Abstract
Background
This study intended to investigate the relationship between the hormone receptors (including estrogen and progesterone receptors (ER/PR), and human epidermal growth factor receptor-2 (HER2) or triple-negative breast cancer (TNBC)) status of BC patients and their response to ovarian stimulation before chemotherapy.
Methods
This is a retrospective cohort study. All patients with pathologically confirmed BC who underwent fertility preservation elected for oocyte or embryo cryopreservation were included in the study. All patients were stratified according to the immunohistochemically expression of receptors. We divided the patients into the exposure groups of ER+ (n = 89)/ ER− (n = 39), PR+ (n = 85)/ PR- (n = 43), HER2+ (n = 46)/ HER2- (n = 82), TNBC (n = 27)/ non-TNBC (n = 101), and Ki67 < 20% (n = 36)/ Ki67 ≥ 20% (n = 74). The primary outcome was total oocytes retrieved.
Results
In total, 128 patients with BC were enrolled in this study. Based on the patients’ baseline characteristics, as well as the ovarian stimulation cycle parameters and their outcomes, no significant differences were observed among patients according to hormone receptor status. The HER2 + group exhibited a significantly higher number of dominant follicles on the trigger day than the HER2- group (p = 0.035); however, no significant differences were noted regarding oocyte count and maturity.
Conclusions
The findings of the current study show that the determinants of BC prognosis, such as ER, PR, TNBC, and Ki67 status, have no effect on patients’ responses to ovarian stimulation. Nevertheless, despite achieving an acceptable number of dominant follicles on the day of trigger, HER2 + status can affect the number of retrieved oocytes, particularly the number of mature oocytes.
Keywords: Oncofertility, Fertility preservation, Breast cancer, Ovarian stimulation, Ovarian response, Estrogen receptor, Progesterone receptor, HER2, TNBC
Background
Breast cancer (BC) is the most prevalent malignancy among women globally. Approximately 1.5 million women under the age of 45 are diagnosed with BC every year, which represents nearly 11% of all cancer cases reported that year [1]. Current statistics indicate that the incidence of BC in women increased, with a yearly rise of 1% from 2012 to 2021. During the same period, the reported increase was 1.4% per year in women under 50 and 2.7% per year among Asian women. On the other hand, the overall BC death rate has steadily decreased by 44% from 1989 to 2022 [2]. This decrease resulted from significant advancements in cancer treatments which, however, elevated the risk of infertility. Specifically, the risk of infertility in BC survivors has been reported as 1.46 times higher. Therefore, it is essential to monitor the reproductive health of female adolescents and young adults diagnosed with BC [3].
International guidelines recommend that clinicians inform young patients early in the disease about the potential risks of treatment and suggest potential fertility preservation strategies [1]. Various techniques are available for fertility preservation, with oocyte or embryo cryopreservation after ovarian stimulation being preferred due to its success rate [4]. Research findings indicate that improved ovarian stimulation protocols in BC patients, e.g., random-start ovarian stimulation, concomitant letrozole administration to suppress estradiol levels, and GnRH-agonist administration for oocyte maturation induction have rendered them effective and safe [5].
Fertility preservation in BC women of reproductive age presents challenges due to the limited window of time available for ovarian stimulation, restricting the number of oocytes that can be recovered before gonadotoxic therapies [4]. Accordingly, there has been an emphasis in oncofertility over the recent years for further research into the mechanisms through which BC affects folliculogenesis and response to ovarian stimulation [6]. Histological and molecular factors influence the function and treatment response in BC [7]. Histological examination has traditionally determined the type and prognosis of BC, including its stage and grade. However, molecular and immunohistochemical analyses have become prominent in the context of contemporary treatments [8]. Breast cancer is a heterogeneous disease characterized by various molecular subtypes, primarily distinguished by the differential expression of cell surface receptors [9]. This malignancy is categorized into three primary types according to the status of these receptors. The first group comprises tumors that may be positive for estrogen receptors (ER) or progesterone receptors (PR). The second type includes tumors that overexpress human epidermal growth factor receptor 2 (HER2), regardless of the presence or absence of estrogen and progesterone receptors. The lack of expression of all three receptors (ER, PR, and HER2) distinguishes the third group, known as triple-negative breast cancer (TNBC). The status of these receptors is acknowledged as a critical factor in predicting prognosis and treatment response in BC [7]. Moreover, it is believed that these prognostic factors for malignancy may influence the response to ovarian stimulation [10].
Different BC subtypes are characterized by distinct molecular, hormonal, inflammatory, and genetic profiles that may potentially influence ovarian physiology even before exposure to chemotherapy. For example, TNBC is more frequently associated with breast cancer gene (BRCA) 1/2 mutations, and previous studies have suggested that BRCA mutation carriers may exhibit reduced ovarian reserve, impaired DNA repair within oocytes, and altered reproductive endocrine function compared with non-carriers [11, 12]. In addition, aggressive BC phenotypes such as TNBC are associated with higher systemic inflammatory activity and oxidative stress, mechanisms that have been hypothesized to adversely affect granulosa-cell function and folliculogenesis [13]. Furthermore, HER-family signaling pathways, particularly epidermal growth factor receptor (EGFR)-related pathways, are involved in granulosa-cell proliferation, cumulus–oocyte communication, and oocyte maturation, providing a biologically plausible rationale for investigating whether HER2-related tumor biology may correlate with ovarian stimulation outcomes [14]. Although these associations remain incompletely understood and are not yet established clinically, emerging evidence has prompted investigation into whether breast cancer immunohistochemical subtype may be associated with ovarian reserve markers and ovarian response prior to chemotherapy.
Methods
Study design and population
This was a retrospective cohort study. All patients with pathologically confirmed BC who underwent fertility preservation elected for oocyte or embryo cryopreservation between January 2016 and March 2024 at the Infertility Clinic of ROYAN Institute, Tehran, Iran were included in the study.
All patients met the following inclusion criteria: women aged between 18 and 42 years, a confirmed diagnosis of invasive ductal carcinoma, and use of the GnRH-antagonist protocol for the ovarian stimulation. If more than one stimulation cycle was performed, only the first one was included in the analysis. Patients with a history of previous chemotherapy or radiation therapy, and cancer recurrence were excluded from the study. Other exclusion criteria included the grade 3–4 endometriosis, unilateral oophorectomy or previous ovarian surgery.
It should be noted that, considering the specific circumstances of patients with cancer and the critical time constraints they face, our center has endeavored to provide all fertility preservation services to these patients as promptly as possible. To this end, all patients referred to this clinic are admitted without any delay in processing. A specialist in obstetrics, gynecology, and infertility examines all patients upon admission and takes their clinical history. Based on the obtained history, if the patient is eligible to receive fertility preservation services, a detailed explanation of the available treatment options is provided to them. After the provision of detailed information, if the patient wishes to receive fertility preservation services, confirmation from an oncologist is required prior to initiating treatment. Blood tests, abdominal and pelvic ultrasound examinations, as well as a consultation with an anesthesiologist, are among the other essential procedures carried out as soon as possible before the start of the patient’s treatment cycle. Other specialized consultations, including consultation with a forensic medicine specialist for virginal patients, psychiatric consultation, and others, are also provided if necessary. Overall, efforts are made to initiate the ovarian stimulation cycle within less than 48 h of referral to the clinic for patients who present with definitive clinical evidence of cancer and who meet the criteria for ovarian stimulation [15].
Prognostic markers
All women with BC were stratified according to the immunohistochemically expression of receptors. ER, PR and HER2 status were determined through immunohistochemistry staining. We divided the women into the exposure groups of ER+/ER−, PR+/PR-, HER2+/HER2-, TNBC/non-TNBC, and Ki67 < 20%/Ki67 ≥ 20%. Women with ER−/PR-/HER2 − status were categorized into the TNBC group. Furthermore, women with either ER+, PR + or HER2 + were categorized into the non-TNBC group.
Ovarian stimulation
The ovarian stimulation was implemented through random-start GnRH-antagonist protocol. In order to suppress the serum estradiol level, all patients were prescribed letrozole during ovarian stimulation.
Early follicular phase
The early follicular phase extends from the onset of the follicular phase to its midpoint, defined by the presence of a dominant follicle smaller than 12 mm and a serum progesterone level below 1.5 ng/ml. The ovarian stimulation is initiated through the administration of gonadotropins. Upon observation of a follicle measuring 12–14 mm, a GnRH-antagonist is administered. Final oocyte maturation is triggered once more than three follicles measuring ≥ 17 mm is observed.
Late follicular phase
The late follicular phase is characterized by the presence of a dominant follicle larger than 12 mm, while the progesterone level remains below 1.5 ng/ml. During this phase, the patient initially receives a GnRH-antagonist for three consecutive days, or alternatively, a single injection of a GnRH-agonist is administered to induce the luteal phase. Three days later, ovarian stimulation is initiated via gonadotropin administration. Upon the emergence of a new dominant follicle measuring 12–14 mm, a GnRH-antagonist is again administered. Ovulation is induced after the observation of a follicle measuring 18 mm.
Luteal phase
The luteal phase is defined by a progesterone level exceeding 1.5 ng/ml. In this phase, ovarian stimulation is initiated in the same manner as the conventional protocol (i.e., daily gonadotropin injections starting on cycle day 2–3), and a GnRH-antagonist is administered upon observation of a follicle measuring 12–14 mm. Final oocyte maturation is triggered following the observation of a follicle measuring 18 mm [15].
Outcome measures
The primary outcome was total oocytes retrieved. The secondary outcome was total number of mature oocytes.
Statistical analysis
Qualitative and quantitative data were presented as the frequency and percentage, as well as mean and standard deviation (SD). The normality of data was assessed with the Kolmogorov-Smirnov test. Continuous variables between the two groups were compared using an independent t-test. Categorical variables were compared using the chi-square test. All analyses were done using SPSS (version 24, SPSS Inc., Illinois, USA), and a P-value less than 0.05 was considered statistically significant.
In our research, there were not any statistically significant differences in multiple subgroup analyses (ER, PR, HER2, TNBC, Ki67) for primary/ secondary outcomes (P-value > 0.05). Therefore, it seems that the multiple comparison correction methods were not probably applicable in our research. However, by Bonferroni adjustment methods, no statistically significant differences were found in our research.
Results
In total, 128 patients with BC were enrolled in this study. The baseline and clinical characteristics of participants are shown in Table 1. We divided the women into the exposure groups of ER+ (n = 89)/ ER− (n = 39), PR+ (n = 85)/ PR- (n = 43), HER2+ (n = 46)/ HER2- (n = 82), TNBC (n = 27)/ non-TNBC (n = 101), and Ki67 < 20% (n = 36)/ Ki67 ≥ 20% (n = 74). The comparison of demographic, clinical, and ovarian stimulation characteristics and their outcomes based on different hormone receptors is shown in Tables 2, 3, 4, 5 and 6.
Table 1.
Demographic and clinical information of women with breast cancer
| Variable | Mean | SD | Minimum | Maximum |
|---|---|---|---|---|
| Age (years) | 33.65 | 4.46 | 21 | 42 |
| BMI (kg/m2) | 24.27 | 3.24 | 16.85 | 33.59 |
| Hormonal profile | ||||
| FSH (IU/L) | 5.45 | 2.93 | 1.60 | 15.70 |
| LH (IU/L) | 5.91 | 3.87 | 1.10 | 18.23 |
| Progesterone (ng/mL) | 4.24 | 5.45 | 0.05 | 19.70 |
| AMH (ng/mL) | 2.90 | 2.73 | 0.10 | 16.5 |
| Stimulation start | ||||
| Early follicular phase | 48 (37.5%) | |||
| Late follicular phase | 21 (16.4%) | |||
| Luteal phase | 59 (46.1%) | |||
| Gonadotropin type | ||||
| r-FSH | 52 (40.6%) | |||
| r-FSH & HMG | 76 (59.4%) | |||
| Gonadotropin start dose (IU) | 254.29 | 83.24 | 150 | 375 |
| Total Gonadotropin dose (IU) | 2435.74 | 1083.17 | 1050 | 5250 |
| Duration of ovarian stimulation | 10.75 | 2.04 | 6 | 14 |
| Trigger | ||||
| HCG | 75 (58.6%) | |||
| GnRH-agonist | 34 (26.6%) | |||
| HCG & GnRH-agonist | 12 (9.4%) | |||
| Estradiol on trigger day (pg/mL) | 308.26 | 134.06 | 106 | 500 |
| Follicles > 12 mm on trigger day | 8.54 | 5.34 | 1 | 33 |
| Total oocytes retrieved | 10.07 | 7.92 | 0 | 39 |
| MII oocytes | 7.42 | 6.06 | 0 | 33 |
| MI oocytes | 0.98 | 1.72 | 0 | 11 |
| GV oocytes | 1.24 | 1.98 | 0 | 9 |
| Degenerated oocytes | 0.41 | 1.03 | 0 | 8 |
| Estrogen receptor | ||||
| Positive | 89 (69.5%) | |||
| Negative | 39 (30.5%) | |||
| Progesterone receptor | ||||
| Positive | 85 (66.4%) | |||
| Negative | 43 (33.6%) | |||
| HER2 | ||||
| Positive | 46 (35.9%) | |||
| Negative | 82 (64.1%) | |||
| Ki67 | ||||
| < 20% | 36 (28.1%) | |||
| ≥ 20% | 74 (57.8%) | |||
| Unknown | 18 (14.1%) | |||
| TNBC | 27 (21.1%) | |||
| Non-TNBC | 101 (78.9%) | |||
Values are presented as the mean ± standard deviation (SD) and number (percent)
BMI body mass index, FSH follicle stimulating hormone, LH luteinizing hormone, AMH anti mullerian hormone, r-FSH recombinant follicle stimulating hormone, HMG human menopausal hormone, HCG human chorionic gonadotropin, GnRH gonadotropin releasing hormone, MII metaphase 2, MI Metaphase 1, GV germinal vesicle, HER2 human epidermal growth factor receptor 2, TNBC triple negative breast cancer
Table 2.
Comparison of breast cancer women with ER + and ER- status
| Variable | ER+ (n = 89) | ER- (n = 39) | P-value* |
|---|---|---|---|
| Age (years) | 34.11 ± 4.40 | 32.61 ± 4.48 | 0.081 |
| BMI (kg/m2) | 23.95 ± 3.08 | 25.01 ± 3.54 | 0.116 |
| Hormonal profile | |||
| FSH (IU/L) | 5.37 ± 3.01 | 5.63 ± 2.76 | 0.648 |
| LH (IU/L) | 5.94 ± 4.09 | 5.85 ± 3.36 | 0.906 |
| Progesterone (ng/mL) | 4.74 ± 5.78 | 3.10 ± 4.48 | 0.152 |
| AMH (ng/mL) | 2.87 ± 2.90 | 2.97 ± 2.35 | 0.860 |
| Stimulation start | 0.479 | ||
| Early follicular phase | 32 (35.9%) | 16 (41.1%) | |
| Late follicular phase | 13 (14.6%) | 8 (20.5%) | |
| Luteal phase | 44 (49.5%) | 15 (38.4%) | |
| Gonadotropin type | 0.951 | ||
| r-FSH | 36 (40.4%) | 16 (41.1%) | |
| r-FSH & HMG | 53 (59.6%) | 23 (58.9%) | |
| Gonadotropin start dose (IU) | 257.02 ± 82.22 | 248.07 ± 86.29 | 0.578 |
| Total Gonadotropin dose (IU) | 2444.66 ± 1036.93 | 2415.38 ± 1196.06 | 0.889 |
| Duration of ovarian stimulation | 10.62 ± 2.05 | 11.02 ± 2.02 | 0.342 |
| Trigger | 0.096 | ||
| HCG | 28 (31.5%) | 6 (15.4%) | |
| GnRH-agonist | 47 (52.8%) | 28 (71.8%) | |
| HCG & GnRH-agonist | 7 (7.9%) | 5 (12.8%) | |
| Estradiol on trigger day (pg/mL) | 309.87 ± 135.48 | 304.87 ± 132.80 | 0.853 |
| Follicles > 12 mm on trigger day | 8.69 ± 5.85 | 8.23 ± 4.11 | 0.657 |
| Total oocytes retrieved | 9.44 ± 7.73 | 11.48 ± 8.28 | 0.182 |
| Mature oocytes (MII) | 6.98 ± 5.85 | 8.43 ± 6.48 | 0.215 |
| Oocyte maturation rate1 (%) | 79.18 ± 21.19 | 76.68 ± 21.89 | 0.553 |
| Fertilization rate2 (%) | 68.93 ± 19.85 | 61.14 ± 25.13 | 0.198 |
Values are presented as the mean ± standard deviation (SD) and number (percent)
ER estrogen receptor, BMI body mass index, FSH follicle stimulating hormone, LH luteinizing hormone, AMH anti mullerian hormone, r-FSH recombinant follicle stimulating hormone, HMG human menopausal hormone, HCG human chorionic gonadotropin, GnRH gonadotropin releasing hormone, MII metaphase two, 2PN two pronuclei
*P-value obtained by independent t-test and chi square test or Fisher’s exact test when more than 20% of cells with expected counts of less than 5 were observable. Statistically significant level < 0.05
1Mature oocytes (MII)/ Total oocytes retrieved
2Number of 2PN/ Number of oocytes injected
Table 3.
Comparison of breast cancer women with PR + and PR- status
| Variable | PR+ (n = 85) | PR- (n = 43) | P-value* |
|---|---|---|---|
| Age (years) | 34.15 ± 4.51 | 32.67 ± 4.25 | 0.077 |
| BMI (kg/m2) | 23.95 ± 3.14 | 24.90 ± 3.39 | 0.148 |
| Hormonal profile | |||
| FSH (IU/L) | 5.39 ± 2.88 | 5.57 ± 3.04 | 0.743 |
| LH (IU/L) | 6.11 ± 4.17 | 5.48 ± 3.18 | 0.406 |
| Progesterone (ng/mL) | 4.77 ± 5.82 | 3.30 ± 4.63 | 0.177 |
| AMH (ng/mL) | 2.98 ± 3.02 | 2.76 ± 2.13 | 0.677 |
| Stimulation start | 0.476 | ||
| Early follicular phase | 31 (36.5%) | 17 (39.5%) | |
| Late follicular phase | 12 (14.1%) | 9 (20.9%) | |
| Luteal phase | 42 (49.4%) | 17 (39.6%) | |
| Gonadotropin type | 0.840 | ||
| r-FSH | 34 (40%) | 18 (41.9%) | |
| r-FSH & HMG | 51 (60%) | 25 (58.1%) | |
| Gonadotropin start dose (IU) | 255.00 ± 81.17 | 252.90 ± 88.17 | 0.894 |
| Total Gonadotropin dose (IU) | 2455.58 ± 1044.38 | 2396.51 ± 1167.86 | 0.772 |
| Duration of ovarian stimulation | 10.60 ± 2.02 | 11.05 ± 2.09 | 0.271 |
| Trigger | 0.637 | ||
| HCG | 24 (28.2%) | 10 (23.3%) | |
| GnRH-agonist | 46 (54.1%) | 29 (67.4%) | |
| HCG & GnRH-agonist | 8 (9.4%) | 4 (9.3%) | |
| Estradiol on trigger day (pg/mL) | 310.12 ± 136.11 | 304.90 ± 131.88 | 0.842 |
| Follicles > 12 mm on trigger day | 8.80 ± 6.10 | 8.06 ± 3.58 | 0.469 |
| Total oocytes retrieved | 9.67 ± 7.83 | 10.86 ± 8.14 | 0.425 |
| Mature oocytes (MII) | 6.98 ± 5.84 | 8.30 ± 6.46 | 0.248 |
| Oocyte maturation rate1 (%) | 77.59 ± 21.73 | 79.63 ± 20.91 | 0.621 |
| Fertilization rate2 (%) | 66.14 ± 19.49 | 66.06 ± 26.12 | 0.990 |
Values are presented as the mean ± standard deviation (SD) and number (percent)
PR progesterone receptor, BMI body mass index, FSH follicle stimulating hormone, LH luteinizing hormone, AMH anti mullerian hormone, r-FSH recombinant follicle stimulating hormone, HMG human menopausal hormone, HCG human chorionic gonadotropin, GnRH gonadotropin releasing hormone, MII metaphase two, 2PN two pronuclei
*P-value obtained by independent t-test and chi square test or Fisher’s exact test when more than 20% of cells with expected counts of less than 5 were observable. Statistically significant level < 0.05
1Mature oocytes (MII)/ Total oocytes retrieved
2Number of 2PN/ Number of oocytes injected
Table 4.
Comparison of breast cancer women with HER2 + and HER2- status
| Variable | HER2+ (n = 46) | HER2- (n = 82) | P-value* |
|---|---|---|---|
| Age (years) | 34.26 ± 3.99 | 33.31 ± 4.69 | 0.253 |
| BMI (kg/m2) | 23.46 ± 3.26 | 24.71 ± 3.18 | 0.089 |
| Hormonal profile | |||
| FSH (IU/L) | 4.91 ± 2.79 | 5.76 ± 2.98 | 0.117 |
| LH (IU/L) | 5.62 ± 3.86 | 6.09 ± 3.89 | 0.523 |
| Progesterone (ng/mL) | 5.44 ± 6.16 | 3.46 ± 4.82 | 0.063 |
| AMH (ng/mL) | 2.90 ± 2.46 | 2.91 ± 2.89 | 0.988 |
| Stimulation start | 0.443 | ||
| Early follicular phase | 18 (39.1%) | 30 (36.6%) | |
| Late follicular phase | 5 (10.9%) | 16 (19.5%) | |
| Luteal phase | 23 (50%) | 36 (43.9%) | |
| Gonadotropin type | 0.797 | ||
| r-FSH | 18 (39.1%) | 34 (41.5%) | |
| r-FSH & HMG | 28 (60.9%) | 48 (58.5%) | |
| Gonadotropin start dose (IU) | 254.34 ± 90.10 | 254.26 ± 79.71 | 0.996 |
| Total Gonadotropin dose (IU) | 2439.13 ± 1078.27 | 2433.84 ± 1092.53 | 0.979 |
| Duration of ovarian stimulation | 10.67 ± 2.01 | 10.86 ± 2.11 | 0.639 |
| Trigger | 0.600 | ||
| HCG | 14 (30.4%) | 20 (24.4%) | |
| GnRH-agonist | 29 (63.1%) | 46 (56.1%) | |
| HCG & GnRH-agonist | 3 (6.5%) | 9 (10.9) | |
| Estradiol on trigger day (pg/mL) | 301.48 ± 135.55 | 319.20 ± 132.44 | 0.493 |
| Follicles > 12 mm on trigger day | 9.84 ± 5.78 | 7.74 ± 4.92 | 0.035* |
| Total oocytes retrieved | 11.30 ± 8.27 | 9.37 ± 7.69 | 0.188 |
| Mature oocytes (MII) | 7.73 ± 5.28 | 7.25 ± 6.48 | 0.667 |
| Oocyte maturation rate1 (%) | 74.91 ± 21.26 | 80.57 ± 21.28 | 0.163 |
| Fertilization rate2 (%) | 67.65 ± 21.89 | 65.24 ± 22.33 | 0.692 |
Values are presented as the mean ± standard deviation (SD) and number (percent)
HER2 human epidermal growth factor receptor 2, BMI body mass index, FSH follicle stimulating hormone, LH luteinizing hormone, AMH anti mullerian hormone, r-FSH recombinant follicle stimulating hormone, HMG human menopausal hormone, HCG human chorionic gonadotropin, GnRH gonadotropin releasing hormone, MII metaphase two, 2PN two pronuclei
*P-value obtained by independent t-test and chi square test or Fisher’s exact test when more than 20% of cells with expected counts of less than 5 were observable. Statistically significant level < 0.05
1Mature oocytes (MII)/ Total oocytes retrieved
2Number of 2PN/ Number of oocytes injected
Table 5.
Comparison of breast cancer women with Ki67 < 20% and Ki67 ≥ 20% status
| Variable | Ki67 < 20% (n = 36) | Ki67 ≥ 20% (n = 74) | P-value* |
|---|---|---|---|
| Age (years) | 33.80 ± 4.43 | 33.51 ± 4.39 | 0.745 |
| BMI (kg/m2) | 24.04 ± 3.49 | 24.70 ± 3.00 | 0.338 |
| Hormonal profile | |||
| FSH (IU/L) | 5.04 ± 1.67 | 5.69 ± 3.26 | 0.270 |
| LH (IU/L) | 6.06 ± 3.78 | 5.02 ± 2.83 | 0.119 |
| Progesterone (ng/mL) | 3.21 ± 4.33 | 3.82 ± 5.07 | 0.578 |
| AMH (ng/mL) | 2.74 ± 2.01 | 2.75 ± 2.19 | 0.976 |
| Stimulation start | 0.851 | ||
| Early follicular phase | 16 (44.4%) | 30 (40.5%) | |
| Late follicular phase | 6 (16.7%) | 11 (14.9%) | |
| Luteal phase | 14 (38.9%) | 33 (44.6%) | |
| Gonadotropin type | 0.388 | ||
| r-FSH | 12 (33.3%) | 31 (41.9%) | |
| r-FSH & HMG | 24 (66.7%) | 43 (58.1) | |
| Gonadotropin start dose (IU) | 262.50 ± 83.13 | 245.27 ± 82.62 | 0.308 |
| Total Gonadotropin dose (IU) | 2570.83 ± 1064.23 | 2406.08 ± 1087.75 | 0.455 |
| Duration of ovarian stimulation | 10.88 ± 2.04 | 10.60 ± 2.13 | 0.542 |
| Trigger | 0.258 | ||
| HCG | 6 (16.7%) | 23 (31.1%) | |
| GnRH-agonist | 25 (69.4%) | 41 (55.4%) | |
| HCG & GnRH-agonist | 4 (11.1%) | 8 (10.9%) | |
| Estradiol on trigger day (pg/mL) | 287.18 ± 140.42 | 323.26 ± 127.30 | 0.194 |
| Follicles > 12 mm on trigger day | 7.82 ± 5.22 | 8.37 ± 3.96 | 0.549 |
| Total oocytes retrieved | 8.69 ± 6.30 | 10.66 ± 7.63 | 0.183 |
| Mature oocytes (MII) | 6.69 ± 4.97 | 7.90 ± 6.02 | 0.299 |
| Oocyte maturation rate1 (%) | 79.94 ± 21.49 | 78.47 ± 19.66 | 0.733 |
| Fertilization rate2 (%) | 67.31 ± 19.14 | 66.46 ± 24.23 | 0.897 |
Values are presented as the mean ± standard deviation (SD) and number (percent)
BMI body mass index, FSH follicle stimulating hormone, LH luteinizing hormone, AMH anti mullerian hormone, r-FSH recombinant follicle stimulating hormone, HMG human menopausal hormone, HCG human chorionic gonadotropin, GnRH gonadotropin releasing hormone, MII metaphase two, 2PN two pronuclei
*P-value obtained by independent t-test and chi square test or Fisher’s exact test when more than 20% of cells with expected counts of less than 5 were observable. Statistically significant level < 0.05
1Mature oocytes (MII)/ Total oocytes retrieved
2Number of 2PN/ Number of oocytes injected
Table 6.
Comparison of breast cancer women with TNBC and non-TNBC status
| Variable | TNBC (n = 27) | non-TNBC (n = 101) | P-value* |
|---|---|---|---|
| Age (years) | 32.37 ± 4.49 | 34.00 ± 4.41 | 0.092 |
| BMI (kg/m2) | 25.34 ± 3.24 | 24.02 ± 3.21 | 0.092 |
| Hormonal profile | |||
| FSH (IU/L) | 5.35 ± 1.86 | 5.48 ± 3.16 | 0.835 |
| LH (IU/L) | 5.45 ± 2.94 | 6.03 ± 4.09 | 0.509 |
| Progesterone (ng/mL) | 2.36 ± 3.74 | 4.75 ± 5.73 | 0.062 |
| AMH (ng/mL) | 2.65 ± 1.64 | 2.98 ± 2.97 | 0.593 |
| Stimulation start | 0.311 | ||
| Early follicular phase | 13 (48.2%) | 35 (34.7%) | |
| Late follicular phase | 5 (18.5%) | 16 (15.8%) | |
| Luteal phase | 9 (33.3%) | 50 (49.5%) | |
| Gonadotropin type | 0.669 | ||
| r-FSH | 10 (37.1%) | 42 (41.6%) | |
| r-FSH & HMG | 17 (62.9%) | 59 (58.4%) | |
| Gonadotropin start dose (IU) | 247.22 ± 87.79 | 256.18 ± 82.34 | 0.621 |
| Total Gonadotropin dose (IU) | 2427.77 ± 1208.82 | 2437.87 ± 1053.61 | 0.966 |
| Duration of ovarian stimulation | 10.91 ± 2.15 | 10.70 ± 2.02 | 0.670 |
| Trigger | 0.073 | ||
| HCG | 3 (11.1%) | 31 (30.7%) | |
| GnRH-agonist | 20 (74.1%) | 55 (54.4%) | |
| HCG & GnRH-agonist | 4 (14.8%) | 8 (7.9%) | |
| Estradiol on trigger day (pg/mL) | 314.23 ± 137.46 | 306.60 ± 133.84 | 0.803 |
| Follicles > 12 mm on trigger day | 7.59 ± 3.44 | 8.81 ± 5.75 | 0.295 |
| Total oocytes retrieved | 11.55 ± 8.01 | 9.67 ± 7.89 | 0.275 |
| Mature oocytes (MII) | 9.14 ± 7.17 | 6.97 ± 5.68 | 0.098 |
| Oocyte maturation rate1 (%) | 80.02 ± 19.83 | 77.84 ± 21.88 | 0.644 |
| Fertilization rate2 (%) | 58.88 ± 24.87 | 68.41 ± 20.81 | 0.160 |
Values are presented as the mean ± standard deviation (SD) and number (percent)
TNBC triple-negative breast cancer, BMI body mass index, FSH follicle stimulating hormone, LH luteinizing hormone, AMH anti mullerian hormone, r-FSH recombinant follicle stimulating hormone, HMG human menopausal hormone, HCG human chorionic gonadotropin, GnRH gonadotropin releasing hormone, MII metaphase two, 2PN two pronuclei
*P-value obtained by independent t-test and chi square test or Fisher’s exact test when more than 20% of cells with expected counts of less than 5 were observable. Statistically significant level < 0.05
1Mature oocytes (MII)/ Total oocytes retrieved
2Number of 2PN/ Number of oocytes injected
There were no significant differences in patient characteristics, including age, body mass index (BMI), hormonal profile (follicle stimulating hormone (FSH), luteinizing hormone (LH), progesterone, and anti-mullerian hormone (AMH)), and ovarian stimulation data, including the cycle start time, type and dose of gonadotropin administered, the duration of ovarian stimulation, and the trigger method. Moreover, no significant differences were observed in serum estradiol levels, dominant follicle count on the trigger day, total oocytes retrieved, mature oocytes (MII), oocyte maturation rate, and fertilization rate among the patients based on their hormone receptor status. The HER2 + group exhibited a significantly higher number of dominant follicles on the trigger day than the HER2- group (p = 0.035); however, no significant differences were noted regarding oocyte count and maturity.
In order to determine the relationship between hormone receptor status and ovarian response, patients classified as poor, normal, or hyper-responders according to the total number of retrieved oocytes and the number of mature oocytes. There were no significant differences in ovarian response patterns among the different hormone receptors status. Also, a multivariate logistic regression analysis was performed with receptor status as the main independent variable, the number of retrieved oocytes as the dependent variable, and age, BMI, and AMH as confounding variables. This analysis also demonstrated that hormone receptor status had no effect on ovarian response.
Discussion
As mentioned earlier in the Introduction, hormone receptor status is recognized as a critical factor in estimating prognosis and treatment response in BC patients [7]. It is assumed that these prognostic factors of malignancy may influence ovarian response to stimulation in patients undergoing fertility preservation [10].
ER signaling is fundamental to the development, progression, and invasion of BC. The majority of breast tumors express ER. The assessment of ER expression is critical for BC diagnosis and serves as a biomarker for predicting treatment response in patients. ER+ tumors exhibit a better prognosis than other types of BC, whereas ER- tumors have a more aggressive phenotype. Mutations in genes encoding the ER first manifest during the early stages of cancer and become increasingly prevalent as the disease progresses. Given the complex nature of ER signaling in BC, it is essential to elucidate the molecular and cellular mechanisms that regulate this signaling pathway [7]. Liu et al. assessed 47 women diagnosed with BC. Consistent with our study, they found no significant difference in mature oocyte count between ER + and ER- patients [6]. The study by Grynberg et al. on 352 women diagnosed with BC also corroborates this finding [10]. In a survey of 214 women diagnosed with BC, Sii et al. concluded that ER+ patients may experience improved outcomes from ovarian stimulation compared to those with ER-, despite the absence of ovarian reserve data, including AMH and antral follicle count (AFC). No differences were reported in gonadotropin dosage, ovarian stimulation duration, and the retrieved mature oocyte count [16]. Kim et al. examined 117 women diagnosed with BC, noting no significant differences in ovarian stimulation outcomes based on the ER status [17]. Balayla et al. reviewed 155 ovarian stimulation cycles in women with BC, finding no significant differences in the total count of retrieved oocytes and mature oocytes relative to ER status [8].
The PR regulates ER functioning in BC and is regarded as a prognostic biomarker. Enhanced PR expression is often associated with better tumor prognosis. This receptor currently has limited practical applications; however, researchers posit that a comprehensive understanding of its complex roles in various contexts may establish it as a significant marker in BC [18]. The research conducted by Grynberg et al. [10] and Kim et al. [17], consistent with our findings, did not indicate a significant difference in ovarian stimulation outcomes based on the PR status.
HER2 functions as a receptor tyrosine kinase. HER2 gene amplification and overexpression are observed in 15–20% of BC patients and are identified as pivotal markers of poor prognosis in this disease [19]. The research by Grynberg et al. indicates that HER2 overexpression do not influence the response to ovarian stimulation and ovarian reserve markers such as AFC and serum AMH levels [10]. Kim et al. found no significant difference in the ovarian stimulation outcomes based on HER2 status [17]. Our study also observed no significant differences in serum AMH levels based on HER2 + or HER2- status. The HER2 + group exhibited a significantly higher number of dominant follicles on the trigger day than the HER2- group; however, no significant differences were noted regarding oocyte count and maturity. Evidence indicates that HER2 plays a role in the oocyte maturation process, and its overexpression in cancer patients can disrupt this process. Oocyte maturation is a process dependent on the surrounding cumulus cells. Some evidence suggests that cancer may impair the maturation process by affecting cholesterol metabolism in these cells. It is plausible that BC, and particularly its molecular subtypes such as HER2+, leads to reduced oocyte maturation by disrupting cholesterol homeostasis in cumulus cells. The number of dominant follicles on the day of trigger primarily reflects the ovarian response to stimulation. This finding suggests that HER2 + status does not negatively affect the number of retrievable follicles; however, the quality of their contents (i.e., the oocytes) is compromised. Excess HER2 disrupts the delicate and complex process of nuclear and cytoplasmic oocyte maturation. Consequently, a smaller proportion of the oocytes within those follicles are able to complete their maturation stage. In other words, although HER2 + status does not adversely affect the initial quantity of ovarian response (the number of dominant follicles), it acts as an independent and potent factor that disrupts the qualitative process of oocyte maturation [8, 20, 21]. Although a low dose of GnRH-agonist is recommended for triggering final oocyte maturation to reduce the risk of ovarian hyperstimulation syndrome, based on the results of the present study, HER2 + patients may benefit from a dual trigger — i.e., concomitant administration of HCG and a low dose of GnRH-agonist — to achieve the maximum number of mature oocytes. However, confirmation of this finding requires a study with a significant sample size.
TNBC is a subtype of BC in which the tumor cells do not express ER, PR, and HER2 on their surface. It represents 15–20% of BC cases and, compared to the other subtypes, tends to develop, in younger women. It also has a mortality rate exceeding 40%. In addition, its recurrence rate is higher than that of other subtypes, reaching 25% [9]. Consistent with our findings, Liu et al. reported no significant difference in mature oocyte count between TNBC and non-TNBC patients [6]. The research by Grynberg et al. indicated that TNBC status had no impact on AFC and AMH or on the response to ovarian stimulation [10]. Contrary to the findings of these studies, Kim et al. demonstrated that mature oocyte count in TNBC patients was significantly higher than that in non-TNBC patients. They identified age as a confounding variable in their study [17]. Balayla et al. reported that the TNBC subtype, among various hormonal receptor profiles in BC, negatively affected fertility preservation outcomes. A statistically significant reduction in mature oocyte count was observed when the TNBC subtype was compared with estrogen and progesterone receptor-positive subtypes, and also when the TNBC subtype was compared with non-TNBC subtypes. They explained this finding by suggesting that more aggressive subtypes, such as TNBC subtypes, induced ovarian damage by activating the systemic inflammatory response, which resulted in a poor response to ovarian stimulation [8].
Our study found no significant differences in serum AMH levels across the various hormone receptors status among the BC patients. Conversely, Raad et al. observed significantly lower serum AMH levels in TNBC patients compared to those with estrogen, progesterone, and HER2-positive receptors status while indicating that hormone receptor status did not influence in vitro maturation (IVM) outcomes [21]. However, Quinn et al. demonstrated that the ovarian reserve status and the ovarian stimulation outcomes in BC patients prior to gonadotoxic treatments were similar to those of the candidates for elective fertility preservation [22]. Some researchers have also compared the impacts of BC stage and grade on ovarian reserve and response to ovarian stimulation in the candidates for fertility preservation and have reported contradictory findings. For example, Cioffi et al. found that higher BC grades were accompanied by decreased AFC and increased gonadotropin doses during ovarian stimulation, yet the number of retrieved mature oocytes was not influenced by these higher BC grades [23]. Volodarsky-Perel et al. demonstrated that high-grade BC negatively impacted the total number of mature oocytes [24]. These contradictory results, which may have stemmed from the studied populations that were heterogeneous and the confounding factors that were not controlled, highlight the need for conducting high quality studies.
Ki67 is known as a proliferation marker in BC. The clinical use of Ki67 is presently restricted to prognostic evaluation in stages I/II BC. Ki67 has a clinical application in prognostic estimation for ER+, HER2- patients as it aids in the identification of the individuals who can avoid adjuvant chemotherapy [25]. In line with the results of our study, the research by Grynberg et al. indicated that elevated Ki67 levels did not influence serum AMH levels, AFC, or ovarian stimulation responses [10].
In order to study the relationship between hormone receptor status and ovarian response, patients receiving ovarian stimulation were classified as poor, normal, or hyper-responders according to the total number of retrieved oocytes and the number of mature oocytes. However, the statistical analysis indicated no significant differences in ovarian response patterns among the different hormone receptors status. Furthermore, the multivariate logistic regression analysis, despite including age, BMI, and AMH as confounding variables, failed to demonstrate any association between hormone receptors status in BC patients and their response to ovarian stimulation.
Our findings and those of similar studies suggest that hormone receptor profiles in BC are determinative of disease prognosis, but they cannot serve as predictive markers for ovarian stimulation response in patients. Accordingly, although patients with ER+/PR+ tumors exhibit the best prognosis among the different hormone receptor profiles in BC, their response to ovarian stimulation is similar to that of patients with ER-/PR- tumors. These findings similarly apply to Ki67 status. In the context of TNBC, which has the worst oncological prognosis, most studies indicate that it cannot influence the response to ovarian stimulation probably because patients promptly pursue fertility preservation following diagnosis before the start of gonadotoxic treatments. In other words, the negative status of estrogen and progesterone receptors, elevated Ki67 levels, and also TNBC status may, over time, contribute to increased disease aggressiveness and potentially affect ovarian reserve and response to ovarian stimulation. Consequently, starting fertility preservation procedures as soon as possible following a cancer diagnosis may yield desirable outcomes. Nevertheless, based on the results of the present study, it should be noted that HER2 overexpression, in addition to its negative effects on disease prognosis, can also influence the response to ovarian stimulation. This underscores the importance of assessing not only numerical indicators (follicle count) but also functional and qualitative indicators (maturation rate) in cancer patients, particularly with consideration of the tumor’s molecular profile.
Contrary to the available studies, Fabiani et al. performed a comparative study to assess the effects of BC on ovarian stimulation outcomes, comparing 105 BC patients with 189 healthy controls who were candidates for IVF due to male or tubal factor infertility. The assessed variables comprised oocyte maturation and quality and retrieved oocyte count. These researchers reported that although BC diagnosis was not related to impaired ovarian reserve, it was linked to decreased oocyte quality. The multivariate analysis indicated that BC diagnosis was accompanied by a fourfold increase in risk of retrieving dysmorphic oocytes. Nevertheless, no significant association was established between oocyte dysmorphology and hormone receptor status, including ER, PR, HER2, TNBC, or even BRCA mutations. These researchers believed that the cancer itself, rather than its prognostic factors, adversely affected granulosa cells, which are the main source of estradiol resulting in decreased estradiol levels and hence, impaired oocyte maturation and quality. Furthermore, the increased catabolic state and elevated stress hormone levels associated with malignancy were likely to adversely impact ovarian reserve and oocyte quality [20].
Notably, some studies have indicated a relationship between BRCA gene mutations and hormone receptor status in BC patients, leading to investigations into the correlation of hormone receptor profiles with ovarian stimulation response and fertility preservation outcomes [6]. A proposed mechanism posits that disruption in the mutated BRCA gene’s ability to modulate DNA repair mechanisms may contribute to oocyte senescence, apoptosis, and meiotic errors [26]. Greenup et al. reported that the prevalence of BRCA1 mutation carriers exceeded 30% among TNBC patients [27]. Li et al. found that 70–80% of BC patients with BRCA2 mutations were ER+, a subtype associated with a poor prognosis. Moreover, a study noted that most women carrying BRCA2 mutations were ER + and HER2- [28].
While these findings highlight the clinical relevance of genetic counseling in women with BC based on hormone receptor status, the sample size in the present study was limited for BRCA gene mutation analysis, thereby impeding the assessment of hormone receptor-BRCA mutation correlations. Due to the limited number of BC patients referred to our center for fertility preservation, a convenience sampling method was employed in this study. Nevertheless, although this study does not have a considerable sample size, we hope that our findings will be useful in this field. We have acknowledged this issue as a limitation of the study, and our findings were not generalized to all BC patients in order to avoid any incorrect judgment due to insufficient statistical power. Additionally, limited access to patient oncological data, such as cancer stage and grade, was a further limitation of the study. The current research used a homogeneous study population and examined the effect of the Ki67 status on ovarian response, an area that is relatively under-explored. These were among its significant strengths.
Conclusions
The findings of the current study show that the determinants of BC prognosis, such as ER, PR, HER2, TNBC, and Ki67 status, have no effect on patients’ responses to ovarian stimulation and need not be considered when selecting an ovarian stimulation approach in BC patients who are candidates for fertility preservation. Nevertheless, despite achieving an acceptable number of dominant follicles on the day of trigger, HER2 + status can affect the number of retrieved oocytes, particularly the number of mature oocytes. To avoid this outcome, the use of a dual trigger for final oocyte maturation is recommended in this subgroup of breast cancer patients.
Acknowledgements
Authors would like to thank the staff of ROYAN Institute for their assistance in this study and the patients who participated in this study.
Abbreviations
- AMH
Anti-mullerian hormone
- AFC
Antral follicle count
- BC
Breast cancer
- BMI
Body mass index
- BRCA
Breast cancer gene
- EGFR
Epidermal growth factor receptor
- ER
Estrogen receptor
- FSH
Follicle stimulating hormone
- GnRH
Gonadotropin-releasing hormone
- HCG
Human chorionic gonadotropin
- HER2
Human epidermal growth factor receptor 2
- IVM
In vitro maturation
- LH
Luteinizing hormone
- MII
Metaphase two
- PR
Progesterone receptor
- SD
Standard deviation
- TNBC
Triple-negative breast cancer
Authors’ contributions
AY: Study design, data management, data analysis, and manuscript writing; SK: Project development, and manuscript editing; FH: Provided clinical expertise; SV: Data analysis; SH: Data collection; FG: Study design, provided clinical expertise and supervision, project development, and manuscript editing. All authors revised manuscript and approved final draft.
Funding
No financial support has been granted.
Data availability
All data generated or analyzed during this study are included in this published article.
Declarations
Ethics approval and consent to participate
All the procedures performed in studies involving human participants were in accordance with the ethical standards committee of the ROYAN Institute and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Name of the ethics committee: Research Ethics Committee of ROYAN Institute
Ethics Approval Code: IR.ACECR.ROYAN.REC.1401.083
Date: 11/06/2022
Informed consent was obtained from all the individual participants included in the study.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Samaneh Kashi is co-first author.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
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Data Availability Statement
All data generated or analyzed during this study are included in this published article.