Oncofertility Treatment Among Breast Cancer Women: A Paradigm Shift of Practice After a Decade of Service

Abstract

Purpose:

Our center is known as a pioneer center initiating oncofertility service since 2010 in Japan. We demonstrate our transition of this service in regional university hospitals ingenuously.

Methods:

We compared two phases of service: initial phase (2011 and 2012) and current phase (2019). The comparison included the number of women attending the oncofertility unit, diversity of breast cancer cases, the acceptability of preservation service, and the type of fertility preservation (FP) option offered in between these phases.

Results:

A total of 58 women were seen during the initial phase as compared with 41 women in the later phase. The mean age at diagnosis was not significantly different between the two periods. The majority of them were married and diagnosed with stage II luminar type. The current phase had a tendency to have a higher anti-Müllerian hormone level although not reaching significance. At least 50% of them declined FP and 84.5% never received ovarian control stimulation in the initial phase. Otherwise, 61% used aromatase inhibitor in the current phase. Only 15.5% in the initial phase received control ovarian stimulation whereas 63.4% in the current phase received it. The ovarian tissue cryopreservation was highly chosen during the initial phase (25.9%), whereas embryo cryopreservation (39%) was highly opted for during the current phase. All of our parameters are comparable between these two phases (p > 0.05).

Conclusion:

The significant changes of oncofertility practice were observed mainly due to the understanding of the oncofertility concept among reproductive physicians and the acceptance environment, including standard guidelines, supportive society, as well as advancements in cryobiology technique.

Introduction

Currently, at least 3%–10% of cancer diagnosed in women is in the reproductive age group, and these women had been exposed to gonadotoxic drugs during the treatment period.¹ This results in a higher incidence of chemotherapy-induced subfertility, which leads to a devastating quality of life despite a significant increase in life expectancy.² Hence, oncofertility care is deemed essential to offer fertility preservation (FP) service before potential gonadotoxic treatment. This concept was introduced in 2005 by Teresa K. Woodruff, and it spread as a prestigious consortium worldwide consistently.³ The support and courage from this consortium to establish good networking was effective, as currently there are more than 60 centers across the United States itself, and about 19 countries had engaged globally, including Japan.⁴

Women with breast cancer are still considered the highest referral cases, as the diagnosis detected during reproductive age was often associated with various hormonal subtypes that required cytotoxic chemotherapy.⁵ Worldwide, breast cancer is also still the highest cancer accounting for 11.6%, with South East Asia contributing at least 4.2% of overall cases.⁶ As the diagnosis is often early, FP can always cater accordingly. Since the 1990s, the cryopreservation techniques were applied for FP and have become an excellent option of treatment for these women.^7–11 Therefore, the choice of embryo or oocytes preservation is often offered. It acts as a guide for the oncofertility center to be tailored as the select option according to the patient's condition and situation.^11–13 At present, the majority of the oncofertility network countries already established their guidelines catering to their own needs and local health protocol.^14–16

Despite being among the highest in vitro ferrtilization (IVF) cycles countries with the total number of IVF cycles, including ICSI being 249,225 cycles per year, the reproductive services in Japan only focus on general subfertility treatment as cryopreservation for oncology cases were rarely offered.¹⁷ The oncofertility waves hit Japan 5 years later after it was led by our university, St. Marianna University School of Medicine.¹⁵ It was founded in 1971 as a private higher education institution and located at Kawasaki city within Kanagawa Prefecture with a population of around 9,000,000.¹⁸ The reproductive center in St. Marianna University Hospital started in early 2000, handling a small number of infertility cases. However, the number of IVF cycles increased throughout the year with currently at least 300–700 IVF cycles being done yearly. Subsequent to that, the oncofertility unit was initiated here in 2010 with a few cases and limited FP options. This initial phase was quite challenging, as the referral network was not organized; there was non-proper selection of cases and poor patients' understanding, acceptability, and belief.

However, this unit managed to sail through and currently become one of the established oncofertility units in Japan. Throughout the years, the improvement of cryobiology witnesses the stability of oocytes freezing, thus making it one of the excellent options for preservation nowadays. The establishment of the Japanese Society for Fertility Preservation (JSFP) in 2012 created a hallmark in oncofertility services in Japan as proper networking and was firmly established.^14,16 The introduction of alternative stimulation regimes such as random start (RS) and aromatase inhibitor (AI) in 2014 and 2015 do help in the improvement of oocytes number collection as well as ovarian tissue cryopreservation (OTC) can also be proposed in cases of highly gonadotoxic treatments, thus creating a better outcome in women with breast cancer. Further, the release of Japan Society of Clinical Oncology (JSCO) Guideline in Fertility Preservation in 2017 as standard guidance further consolidated these services in Japan.¹⁶

Now, 10 years along the line, this study was aimed at assessing the changes by comparing the services offered during the initial phase and current phase by this center. This comparison will help to highlight the overall progression and identify room for improvement. The study findings also serve as a useful reference for a beginner center.

Methods

This is a retrospective historical cohort study conducted in the Oncofertility Unit Outpatient Clinic in St. Marianna University, Kawasaki city, Kanagawa Japan. The retrospective data were reviewed and divided into two phases: combination data in 2011–2012 as the initial phase and data in 2019 as the current phase. Women who were diagnosed as having breast cancer and visited for FP consultation who had either attempted or not attempted cryopreservation were included in this study (Fig. 1). The exclusion criteria were cases with missing or incomplete data. The completeness of the data was 97% for both phases. The primary endpoint was the comparison of the number of women attending oncofertility clinic, stage of the breast, acceptability of FP, and type of FP treatment between these two phases. Approval from Institute for Research Board (IRB), St. Marianna University School of Medicine (3463; 3486; 1588) was obtained for this study.

FIG. 1.

Flow chart of the study.

SPSS version 22.0 was used for analysis. For identifying characteristics of the study population, chi-square test or Fisher's exact test was used depending on the fulfilment of assumption. Standard distributed data were analyzed by using the parametric test, and skewed data were analyzed by using nonparametric analysis. Continuous data such as bleeding pattern was evaluated by using an independent-sample t-test. Categorical data were compared by using the chi-square test with p < 0.05 taken as significance level.

Results

A total of 58 women attended our center in the initial phase compared with 41 women in the current phase. In the initial phase, most of the women were older, between 36 and 44 years old during cancer diagnosis and initial consultation compared with 35 to 40 years old in the current phase. They also had lower anti-Müllerian hormone (AMH) level: 1.6 ng/mL compared with the current phase; 4.0 ng/mL. Otherwise, the majority of them married and were diagnosed with stage II luminal type of breast cancer in both phases. All of our parameters are comparable between these two phases (p > 0.05). The women in the current phase were referred within 2 weeks of a cancer diagnosis for oncofertility consultation as compared with a longer interval in the initial phases (Table 1).

Table 1.

Demographic Characteristic

	Initial phase, n (%)	Current phase, n (%)	p
Number of referrals	58 (100)	41 (100)	—
Age (at diagnosis), mean (±SD)	36.7 (6.6)	34.9 (4.6)	0.358^b
Level AMH (ng/mL), mean (±SD)	1.4 (1.5)	4.0 (4.11)	0.129^b
Interval of referral (weeks), mean (±SD)	10 (17.4)	2 (1.42)	0.112^b
Marital status			—
Single	28 (48.3)	19 (46.3)
Married	30 (51.7)	22 (53.7)
Type of breast cancer			0.067^a
Luminar type	50 (86.2)	37 (90.2)
Triple negative	8 (13.8)	4 (9.8)
Stage of breast cancer			0.079^a
Stage I	0 (0)	4 (9.8)
Stage II	35 (60.3)	33 (80.5)
Stage III	1 (1.7)	4 (9.8)
Stage IV	2 (3.4)	0 (0)

Chi-square test.

Independent t-test.

AMH, anti-Müllerian hormone; SD, standard deviation.

There were 65.9% of women who opted for FP during the current phase, and 63.4% received ovarian control stimulation (COS). Meanwhile, at least 41.4% of women selected for FP but only 15.5% of women received COS during the initial phase. All women in the initial phase received conventional protocol whereas the variation of the type of stimulation, such as RS and Duo stimulation, was only seen during the current phase. Surprisingly, the OTC was the highest whereas oocytes cryopreservation was the least option among women during the initial phase. In contrast, the majority of women opted for embryo cryopreservation as compared with only one case that received OTC seen during the current phase (Table 2).

Table 2.

Overview of Cryopreservation Services

	Initial phase, n (%)	Current phase, n (%)	p
Acceptability of FP			0.084^a
Yes	24 (41.4)	27 (65.9)
No	28 (48.3)	13 (31.7)
Not applicable	6 (10.3)	1 (2.4)
Types of cryopreservation			0.077^a
Oocytes	2 (3.4)	10 (24.4)
Embryos	7 (12.1)	16 (39)
Ovarian	15 (25.9)	1 (2.4)
Not applicable	34 (58.6)	14 (34.1)
Ovarian stimulation protocol			—
Natural	1 (1.7)	0 (0)
Others	1 (1.7)	1 (2.4)
FSH+clomid	3 (5.2)	0 (0)
HMG+clomid	3 (5.2)	0 (0)
FSH+AI	0 (0)	7 (17.1)
Antagonist	1 (1.7)	0 (0)
Antagonist+AI	0 (0)	18 (43.9)
Not done	49 (84.5)	15 (36.6)
Type of ovarian stimulation			—
Conventional start	9 (15.5)	16 (39)
Random start	0 (0)	8 (19.5)
Duo stimulation	0 (0)	2 (4.9)
Not done	49 (84.5)	15 (36.6)

Chi-square test.

AI, aromatase inhibitor; FP, fertility preservation.

Discussion

The formation of referral networking was almost impossible in the beginning. In the initial phase, the hurdle of getting an oncofertility referral was challenging. Despite that, we manage to receive at least 58 cases for oncofertility consultation. In 2014, the collaboration of the Japan Society of Obstetrics and Gynaecology (JSOG) and Japan Society of Reproductive Medicine (JSRM) sparked a light at the end of the tunnel.^14,20 The oncofertility network spread rapidly as JSOG started implementing the oncofertility center registry to facilitate the oncofertility service and its expansion.¹⁴ Since then, the numbers of oncofertility centers have started increasing. At least 432 Cancer Hospitals with 15 Pediatrics Cancer Hospitals and 605 Assisted Reproductive Centers (ARCs) were registered in 2018 with JSOG and started providing an oncofertility service, which later led to proper referral coordination. In November 2018, an oncofertility network was established in 22 prefectures around Japan.^16,20 Therefore, we see an increment of referral in our center during the current phase as reflected in a balance of oncofertility cases distribution among established centers in Japan. This is because during the initial phase, a total of 58 cases was a combination of 2 years (2010–2011), whereas during the current phase, 41 cases were seen only in the single year of 2018.

It is noteworthy that the majority of our breast cancer cases were luminar type and diagnosed as stage II cancer in both phases. Our findings were in concert with a previous study, as they reported that at least half of breast cancer women, 47.8% in Japan were diagnosed as having stage II cancer and 81.0% were categorized as having the invasive type, including luminar type.²¹ We also found out that the interval of oncofertility referral was improved tremendously during the current phase. Our outcome was agreeable with a previous published study, as they recommended that early oncofertility referral, especially before the surgery, can lead to earlier stimulation, thus conferring a good preservation outcome.²² The shorter time frame also allowed a higher number of cryopreservation cycles that can be offered if needed to ensure a better fertility outcome as numerous embryo/oocytes can be frozen.²³ Nevertheless, the establishment of an oncofertility network in Japan, undoubtedly, contributed to this trend.¹⁴ The JSCO produced the very first Japanese FP guideline and also led to a shorter referral interval to an oncofertility center.¹⁵

The AMH level also differs in between these two phases. Although some conflicting evidence showed that AMH is lower in breast cancer women, it is mainly seen in breast cancer type susceptibility protein (BRCA) mutation as compared with sporadic cases.²⁴ However, we are not performing any BRCA gene testing to all our cases, as it is not routinely done with regard to cost-related issues. On the other hand, in a previous study, they found that the AMH level did not differ significantly by breast cancer status. By comparing with healthy women, they concluded that the age adversely impacts AMH level and worse by the cancer status.²⁵ This is consistent with our findings, as our women in the current phase are younger, with a higher AMH level as compared with the initial phase. Otherwise, low AMH level during the initial phase was also correlated to the earlier exposure of chemotherapy before FP treatment. This was consistent with a previous finding that concluded that low AMH is mainly due to chemotherapy effect.²⁶ Otherwise, there is the likelihood of the BRCA gene carrier among our initial phase women who reflect low AMH among themselves as compared with the current phase.

The improvement of both provider and patient knowledge to understanding the fundamentals of oncofertility treatment is paramount to create engagement and acceptability of FP treatment.²⁷ In the initial phase, the knowledge and idea regarding the oncofertility concept are limited as the field of FP is relatively new. The safety issues of hormonal stimulation status among breast cancer women were still inconclusive at that time, thus leading to higher rejection of FP treatment.²⁰ Therefore, almost half of our women, 48.3% declined FP during the initial phase. However, throughout the years, the FP awareness was carried out by implementing the training and education with supplementation of guidelines by JSCO, which was based on American Society of Clinical Oncology (ASCO) guidelines.²⁸ The health education was assessable in web pages in the native language with layman vocabulary.^19,28 Various pamphlets also were made available at oncofertility centers to share the concept of FP treatment among the patients and family members as a guide before consultation.¹⁶ As a result, we found out at least 50% improvement among women who declined FP during the current phase. Nevertheless, targeted training for oncofertility specialists also leads to better consultation and provides the ability to tailor the appropriate FP option according to the patient's background.²⁹ By sharing the latest evidence provided by the international society and proper recommendation, it has proven to ease patient anxiety, boost their confidence with FP treatment, and lead to improved acceptability of FP treatment during this current phase.³⁰

The international recommendation and advancement of cryobiology influenced the oncofertility option and trend of management.^15,19,31,32 In the initial phase, the primary concern is the safety of hormonal stimulation among breast cancer women, especially in the hormonal receptor-positive subtype. The fear of recurrences and further upstage of disease lead to low acceptability of embryo cryopreservation in this center, although it is the most established cryopreservation method worldwide.²⁰ As compared with the embryo, oocytes cryopreservation is still considered as experimental during the initial phase, thus being limitedly offered as one of the options for FP treatment.³³ Therefore, there were a higher number of OTC observed with less in this initial phase as no hormonal stimulation was needed, which was presumably a safer option at that time.

However, the improvement of cryobiology field results in the sustainability of thawed oocytes quality leads to a higher number of a successful pregnancy. Therefore, it was no longer considered as experimental since 2012.³² Not surprisingly, we found a higher number of FP using oocytes cryopreservation in the current phase. Further, an AI was added to the existing hormonal stimulation as safety measures in controlling the level of estradiol during ovarian stimulation among breast cancer women.^33–35 Meanwhile, the strategy of luteal phase stimulation by implementation of the “Random Start” and “Duo” protocol helps to undo the previous delay of conventional follicular phase stimulation, thus making the ovarian stimulation very much possible despite limited time before primary cancer treatment.^34–36 Those protocols were proven to be safe and effective to be applied among breast cancer women. To date, there is at least a 60% combination of oocytes and embryo cryopreservation done in this center.

On the other hand, the OTC is still considered as experimental up to now.^28,31,32 Various international bodies currently recommended the use of Edinburgh criteria as a guide in offering OTC for FP treatment.^36,37 The proper selection of OTC candidates was revised throughout the years with strict adherence to this recommendation to ensure good FP outcome. Based on the guidance of breast cancer treatment, prolonged hormonal suppression treatment (mainly tamoxifen) is often required to reduce the risk of future recurrence.⁵ This will result in low FP potential outcome despite undergoing ovarian tissue transplantation due to the nature of the aging process. Therefore, currently, the OTC is reserved for other conditions and is rarely offered to women with breast cancer unless it is proven necessary.^5,28,31 As a result, a significant reduction of OTC cases from 15 cases to only 1 case is seen among breast cancer women in our center as adherence to the current recommendation. Otherwise, higher OTC cases are seen among childhood cancer girls in our center nowadays.

Nevertheless, our study is limited up to the COS phase only, as the outcomes of live birth among these women are still pending, especially during the current phase, thus making the comparison seem impossible for these two phases. This is due to a longer interval being needed for them to complete the primary cancer treatment before allowing for pregnancy. A longer time frame is required to analyze their reproductive performance, thus, it should be evaluated in future studies.

Conclusion

Significant changes of oncofertility practice were observed between these two phases. This change was seen as an excellent progression based on a few factors. The improvement of the understanding of the oncofertility concept among reproductive physicians coupled with the evolution of the acceptance environment, including standard guidelines, supportive society, as well as enhancement of the cryobiology technique, leads to the excellent overall outcome of the oncofertility field in our center.

Footnotes

Authors' Contributions

M.F.A drafted and wrote the article. S.T, Y.H, Y.S., Y.S., and N.S. revised the article. S.T, Y.H, Y.S., Y.S., and N.S designed the research and contributed to the critical discussion. M.F.A and Y.H. contributed to collecting and analyzing data.

Acknowledgments

The authors gratefully acknowledge the support provided by the Oncofertility Unit Outpatient Department and Reproductive Center, St. Marianna University Hospital.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was obtained for this study.

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