Abstract
Purpose
Breast cancer is the most common cancer diagnosed during childbearing age, and fertility preservation is becoming increasingly more essential. However, recent studies indicate a possible poorer response to controlled ovarian hyperstimulation (COH) in cancer patients than in non-cancer controls and a negative impact of BRCA mutations on female fertility. This study aims to evaluate ovarian response and the number of mature oocytes (MII) vitrified in women with breast cancer, with or without BRCA mutation, comparing them to the expected response according to an age-related nomogram.
Methods
This is a retrospective observational study involving sixty-one breast cancer patients who underwent COH for oocyte cryopreservation. The age-specific nomogram was built using 3871 patients who underwent COH due to oocyte donation, fertility preservation for non-medical reasons, or FIVET for male factor exclusively.
Results
The mean number of oocytes retrieved was 13.03, whereas the mean number of MII oocytes was 10.00. After the application of the z-score, no statistically significant differences were found compared with the expected response in the general population, neither by dividing patients according to the presence or absence of BRCA mutation nor according to the phase in which they initiated stimulation.
Conclusion
The results obtained do not support the notion of a negative impact of the BRCA mutation on the ovarian response of women with breast cancer. Women with breast cancer undergoing COH for fertility preservation can expect the ovarian response predicted for their age.
Keywords: Fertility preservation, Breast Cancer, BRCA, Ovarian response, Controlled ovarian hyperstimulation, Nomogram
Introduction
Unfortunately, cancer is not a rare disease among women of reproductive age. Indeed, recent American statistics have shown that cancer is the second leading cause of death among women of all ages and more particularly the second leading cause of death among women under 39 years following accidents (unintentional injures). The probability of a woman developing invasive cancer by the age of 49 is 5.4% (1 in 18) [1]. Breast cancer is the most commonly diagnosed malignancy in women, with an estimated 1.7 million cases in 2012, and is the most common cancer diagnosed during childbearing age. In high-income countries, 5-year survival is 85% or higher, and it has been calculated that in 2012 about 6.2 million women worldwide had survived breast cancer thanks to advances in oncology treatments [2].
Cancer treatments in premenopausal patients have a negative impact on female fertility because of the gonadotoxic effect of anticancer therapies, with a reduction in follicular pool, also demonstrated by a rapid decline in the AMH value during chemotherapy [3–5], with a percentage of acute ovarian failure after cancer treatments of 7–9% in breast cancer patients [6, 7]. In addition to fertility problems, cancer survivors may present a series of symptoms caused by the loss of endocrine function related to primary ovarian insufficiency, with a deterioration in quality of life. The potential side effects of cancer treatments have therefore led to the need for fertility preservation in patients of childbearing age with cancer. The American Society of Clinical Oncology (ASCO) published the first guidelines on fertility preservation in 2006 and updated its guidelines in 2013 and 2018 to provide all clinicians with guidance in correct management. Of the different options available for fertility preservation (i.e., ovarian suppression with GnRH agonists, ovarian transposition, or ovarian tissue cryopreservation), the most commonly used methods are oocyte or embryo cryopreservation [8–10]. To guarantee the best possible option, women should be referred immediately to a fertility specialist center before the cancer treatment is initiated. To obtain mature oocytes for cryopreservation, controlled ovarian hyperstimulation (COH) is usually performed with exogenous gonadotropins, aromatase inhibitors, and GnRH analogues.
In recent years, there has been a debate in the literature regarding a possible poorer response to COH in cancer patients than in non-cancer controls, as shown in some studies [11, 12]. However, other authors have refuted these results, not demonstrating significant differences between both groups [13–15]. In addition, some studies sought to particularly evaluate ovarian stimulation outcomes in breast cancer patients, albeit without reaching a consensus on results. A study in 2012 indicated a weaker response to COH in patients with malignancy, above all in women with a hormone-dependent cancer [11], although another more recent study demonstrated that breast cancer did not impact gonadal function as measured by antral follicle count (AFC) or ovarian stimulation outcomes [16].
In recent decades, interest in the possible mutations related to breast cancer has increased, especially the BRCA1 and BRCA2 mutations. Recent estimates show that 1–7% of breast cancer patients carry one of these two mutations, although the incidence can increase to up to 20% in women with a family history of breast/ovarian cancer [17–19]. The subject of debate was the relationship between the BRCA mutations and their negative impact on female fertility, although the published studies remain inconsistent [20, 21].
We sought to analyze the outcome of COH for fertility preservation in breast cancer patients treated in our center. The main outcome of this study was to evaluate ovarian response and the number of mature oocytes (MII) vitrified in women with breast cancer who underwent COH. The secondary outcome was to compare breast cancer response between BRCA carriers and non-carriers. We standardized these results by age and transformed them into a z-score to compare the number of retrieved oocytes between women with breast cancer, with or without BRCA mutation, and the expected response according to an age-related nomogram of retrieved oocytes.
Materials and methods
This is a retrospective observational study involving women who underwent COH and oocyte cryopreservation in a university-affiliated clinic (Hospital Universitari Dexeus, Reproductive Medicine Service, Barcelona), between 2009 and 2019. Women who had not performed oocyte retrieval were not considered for the study.
Patients
Women with a breast cancer diagnosis confirmed by histopathology underwent COH for fertility preservation purposes before the beginning of their cancer treatment. In order to ascertain pre-cancer treatment ovarian reserve status, AMH was analyzed, and a transvaginal ultrasound was performed to assess antral follicle count. Routine preoperative exams, ECG, and infection screening were also carried out.
Controlled ovarian hyperstimulation and oocyte cryopreservation
COH has been described previously [22]. Briefly, stimulation was initiated in the follicular phase or randomly, depending on the menstrual cycle day at the time of consultation with the fertility specialist, to avoid an excessive delay in beginning the cancer treatment. For the purpose of this analysis, the beginning of stimulation was therefore divided into three groups, according to the last menstrual period: early follicular phase (< 7 days), late follicular phase (8–14 days), and luteal phase (> 14 days) [23].
The initial dose of gonadotropin was defined according to age, BMI, and ovarian reserve, and the dosage could be adjusted according to the response during stimulation. Ovarian response was monitored by ultrasound examination and plasma estradiol levels starting after 5 days of stimulation and every second day thereafter until the criteria for final maturation trigger were met.
To prevent spontaneous premature LH surge, GnRH antagonist (0.25 mg/day) was administered when the ultrasound scan detected a leading follicle of 14 mm until the ovulation trigger day. Final oocyte maturation was triggered when 3 or more follicles reached at least 18 mm, with administration of rhCG (250 μg) or GnRH agonist triptorelin (0.2 mg). Oocyte retrieval was performed 36 h after ovulation trigger under transvaginal ultrasound guidance.
Regardless of the presence or absence of estrogen receptors in the breast biopsy histology, aromatase inhibitor (5 mg/day) was administrated concurrently with gonadotropins to limit the potential adverse effect of a high level of estradiol on cancer and was continued until the next menstruation [24–26]. Mature oocytes (metaphase II) were vitrified [27].
Outcomes
The main outcome of this study was to evaluate ovarian response in patients with breast cancer who underwent COH for fertility preservation, compared with an age-related nomogram built with healthy women. We standardized these results by age and transformed them into a z-score to compare the number of retrieved oocytes between women with breast cancer, with or without BRCA mutation, and the expected response according to the nomogram.
We evaluated the following data for each patient: AMH, BMI, antral follicle count, stimulation start phase, total gonadotropin dose, duration of stimulation, peak serum estradiol level on the day of the trigger, the drug used for the trigger, number of total oocytes retrieved, and number of mature oocytes vitrified. Control group AFC and AMH analyses have been reported previously [22].
Statistical analysis
Ovarian response in women with breast cancer was compared with an expected ovarian response calculated through an age-specific nomogram that assessed the number of retrieved oocytes. This age-specific nomogram was built using the ovarian response of 3871 patients who underwent ovarian stimulation in our institution due to oocyte donation, fertility preservation for non-medical reasons, or IVF/ICSI for male factor exclusively. All 3871 cycles were performed with a GnRh antagonist protocol, and we considered only the first cycle of every woman in the nomogram.
The GAMLSS method with R software was used for the construction of the nomogram curves [28, 29]. The z-score was used to compare the number of retrieved oocytes between women with cancer and the expected response according to the nomogram. The z-score was defined as the number of oocytes retrieved in oncological patients minus the mean number of oocytes retrieved in the reference population used to build the nomogram (at the same age) divided by the standard deviation (at the same age). We calculated the 95% confidence interval (CI) for the z-scores. A confidence interval including zero means that there are no statistically significant differences between the studied population and the reference population. An analysis of variance (ANOVA) with Bonferroni multiple testing correction was performed to compare the means of z-scores between the different variables, taking BRCA status and stimulation start time into account.
Results
Between January 2009 and May 2019, sixty-one patients underwent controlled ovarian stimulation for fertility preservation after an anatomopathological diagnosis of breast cancer.
The patients’ baseline characteristics and the stimulation details are shown in Table 1. The mean AMH was 1.90 ng/ml (range 0.36–5.50 ng/ml), and the mean AFC was 11.37 (range 3–23 follicles).
Table 1.
Baseline characteristics, stimulation parameters and outcomes of cycles
| Characteristics and parameters | No. of patients = 61 |
|---|---|
| Age (year) | 34.79 ± 4.04 |
| Body mass index (Kg/m2) | 21.34 ± 2.22 |
| Antral follicle count | 11.37 ± 5.52 |
| AMH (ng/ml) | 1.90 ± 1.34 |
| Duration of stimulation (days) | 10.18 ± 4.06 |
| Total gonadotropin dose (UI) | 2580.26 ± 1028.48 |
| Duration of GnRh antagonist (days) | 5.61 ± 2.24 |
| Total letrozole dose (mg) | 47.79 ± 25.39 |
| Peak estradiol levels (pg/ml) | 581.50 ± 392.73 |
| Follicles ≥ 14 mm at the day of the trigger (follicles) | 10.90 ± 6.59 |
| No. of oocytes retrieved | 13.03 ± 9.04 |
| No. of MII oocytes | 10.00 ± 8.50 |
Data are expressed in mean (± standard deviation)
Thirty-nine women (63.9%) started the stimulation in the early follicular phase, ten women (16.4%) started in the late follicular phase, and the remaining twelve patients (19.7%) started in the luteal phase.
Ten patients were triggered with rhCG and fifty-one patients with GnRH agonist triptorelin.
The mean number of oocytes retrieved was 13.03, while the mean number of mature oocytes (metaphase II) was 10.00.
Regarding BRCA status, four patients were BRCA1 carriers, six patients were BRCA2 carriers, and eleven patients were BRCA-negative, although the BRCA status was unknown for most women.
Figure 1 shows the plot of the age-specific nomogram for the number of retrieved oocytes, and Table 2 shows the same results numerically.
Fig. 1.
Age-specific nomogram. X-axis age, Y-axis oocytes. Gray line 10th centile, yellow line 25th centile, light blue line 50th centile, blue line 90th centile
Table 2.
Age-specific nomogram (centiles are shown as a function of age)
| Age (year) | 2nd | 10th | 25th | 50th | 75th | 90th | 98th |
|---|---|---|---|---|---|---|---|
| 18 | 5 | 8 | 12 | 16 | 21 | 26 | 35 |
| 19 | 5 | 8 | 11 | 16 | 21 | 26 | 35 |
| 20 | 5 | 8 | 11 | 15 | 20 | 26 | 35 |
| 21 | 5 | 8 | 11 | 15 | 20 | 26 | 35 |
| 22 | 5 | 8 | 11 | 15 | 20 | 26 | 35 |
| 23 | 5 | 8 | 11 | 15 | 20 | 26 | 35 |
| 24 | 5 | 8 | 11 | 15 | 20 | 26 | 35 |
| 25 | 4 | 8 | 11 | 15 | 20 | 26 | 35 |
| 26 | 4 | 7 | 11 | 15 | 20 | 25 | 34 |
| 27 | 4 | 7 | 10 | 15 | 20 | 25 | 34 |
| 28 | 4 | 7 | 10 | 14 | 19 | 25 | 34 |
| 29 | 4 | 7 | 10 | 14 | 19 | 24 | 33 |
| 30 | 4 | 6 | 9 | 14 | 18 | 24 | 32 |
| 31 | 3 | 6 | 9 | 13 | 18 | 23 | 32 |
| 32 | 3 | 6 | 9 | 13 | 17 | 23 | 31 |
| 33 | 3 | 5 | 8 | 12 | 17 | 22 | 30 |
| 34 | 3 | 5 | 8 | 11 | 16 | 21 | 29 |
| 35 | 2 | 5 | 7 | 11 | 15 | 20 | 28 |
| 36 | 2 | 4 | 7 | 10 | 15 | 20 | 27 |
| 37 | 2 | 4 | 6 | 10 | 14 | 19 | 26 |
| 38 | 2 | 4 | 6 | 9 | 13 | 18 | 25 |
| 39 | 1 | 3 | 6 | 9 | 13 | 17 | 25 |
| 40 | 1 | 3 | 5 | 8 | 12 | 17 | 24 |
| 41 | 1 | 3 | 5 | 8 | 12 | 16 | 24 |
| 42 | 1 | 3 | 4 | 7 | 11 | 16 | 23 |
| 43 | 1 | 2 | 4 | 7 | 11 | 15 | 23 |
| 44 | 1 | 2 | 4 | 7 | 10 | 15 | 22 |
| 45 | 1 | 2 | 4 | 6 | 10 | 14 | 22 |
In our study, first we used the z-score to compare the number of retrieved oocytes between patients with breast cancer and the expected response in the general population according to the previously discussed age-specific nomogram (Fig. 2). The results obtained showed a z-score of 0.29 with a 95% confidence interval (− 0.02, + 0.61) and a standard deviation of 1.25, therefore without a statistically significant difference (Table 3).
Fig. 2.
Z-score. Black line, expected response according to the nomogram. Red line, empirical response in patients with breast cancer. Mean, 0.29. Standard deviation, 1.25
Table 3.
Z-scores, 95% confidence interval, and standard deviation
| Z-score | 95% CI | Standard deviation | |
|---|---|---|---|
| All breast cancer patients (no. 61) | 0.29 | − 0.02 to + 0.61 | 1.25 |
| Start of stimulation | |||
| Early follicular phase | 0.22 | − 0.19 to + 0.65 | 1.30 |
| Late follicular phase | 0.12 | − 0.59 to + 0.84 | 1.00 |
| Luteal phase | 0.62 | − 0.18 to + 1.44 | 1.27 |
| BRCA status | |||
| BRCA 1 + | − 0.39 | − 2.38 to + 1.60 | 1.25 |
| BRCA 2 + | − 0.10 | − 0.96 to + 0.75 | 0.81 |
| BRCA - | 0.27 | − 0.56 to + 1.12 | 1.25 |
We subsequently applied the z-score to compare the response of the breast cancer patients to the general population, specifically evaluating the time of the menstrual cycle phase in which COH started. No statistically significant differences were found for women who underwent COH in the early follicular phase (z-score 0.22; 95% CI (− 0.19, + 0.65)), in the late follicular phase (z-score 0.12; 95% CI (− 0.59, + 0.84)), or in the luteal phase (z-score 0.62; 95% CI (− 0.18, + 1.44)). No statistically significant differences were found even when the patients were divided according to the presence or absence of BRCA mutation or according to the drug used for final oocyte maturation. All the z-score results and their 95% CI are shown in Table 3 and Fig. 3–4.
Fig. 3.
Start of stimulation chart. X-axis, start of stimulation phase; Y-axis, z-score oocytes
Fig. 4.
BRCA status chart. X-axis, BRCA status; Y-axis, z-score oocytes
A post hoc test was used to perform a multiple comparison between the variables regarding the start of stimulation or BRCA status, without a statistically significant result, as demonstrated in Table 4.
Table 4.
Post hoc test (Bonferroni)
| Means difference | p | 95% CI | ||
|---|---|---|---|---|
| Start of stimulation | ||||
| Early follicular phase | Late follicular phase | + 0.103 | 1 | − 0.998 to + 1.204 |
| Luteal phase | − 0.400 | 1 | − 1.425 to + 0.625 | |
| Late follicular phase | Early follicular phase | − 0.103 | 1 | − 1.204 to + 0.998 |
| Luteal phase | − 0.503 | 1 | − 1.833 to + 0.826 | |
| Luteal phase | Early follicular phase | + 0.400 | 1 | − 0.625 to + 1.425 |
| Late follicular phase | + 0.503 | 1 | − 0.826 to + 1.833 | |
| BRCA status | ||||
| BRCA 1 + | BRCA 2+ | − 0.284 | 1 | − 2.247 to + 1.679 |
| BRCA - | − 0.666 | 1 | − 2.442 to + 1.109 | |
| BRCA 2 + | BRCA 1+ | + 0.284 | 1 | − 1.679 to + 2.247 |
| BRCA - | − 0.382 | 1 | − 1.926 to + 1.161 | |
| BRCA - | BRCA 1+ | + 0.666 | 1 | − 1.109 to + 2.442 |
| BRCA 2+ | + 0.382 | 1 | − 1.161 to + 1.926 | |
Dependent variable: z-score oocytes
Discussion
Our study shows that ovarian response in women with a diagnosis of breast cancer who underwent COH was as expected according to their age in terms of oocyte yield and that the BRCA status did not present a negative impact.
Oocyte cryopreservation is a well-established and reliable fertility preservation technique which since 2012 is no longer considered an experimental practice, as indicated in the American Society of Clinical Oncology guidelines [8, 9]. Since then, numerous authors have compared COH outcomes in patients with a cancer diagnosis to healthy controls.
Domingo et al. published a study carried out on 223 ovarian stimulation cycles performed in cancer patients, showing significant differences in the number of retrieved oocytes and estradiol levels. Cancer patients were further divided into a hormone-dependent (HD) cancer group and a non-hormone-dependent cancer group, showing that only HD women had a lower number of retrieved oocytes than the controls, while there was no difference in non-HD women. The authors found no significant differences in the percentage of MII oocytes between the groups [11].
Several other studies had published conflicting results and a certain tendency to present poorer outcomes in oncological patients. Moria et al. in 2011 showed a lower number of retrieved oocytes in breast cancer patients but no significant differences in antral follicle count and in MII oocyte number compared with the control group; another observational multicenter study presented similar COH results in women with and without cancer, albeit with a lower percentage of MII in the cancer group [13–15].
Quintero et al. did not demonstrate significant differences in the number of oocytes retrieved and mature oocytes, although they did observe a weaker response in cancer patients with a longer duration of stimulation and a higher total dose of gonadotropins [30].
The main limitations of these studies were the small patient sample, healthy control patients not always age-matched, and non-homogeneous stimulation protocols with no differentiation based on the stimulation start phase. Furthermore, many studies make no distinction in COH outcomes on the basis of tumor type.
A recent metanalysis analyzed the results of ten studies that included 713 women with cancer and 1830 controls, showing that cancer is not associated with a reduced response to ovarian stimulation. This metanalysis also evaluated outcomes for breast cancer women separately, finding no differences in the mean number of total and mature oocytes versus the controls [31], albeit with several limitations, including, among others, the heterogeneity of the COH protocols used, the total dose and timing of gonadotropin administration, and the triggering type.
In 2014, for the first time ever in fertility preservation studies, our group used an age-specific nomogram to compare 48 cancer patients to 1536 healthy controls. Most of these women had a gynecological cancer (37 out of 48). Despite the limitations of a small sample size and the heterogeneity of the type of cancer, this study indicated an ovarian response in oncological patients as expected by age, with no statistically significant differences regarding the number of retrieved oocytes (z-score 0.23; 95% CI (− 0.13, + 0.60)) [22].
The reason why ovaries may give a poorer response in cancer patients is unclear: some authors have suggested that cancer could be associated with an increased catabolic state and malnutrition [32, 33].
In recent years, many studies have focused specifically on women with a diagnosis of breast cancer. While Domingo et al. demonstrated worse results, particularly in hormone-dependent cancers [11], other works indicated similar outcomes in both cancer and healthy patients.
Quinn et al. compared 191 breast cancer patients to 398 healthy controls who underwent elective cryopreservation, proving that there were no differences between the two groups with regard to ovarian response to stimulation and baseline ovarian reserve, measured by AFC, even after the patients had been categorized by age (the patients were divided into five groups: 18–34 years, 35–37 years, 38–40 years, 40–42 years, > 43 years) [16].
However, not all the studies addressing COH outcomes in women with breast cancer take BRCA status into account.
BRCA 1 and BRCA 2 genes are involved in double-stranded DNA repair and the conservation of telomere length; hence, BRCA carriers present an increased risk of cancer, especially breast and ovarian cancer [34]. It has been suggested that ovarian reserve could be reduced in BRCA mutation carriers with potential negative effects on ovarian stimulation, possibly because of DNA damage [20]. However, a recent study has demonstrated that BRCA mutation carriers (with and without malignancy) present comparable ovarian reserve and responses to COH compared with BRCA-negative patients (with and without malignancy) [35].
Our study was designed to compare ovarian response in women with a diagnosis of breast cancer undergoing COH to healthy controls. The standardization of results by age by means of the z-score and an age-specific nomogram allowed us to compare the number of retrieved oocytes between women with breast cancer and the expected response according to the nomogram. The use of the specific nomogram enabled us to avoid age-related bias, which is common in the literature.
According to our results, no statistically significant differences were demonstrated in oocyte yield in patients with breast cancer, and a value according to that which is expected by age was obtained. These results were also confirmed by analyzing patients separately by stimulation start phase. BRCA status was assessed, and we demonstrated that the presence or absence of the mutation does not negatively affect COH outcomes.
Nevertheless, the current study has certain limitations, firstly its retrospective nature and secondly the small sample size. One strong point of our study is sample homogeneity, as all our patients had a diagnosis of breast cancer, although we only obtained data about BRCA for a small number of women. For this reason, the results must be interpreted with caution and will require confirmation in a larger population sample.
In conclusion, the results obtained hitherto are encouraging in that they support the fundamental role of fertility preservation with oocyte cryopreservation in breast cancer patients with or without BRCA mutations: women with breast cancer undergoing COH for fertility preservation can expect the ovarian response predicted for their age.
Authors’ contributions
Elisa Malacarne, Marta Devesa, and Francisca Martinez have designed and developed the study and participated in the literature review and manuscript drafting; Ignacio Rodriguez has contributed to the design and statistics and critically revised the manuscript; and Buenaventura Coroleu has contributed with the critical review of the manuscript. All authors read and approved the final manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
The study was approved by the Institutional Review Board (CIOG 1020190522/01).
Footnotes
This work was performed under the auspices of the Càtedra d’Investigació en Obstetrícia I Ginecologia of the Department of Obstetrics and Gynecology, Hospital Universitari Dexeus, Universitat Autònoma de Barcelona.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30. doi: 10.3322/caac.21387. [DOI] [PubMed] [Google Scholar]
- 2.Torre LA, Islami F, Siegel RL, Ward EM, Jemal A. Global cancer in women: burden and trends. Cancer Epidemiol Biomark Prev. 2017;26(4):444–457. doi: 10.1158/1055-9965.EPI-16-0858. [DOI] [PubMed] [Google Scholar]
- 3.Lee SJ, Schover LR, Partridge AH, Patrizio P, Wallace WH, Hagerty K, Beck LN, Brennan LV, Oktay K, American Society of Clinical Oncology American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol. 2006;24(18):2917–2931. doi: 10.1200/JCO.2006.06.5888. [DOI] [PubMed] [Google Scholar]
- 4.Decanter C, Morschhauser F, Pigny P, Lefebvre C, Gallo C, Dewailly D. Anti-Mullerian hormone follow-up in young women treated by chemotherapy for lymphoma: preliminary results. Reprod BioMed Online. 2010;20(2):280–285. doi: 10.1016/j.rbmo.2009.11.010. [DOI] [PubMed] [Google Scholar]
- 5.Anderson RA, Themmen APN, Qahtani AA, Groome NP, Cameron DA. The effects of chemotherapy and long-term gonadotrophin suppression on the ovarian reserve in premenopausal women with breast cancer. Hum Reprod. 2006;21(10):2583–2592. doi: 10.1093/humrep/del201. [DOI] [PubMed] [Google Scholar]
- 6.Letourneau JM, Ebbel EE, Katz PP, Oktay KH, McCulloch CE, Ai WZ, Chien AJ, Melisko ME, Cedars MI, Rosen MP. Acute ovarian failure underestimates age-specific reproductive impairment for young women undergoing chemotherapy for cancer. Cancer. 2012;118(7):1933–1939. doi: 10.1002/cncr.26403. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Kil WJ, Ahn SD, Shin SS, Lee SW, Choi EK, Kim JH, Son BH, Ahn SH, Kim WK, Kim SB. Treatment-induced menstrual changes in very young (<35 years old) breast cancer patients. Breast Cancer Res Treat. 2006;96(3):245–250. doi: 10.1007/s10549-005-9059-x. [DOI] [PubMed] [Google Scholar]
- 8.Oktay K, Harvey BE, Partridge AH, Quinn GP, Reinecke J, Taylor HS, Wallace WH, Wang ET, Loren AW. Fertility preservation in patients with Cancer: ASCO clinical practice guideline update. J Clin Oncol. 2018;36(19):1994–2001. doi: 10.1200/JCO.2018.78.1914. [DOI] [PubMed] [Google Scholar]
- 9.Loren AW, Mangu PB, Beck LN, Brennan L, Magdalinski AJ, Partridge AH, Quinn G, Wallace WH, Oktay K, American Society of Clinical Oncology Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31(19):2500–2510. doi: 10.1200/JCO.2013.49.2678. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Martinez F. Update on fertility preservation from the Barcelona International Society for Fertility Preservation-ESHRE-ASRM 2015 expert meeting: indications, results and future perspectives. Hum Reprod. 2017;32(9):1802–1811. doi: 10.1093/humrep/dex218. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Domingo J, Guillén V, Ayllón Y, Martínez M, Muñoz E, Pellicer A, Garcia-Velasco JA. Ovarian response to controlled ovarian hyperstimulation in cancer patients is diminished even before oncological treatment. Fertil Steril. 2012;97(4):930–4. doi: 10.1016/j.fertnstert.2012.01.093. [DOI] [PubMed] [Google Scholar]
- 12.Klock SC, Zhang JX, Kazer RR. Fertility preservation for female cancer patients: early clinical experience. Fertil Steril. 2010;94(1):149–155. doi: 10.1016/j.fertnstert.2009.03.028. [DOI] [PubMed] [Google Scholar]
- 13.Moria A, Das M, Shehata F, Holzer H, Son WY, Tulandi T. Ovarian reserve and oocyte maturity in women with malignancy undergoing in vitro maturation treatment. Fertil Steril. 2011;95(5):1621–1623. doi: 10.1016/j.fertnstert.2010.12.041. [DOI] [PubMed] [Google Scholar]
- 14.Levin I, Almog B. Effect of cancer on ovarian function in patients undergoing in vitro fertilization for fertility preservation: a reappraisal. Curr Oncol. 2013;20(1):e1–e3. doi: 10.3747/co.20.1193. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Garcia-Velasco JA, Domingo J, Cobo A, Martínez M, Carmona L, Pellicer A. Five years' experience using oocyte vitrification to preserve fertility for medical and nonmedical indications. Fertil Steril. 2013;99(7):1994–1999. doi: 10.1016/j.fertnstert.2013.02.004. [DOI] [PubMed] [Google Scholar]
- 16.Quinn MM, Cakmak H, Letourneau JM, Cedars MI, Rosen MP. Response to ovarian stimulation is not impacted by a breast cancer diagnosis. Hum Reprod. 2017;32(3):568–574. doi: 10.1093/humrep/dew355. [DOI] [PubMed] [Google Scholar]
- 17.Maxwell KN, Domchek SM, Nathanson KL, Robson ME. Population frequency of germline BRCA1/2 mutations. J Clin Oncol. 2016;34(34):4183–4185. doi: 10.1200/JCO.2016.67.0554. [DOI] [PubMed] [Google Scholar]
- 18.Balmana J, et al. BRCA in breast cancer: ESMO Clinical Practice Guidelines. Ann Oncol. 2011;22(Suppl 6):vi31–vi34. doi: 10.1093/annonc/mdr373. [DOI] [PubMed] [Google Scholar]
- 19.Nelson HD, Pappas M, Zakher B, Mitchell JP, Okinaka-Hu L, Fu R. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: a systematic review to update the U.S. preventive services task force recommendation. Ann Intern Med. 2014;160(4):255–266. doi: 10.7326/M13-1684. [DOI] [PubMed] [Google Scholar]
- 20.Peccatori FA, Mangili G, Bergamini A, Filippi F, Martinelli F, Ferrari F, Noli S, Rabaiotti E, Candiani M, Somigliana E. Fertility preservation in women harboring deleterious BRCA mutations: ready for prime time? Hum Reprod. 2018;33(2):181–187. doi: 10.1093/humrep/dex356. [DOI] [PubMed] [Google Scholar]
- 21.Lambertini M, Goldrat O, Toss A, Azim HA, Jr, Peccatori FA, Ignatiadis M, del Mastro L, Demeestere I. Fertility and pregnancy issues in BRCA-mutated breast cancer patients. Cancer Treat Rev. 2017;59:61–70. doi: 10.1016/j.ctrv.2017.07.001. [DOI] [PubMed] [Google Scholar]
- 22.Devesa M, Martínez F, Coroleu B, Rodríguez I, González C, Barri PN. Ovarian response to controlled ovarian hyperstimulation in women with cancer is as expected according to an age-specific nomogram. J Assist Reprod Genet. 2014;31(5):583–588. doi: 10.1007/s10815-014-0183-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Cakmak H, Katz A, Cedars MI, Rosen MP. Effective method for emergency fertility preservation: random-start controlled ovarian stimulation. Fertil Steril. 2013;100(6):1673–1680. doi: 10.1016/j.fertnstert.2013.07.1992. [DOI] [PubMed] [Google Scholar]
- 24.Azim AA, Costantini-Ferrando M, Lostritto K, Oktay K. Relative potencies of anastrozole and letrozole to suppress estradiol in breast cancer patients undergoing ovarian stimulation before in vitro fertilization. J Clin Endocrinol Metab. 2007;92(6):2197–2200. doi: 10.1210/jc.2007-0247. [DOI] [PubMed] [Google Scholar]
- 25.Oktay K, Hourvitz A, Sahin G, Oktem O, Safro B, Cil A, Bang H. Letrozole reduces estrogen and gonadotropin exposure in women with breast cancer undergoing ovarian stimulation before chemotherapy. J Clin Endocrinol Metab. 2006;91(10):3885–3890. doi: 10.1210/jc.2006-0962. [DOI] [PubMed] [Google Scholar]
- 26.Oktay K, Buyuk E, Libertella N, Akar M, Rosenwaks Z. Fertility preservation in breast cancer patients: a prospective controlled comparison of ovarian stimulation with tamoxifen and letrozole for embryo cryopreservation. J Clin Oncol. 2005;23(19):4347–4353. doi: 10.1200/JCO.2005.05.037. [DOI] [PubMed] [Google Scholar]
- 27.Sole M, Santalo J, Boada M, Clua E, Rodriguez I, Martinez F, Coroleu B, Barri PN, Veiga A. How does vitrification affect oocyte viability in oocyte donation cycles? A prospective study to compare outcomes achieved with fresh versus vitrified sibling oocytes. Hum Reprod. 2013;28(8):2087–2092. doi: 10.1093/humrep/det242. [DOI] [PubMed] [Google Scholar]
- 28.Rigby RA, Stasinopoulos DM. Generalized additive models for location, scale and shape. J R Stat Soc: Ser C: Appl Stat. 2005;54(3):507–554. [Google Scholar]
- 29.R Development Core Team . R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2008. [Google Scholar]
- 30.Quintero RB, Helmer A, Huang JQ, Westphal LM. Ovarian stimulation for fertility preservation in patients with cancer. Fertil Steril. 2010;93(3):865–868. doi: 10.1016/j.fertnstert.2008.10.007. [DOI] [PubMed] [Google Scholar]
- 31.Turan V, Quinn MM, Dayioglu N, Rosen MP, Oktay K. The impact of malignancy on response to ovarian stimulation for fertility preservation: a meta-analysis. Fertil Steril. 2018;110(7):1347–1355. doi: 10.1016/j.fertnstert.2018.08.013. [DOI] [PubMed] [Google Scholar]
- 32.Agarwal A, Said TM. Implications of systemic malignancies on human fertility. Reprod BioMed Online. 2004;9(6):673–679. doi: 10.1016/s1472-6483(10)61779-8. [DOI] [PubMed] [Google Scholar]
- 33.Schenker JG, Meirow D, Schenker E. Stress and human reproduction. Eur J Obstet Gynecol Reprod Biol. 1992;45(1):1–8. doi: 10.1016/0028-2243(92)90186-3. [DOI] [PubMed] [Google Scholar]
- 34.Oktay K, Turan V, Titus S, Stobezki R, Liu L. BRCA mutations, DNA repair deficiency, and ovarian aging. Biol Reprod. 2015;93(3):67. doi: 10.1095/biolreprod.115.132290. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Gunnala V, Fields J, Irani M, D'Angelo D, Xu K, Schattman G, Rosenwaks Z. BRCA carriers have similar reproductive potential at baseline to noncarriers: comparisons in cancer and cancer-free cohorts undergoing fertility preservation. Fertil Steril. 2019;111(2):363–371. doi: 10.1016/j.fertnstert.2018.10.014. [DOI] [PubMed] [Google Scholar]