surgery and the use of radiotherapy, a significant difference was noted in the type of adjuvant therapy between the two groups (P = 0.009): the proportion of ‘ET plus CT’ was higher in the non-childbirth group.

Among patients with the desire of pregnancy, LHRHa was used during chemotherapy in 6 of 11 patients in the childbirth group and 17 of 62 patients in the non-childbirth group. There were no significant differences between the two groups (P = 0.089).

Completion and discontinuation of endocrine therapy

Among 302 patients who received post-operative ET, patients who completed the therapy were 37.5% in the childbirth group, which was significantly lower than that in the non-childbirth group (71.7%) (P = 0.003, Table 2). The main reason for discontinuation was an intention to become pregnant (70.0%) in the childbirth group and recurrence (29.3%) in the non-childbirth group. Of the 16 HR-positive patients in the childbirth group, 6 patients completed 5 years of ET without interruption. Ten patients had interrupted ET, and all of the 10 patients did not resume. In accordance with the guidelines of the time, ET was to be completed in 5 years.

Type of systemic therapy and age at childbirth

The time from surgery to childbirth and maternal age at delivery in the childbirth group are shown in Table 3. The time from surgery to childbirth was significantly longer in patients who received ‘ET plus CT’ (7.4 years) than in those who received either ET (5.2 years) or CT (4.3 years) (P = 0.009). The age at childbirth was significantly older (40.8 years) in patients who received ‘ET plus CT’ than in patients who received other treatments (P = 0.04).

Survival

Recurrence-free survival (RFS) and overall survival (OS) were compared between the two groups. Because most of the patients who experienced recurrence gave up giving birth, which caused the guarantee-time bias, the conditional landmark analysis was performed with the landmark time set at 5 years after surgery (8). The Kaplan–Meier curves for the conditional landmark analysis are shown in Fig. 2. There was no significant difference in RFS between the two groups. Even after adjusting for the stage and subtype, RFS was not different between the two groups (Table 4). There was no difference in the OS between the two groups because of no death case. The survival analyses without considering the guarantee-time bias are shown in Supplementary Figs 1 and 2, which show no difference in the RFS or OS between the two groups.

Discussion

This study revealed the associations between childbirth after systemic therapy and younger age at surgery, the use of ART and less advanced disease in the breast cancer patients of reproductive age. Moreover, the age at childbirth in patients who received both ET and CT was significantly older than in patients who received either alone.

Age is one of the significant factors for successful childbirth. Doyle et al. reported that the rate of live births from frozen eggs in general women was 8.2% for 30–34 years old, 7.3% for 35–37 years old, 4.5% for 38–40 years old and 2.5% for 41–42 years old, indicating that the birth rate becomes low for those over 40 years old (9). Consistently, in this study, the maximum age at childbirth was 42 years, and the mean age at surgery in the childbirth group was 32.2 years, which was significantly younger than in the non-childbirth group. Therefore, age is an important factor for childbirth in patients with breast cancer after systemic therapy.

In this study, patients in the childbirth group had less HR-positive breast cancer than in the non-childbirth group because 5-year or longer administration of endocrine therapy as standard adjuvant treatment may have reduced the chance of childbirth in patients with HR-positive breast cancer. In 2015, an international collaborative study, the Positive trial, examined the safety of interrupting endocrine treatment to become pregnant (10). In the trial, patients who have received ET for 18–30 months take a 3-month break in treatment before attempting pregnancy and stop therapy for up to 2 years before attempting pregnancy, delivery and breastfeeding. If safety is ensured in this trial, patients may reduce their waiting time for pregnancy.

In our study, the mean age at childbirth was 40.8 years in patients who received ‘ET plus CT,’ which was significantly higher than in those who received other treatments (Table 3). However, the mean age at surgery showed no difference between these patients, suggesting that the difference in the treatment method contributed to the difference in age at childbirth. The duration from surgery to childbirth was significantly longer in those who received ‘ET plus CT’ than in those who received either alone. Possible reasons for a prolonged duration from surgery to pregnancy included the long-term treatment of a combined CT and ET, the use of multiple drugs that led to prolonged duration for ovarian function recovery or the awareness of the recurrence leading to delayed pregnancy attempt. Therefore, the patients who will receive ‘ET plus CT’ should be informed that it will take a long time to complete the treatment and they may give birth at an older age. Furthermore, information on fertility preservation should be provided to patients before the initiation of systemic therapy.

Patients in the childbirth group had significantly more ART use than those in the non-childbirth group. Goldrat et al. compared the prognosis between breast cancer patients who got pregnant with and without ART and reported that the use of ART did not adversely affect the prognosis (11). Munoz et al. reported no significant difference in the disease-free survival and OS between breast cancer patients with and without ovarian stimulation (12). Considering that systemic therapy for breast cancer affects subsequent fertility and ART safety was reported in several studies (13,14), information on ART should be given to patients with breast cancer who wish to become pregnant. The ASCO guidelines and other studies recommend that patients should be referred to a reproductive endocrinologist for fertility preservation (6,15).

This study showed no significant difference in the RFS and OS between the childbirth and non-childbirth groups, even after adjusting for stage and subtypes in the conditional landmark analysis. It is indicated that the so-called ‘healthy mother effect,’ in which women who feel healthy or at a low risk of recurrence with less advanced disease give birth, causes a good prognosis in breast cancer. Moreover, some patients who desire pregnancy may have given up childbirth because of early recurrence after the treatment completion, which might have caused the guarantee-time bias. Azim et al. conducted a meta-analysis with 14 studies to compare the prognosis of breast cancer patients with and without pregnancy (16). Their analysis taking account of the healthy mother effect indicated that there was no significant difference in survival between those with and without pregnancy, in agreement with our study.

There are some limitations in this study. First, this study is a single-institutional retrospective study, and the number of patients is relatively small because of missing data. The childbirth status after treatment was unavailable in 209 of 590 patients. Moreover, the desire for pregnancy was unknown in ~30% of the remaining 381 patients (Table 1). The finding indicated the unawareness of fertility issues by breast oncologists during the period, as shown in other studies (17,18). Thus, detailed analyses could not be made, such as the effect of different systemic therapies on successful pregnancy. At present, information on the desire for childbirth is collected at the initial visit. The system in which patients who desire to bear a child can be referred to a reproductive endocrinologist has been established in our hospital. Thus, more detailed data analysis will be possible in the future. Another limitation was unknown methods of ART, including egg freezing, ovarian freezing, fertilized egg freezing and artificial insemination. Currently, a multicentre prospective observational study to investigate the proportion of patients who have received ART, the safety of ART and the psychosocial influence of ART in patients with early-onset breast cancer is ongoing in Japan and Italy (19,20). Moreover, the number of patients who bore a child was small in our study; a larger study with more patients is necessary.

In conclusion, this study revealed that patients bearing a child after systemic therapy were younger, had more intention to become pregnant at the treatment start and had more use of ART than those without childbirth. Moreover, systemic therapy with a combination of chemo-endocrine agents prolongs to conceive. In patients with breast cancer who are indicated to receive drug therapy, their desire to bear a child should be recognized before treatment initiation and provided information about fertility preservation to support their decision-making.

Acknowledgements

The authors thank the CIH staff and Ms Rie Gokan for their efforts in medical practice and registration for the database.

Conflict of interest statement

The authors declare that they have no conflicts of interest with respect to this study.

Funding

Funding Information is not available.

References