Abstract
Purpose
To determine the frequency of hereditary breast cancer associated with different mutated genes and to evaluate fertility preservation (FP) outcomes among young women with hereditary breast cancer when compared to non-hereditary breast cancer.
Material and methods
A retrospective cohort study of women with breast cancer who underwent fertility preservation treatment at our academic fertility center between 2005 and 2019. We included all women with breast cancer aged < 40 years who had a genetic testing and underwent fertility preservation before starting gonadotoxic therapy (n = 132). Our objective was to evaluate the total number of oocytes retrieved, mature oocytes MII, embryos (where appropriate), cryopreserved oocytes, and/or embryos.
Results
Of 132 women with breast cancer, 40 women were found to be genetically positive (31.4%), 31 women of 40 (77.5%) had a BRCA mutation, 3 (7.5%) had ATM, 2 (5%) had CHK2, and one (2.5%) for each of the following genes: PALP2, NF, MUTYH.c.536A, and TP53. There was no significant difference between the groups in the total number of eggs retrieved and the number of MII oocytes and cryopreserved oocytes. The numbers of fertilized oocytes and cryopreserved embryos in the hereditary (n = 40) and non-hereditary (n = 92) group were (5.15 ± 6.6 vs 2.90 ± 4.2, P = 0.054) and (3.35 ± 3.7 vs 1.9 ± 2.8, P = 0.046) respectively.
Conclusion
More than three quarters of positive mutated genes in women with breast cancer are BRCA mutations. Compared to those with non-hereditary breast cancer, women with hereditary breast cancer attained higher number of cryopreserved embryos.
Keywords: Hereditary breast cancer, Fertility preservation, Embryo cryopreservation, Ovarian response, BRCA
Introduction
Breast cancer is one of the most common gynecological malignancies in the developed world [1], and it affects 4–6% of women under the age of 40 years [2]. One of the most concerning factors in cancer treatment among young women is the gonadotoxic chemotherapy or radiotherapy effect that could diminish future reproductive potential [3]. Accordingly, they can be offered fertility preservation before the treatment begins. In women with breast cancer, several factors should be considered including type of cancer, stage and grade of cancer, time before starting chemotherapy, presence or absence of partner, and patient age at the time of cancer diagnosis [4].
Breast cancer is a multifactorial disease that can be inherited from generation to generation or non-hereditary which occurs without a known reason. Almost 80% of breast cancers are sporadic, and nearly 5–10% of breast cancer cases are related to an inherited gene mutation [5]. Hereditary breast cancer is associated with onset at a young age, bilateral disease and/or multiple primary cancers, and a history of first- or second-degree family members with a similar diagnosis [6]. Among hereditary breast cancers, those associated with BRCA gene mutations are the most common. Other genes have also been linked to breast cancer including high penetrant genes such as TP53, STK11, and PTEN and less penetrant genes such ATM, CHEK2, PALB2, and NF genes [7].
Results of studies on the impact of BRCA gene mutation on the reproductive potential in patients with and without cancer have been mixed. The outcome of fertility preservation among young breast cancer patients who carried hereditary genes mutation, BRCA, and other genes has not been adequately studied. Shapira and others reported a normal ovarian response in IVF cycles [8]. Oktay recorded that a patient with BRCA mutation who underwent IVF-FP has a comparable pregnancy rate to those expected in non-cancer population who conceive through IVF [9].
The objective of our study was to evaluate fertility preservation outcome in young women with hereditary or non-hereditary breast cancer. We also evaluated the frequency of hereditary breast cancer associated with different mutated genes.
Materials and methods
We evaluated women with breast cancer who underwent fertility preservation at McGill University Health Center (MUHC) between July 2005 and December 2019. The MUHC Research and Ethics Board (MUHC REB) approved the study (REB #2020–6219). We included all breast cancer patients under the age 40 years with known genetic testing result who had undergone fertility preservation before starting gonadotoxic therapy and no ovarian disease at the time of treatment. We evaluated only the first IVM or IVF cycle. Genetic testing was previously ordered by the referring medical oncologists. The criteria for genetic testing are (1) women diagnosed with breast cancer at < 35 years old, (2) triple hormonal receptor-negative breast cancer and/or (3) women with a strong family history with early onset of breast and/or ovarian cancer in the first -and/or second-degree relative, and (4) having breast and ovarian cancer in the same individual or bilateral breast cancer. Staging of breast cancer includes tumor, node, and metastasis (TNM) classification of malignant tumors according to the American Joint Committee on Cancer [10].
We excluded women who had received chemotherapy or radiotherapy before fertility preservation treatment and those with genetic results variants with unknown significant or non-pathogenic variants. The following demographic data were collected: age, body mass index (BMI), antral follicle count (AFC), day 3 follicle stimulating hormone (FSH) level, stage of breast cancer, type of fertility preservation, dose of gonadotropin received, stimulation days (when appropriate), and genetic testing results. Outcome measures included number of total eggs retrieved and number of mature MII oocytes in hereditary and non-hereditary groups as well as fertilization rate and number of oocytes and/or embryos cryopreserved.
In our center, IVM fertility preservation was the first option in women with breast cancer since ovarian hormonal stimulation was not a preferred option among these types of patients [11]. Accordingly, they were treated mainly with IVM fertility preservation from 2005 to 2011. As many publications suggested minimal risks of hormonal stimulation in these patients, IVF fertility preservation became the preferred option providing the oncologic treatment could be postponed (Table 1) [12, 13].
Table 1.
Number of patients with breast cancer who underwent IVF or IVM for fertility preservation from 2005 to 2019
| 2005 to 2011 | 2012 to 2019 | |
|---|---|---|
| IVM (n) | 24 (77.4%) | 32 (33%) |
| IVF (n) | 7 (22.5%) | 64 (67%) |
IVF and oocyte collection protocol
For IVF cycles, we used antagonist protocol using a combination of either recombinant FSH (Gonal-F, Merck-Serono, Geneva, Switzerland) and/or human menopausal gonadotropin (Menopur, Ferring, France) and GnRH antagonist (Cetrotide, Merck-Serono, Geneva, Switzerland).When at least 3 leading follicles with mean diameter reached to 17–20 mm, 0.25 mg recombinant HCG (Ovidrel, EMD Serono, MA, USA) was administrated subcutaneously, and oocyte retrieval was performed 36 h later. All patients received letrozole 5 mg daily starting from the first day of stimulation until the day of egg collection.
IVM and oocyte and embryo vitrification protocols
In this protocol, gonadotropin was not used. Retrieval of the IVM oocytes was performed by an experienced and specifically trained physician 38 h after a subcutaneous administration of 10,000 IU of HCG (Profasi; Serono, Oakaville, ON, Canada) in accordance with the center’s standard IVM practice [14]. Transvaginal ultrasound-guided retrieval of oocytes was performed using a 19-gauge single-lumen needle (K-OPS-7035-RWH-ET;Cook Australia) with a reduced aspiration pressure of 7.5 kPa, under conscious sedation. Often, this was done between day 6 and day 8 of the cycle and when lead follicles reached 10 mm and the endometrium 8 mm. Immature germinal vesicle (GV) oocytes were matured in an organ tissue culture dish (60 × 15 mm, Falcon, Franklin Lakes, NJ) flooded with 1 mL of IVM-Medium (Cooper Surgical, Trumbull, CT) supplemented with 75 mIU/mL of FSH and luteinizing hormone (LH) under 6% CO2, 5% O2, and 89% N2 atmosphere at37°. Oocyte and embryo cryopreservation was performed using the vitrification method as previously published [15].
Statistical analysis
Statistical analysis was performed using SPSS 23.0 (IBM Corporation, Chicago, USA). Data distribution was evaluated using the Kolmogorov Smirnov test. Continuous data were analyzed using the Student’s t test. Categorical data were analyzed using chi-squared test. All continuous data were normally distributed. Data are presented as mean ± standard deviation or percentage.
Results
Of a total 244 women with breast cancer, genetic results were available in 132 women, and 40 of these 132 women had a positive genetic test (31.4%). Of those, 31 (77.5%) women had a BRCA mutation, 3 (7.5%) had ATM, 2 (5%) had CHK2, and one (2.5%) for each of the following genes: PALP2, NF, MUTYH.c.536A, and TP53. See Fig. 1. Five women had received radiotherapy or chemotherapy before fertility preservation leaving a total of 127 patients for analysis. Of 87 women who were genetically negative (68.5%), 48 women underwent IVF (55.17%), and 39 others underwent IVM treatment (44.82%). Of 40 women who were genetically positive, 23 women underwent IVF (57.5%) and 17 others IVM (42.5%). Stage 1 cancer was found in 38 women in the hereditary group (95%) and in 77 others in non-hereditary group (88.5%). The remainders had stage 2 cancer. The ovarian reserve of both groups including the level of FSH and AFC, as well as BMI, parity, and stage of cancer, was comparable. The proportion of women undergoing IVF or IVM and their outcome were similar in the two groups. Total gonadotropin dose and days of stimulation were also comparable. See Table 2.
Fig. 1.
Proportions of hereditary genes in women with breast cancer
Table 2.
Demography of women with hereditary and non-hereditary breast cancer
| Hereditary (n: 40) | Non-hereditary (n: 87) | P value | 95% CI | |
|---|---|---|---|---|
| Age at diagnosis (years) | 30.7 ± 4.4 | 32.4 ± 3.96 | 0.034 | 0.13 to 3.22 |
| FSH (IU/L) | 5.9 ± 2.4 | 6.8 ± 3.29 | 0.31 | − 069 to 2.46 |
| AFC | 16.3 ± 9.8 | 16.6 ± 9.3 | 0.81 | − 3.31 to 3.95 |
| BMI | 24.5 ± 3.1 | 24.1 ± 4.04 | 0.66 | − 2.11 to 1.21 |
| Gravidity | 0.7 ± 0.9 | 0.8 ± 1.28 | 0.66 | − 0.34 to 0.56 |
| Parity | 0.5 ± 0.7 | 0.4 ± 0.62 | 0.36 | − .372 to 0.13 |
| Gonadotropin use (IU) | 2340.4 ± 1410.4 | 2111.2 ± 971.97 | 0.43 | − 811.5 to 353.1 |
| Stimulation duration (days) | 9.8 ± 5.1 | 9.1 ± 4.4 | 0.48 | − 2.722 to 1.20 |
There was no significant difference between the groups in the total number of eggs retrieved, the number of MII oocytes collected, and the number of cryopreserved oocytes. The numbers of fertilized oocytes and cryopreserved embryos in the hereditary and non-hereditary group were (5.15 ± 6.6 vs 2.90 ± 4.2) (P = 0.054) and (3.35 ± 3.7 vs 1.9 ± 2.8) (P = 0.046) respectively. Outcomes following IVF and IVM were similar. See Table 3.
Table 3.
Fertility preservation outcomes in hereditary and non-hereditary breast cancer
| Hereditary (n = 40) | Non-hereditary (n = 87) | P value | 95% CI | |
|---|---|---|---|---|
| Total number of egg retrieval | 13.32 ± 8.63 | 11.72 ± 8.63 | 0.34 | − 4.95 to 1.75 |
| Number of eggs in IVM | 12.40 ± 10.5 | 10.20 ± 9.21 | 0.46 | − 8.16 to 3.76 |
| Number of eggs in IVF | 13.91 ± 7.36 | 13.00 ± 8.11 | 0.65 | − 4.92 to 3.10 |
| Number of mature eggs | 5.35 ± 6.45 | 5.46 ± 6.21 | 0.92 | − 2.20 to 2.48 |
| Number of fertilized eggs | 5.15 ± 6.63 | 2.90 ± 4.29 | 0.054 | − 4.55 to 0.044 |
| Number of oocytes cryopreserved | 4.30 ± 6.63 | 5.71 ± 7.77 | 0.34 | − 1.51 to 4.34 |
| Number of embryos cryopreserved | 3.35 ± 3.74 | 1.94 ± 2.81 | 0.046 | − 2.79 to − 0.209 |
Patient with hereditary breast cancer had a significantly lower chance of estrogen receptor (ER) (42.5% VS 65.5%, P = 0.04) and human epidermal growth factor receptor-2(Her-2) (7.5% vs 32.1%, P = 0.004) than non-hereditary breast cancer patient. See Table 4.
Table 4.
Hormonal receptor status among breast cancer patient who underwent fertility preservation treatment
| Hereditary (40) | Non-hereditary (87) | P value | |
|---|---|---|---|
|
E2 R Positive |
17 (42.5%) | 57 (65.5%) | 0.041 |
|
Prog R Positive |
19 (47.5%) | 58 (66.6%) | 0.10 |
|
Her R Positive |
3 (7.5%) | 28 (32.1%) | 0.004 |
Among the 40 hereditary breast cancer patients who underwent FP, 5 patients returned to fertility center (12.5%), a patient with CHK-2 had successful pregnancy and live birth, and one BRCA patient returned to have PGD test. The latter had a normal embryo; yet, embryo transfer had not been done due to patient’s request (Table 5).
Table 5.
Fertility preservation outcome among hereditary breast cancer patients
| Gene mutations | Year of FP | Age at FP | Type FP | Frozen reproductive materials | Year of return | Age at return | ET | Outcome | |
|---|---|---|---|---|---|---|---|---|---|
| 1 | BRCA | 2014 | 33 | IVF | 4 embryos | 2018 | 37 | No | PGD done, one resulted normal. but no ET yet |
| 2 | BRCA | 2012 | 23 | IVF | 6 embryos | 2017 | 28 | Yes | ET to surrogate, no pregnancy |
| 3 | BRCA | 2010 | 30 | IVM | 27 eggs | 2016 | 36 | No | Severe male factor, no embryo obtained |
| 4 | CHEK2 | 2009 | 33 | IVM | 10 embryos | 2015 | 39 | Yes |
In 2015, failed ET, no pregnancy In 2018, successful ET, pregnancy resulted in a live birth |
| 5 | BRCA | 2008 | 27 | IVM | 9 embryos | 2013 | 32 | No | Discarded as per patient request; patient passed away in 2016 |
Discussion
In our study, we found that most women with hereditary breast cancer have BRCA mutation, and the numbers of cryopreserved embryos in women with hereditary breast cancer were higher than in those with non-hereditary breast cancer.
It has been reported that 10–15% of breast cancers are associated with hereditary factors [5]. In our study, 40 of a total 132 women with breast cancer (31.4%) referred for fertility preservation was found to have a positive genetic test. Our finding represents only patients who underwent fertility presentation and genetic testing. This high proportion does not represent women in general population. The difference could also be explained that our patients were in the reproductive age, and we did not study women over 40 years of age. Indeed, women with breast cancer over 40 years were less likely to have positive genetic testing. Ethnic differences could also play a role. Churpek et al. reported that 65 of 289 African American women with breast cancer (22%) had positive genetic testing to 8 different gene mutations [16]. Wong et al. found a figure of 30% among 220 Asian women with breast cancer [17].
Besides BRCA gene mutations, genetic testing panel includes other non-BRCA gene mutations that had been linked to breast cancer development like ATM, CHEK2, PALB2, NF, MYUTH, and TP53 [7]. The second most common gene and yet only a small proportion of gene (7%) found in women with hereditary breast cancer is Ataxia-telangiectasia mutated (ATM) gene. Only individuals with 2 copies of ATM mutation can develop a rare condition called ataxia-telangiectasia, which is a neurodegenerative disease resulting in cerebellar ataxia, telangiectasis, and immune deficiency [18]. Other genes were found in ≤ 5% of women with hereditary breast cancer. BRCA1 and BRCA2 gene mutations contribute to two-thirds of hereditary breast and ovarian cancer [6, 16, 19, 20]. This is in agreement with our findings; 31 of 40 patients (77.5%) were tested positive for BRCA1 (n = 21), BRCA2 (n = 9) and one patient tested positive for both BRCA1 and BRCA2.
Carrying mutated genes does not appear to have a deleterious effect on the ovarian reserve as measured by day 3 FSH and AFC. These results in women with hereditary breast cancer were comparable to those with non-hereditary breast cancer. Obviously, AMH levels would have been helpful, but as this study included patients before, AMH testing became a standard test. Yet, Van Tilborg et al. reported that women with BRCA1/2 mutation carriers did not have a lower serum AMH level in comparison to non-carriers [21]
Data on the impact of BRCA gene mutation on the reproductive potential and the fertility preservation outcome have been mixed. Many studies had shown that BRCA carriers had lower ovarian reserve and earlier menopause when compared to non-BRCA carriers [22–24]. Others reported poor ovarian stimulation response in BRCA cancer patients when compared to those with non-BRCA [25] or comparable ovarian response independent of the BRCA status [26].
It is known that BRCA gene plays an important role in DNA repair. A mutant BRCA gene will fail to do the repair, leading to accumulation of unrepaired DNA. This may lead to changes that promote ovarian aging and decreased ovarian reserve. Giordano et al. (2016) reported that BRCA1-positive women of > 35 years old had 10 times the odds of a low AMH (< 0.5 ng/mL) compared to women at or younger than 35 years. Lin et al. (2017) found that BRCA1 carriers had increased DNA double-strand break that appeared to be accelerated in the primordial follicle oocyte with subsequent loss of oocytes at age 30 years or over.
Perhaps more importantly, in this study, both groups responded similarly to gonadotropin stimulation with similar doses and duration of stimulation. The number of mature oocytes, fertilized oocytes, cryopreserved oocytes, and embryos was comparable. Most of our patients with BRCA mutation were stage 1 breast cancer. In this study, we did not evaluate the grade of cancer. However, we previously reported that low-grade breast cancer is associated with good fertility preservation outcome [27].
Patient with hereditary breast cancer presented at a younger age than those with non-hereditary breast cancer. Of 40 patients, 18 women aged at ≤ 30 years (45%) and only 4 others above 35 years old (10%). Young age at the time of presentation could explain the better embryo quality and the higher number of frozen embryos among women with hereditary breast cancer.
Several previous studies showed that BRCA1 tumor had been found to be more frequently having estrogen, progesterone, and Her-2 receptors status negative [28]. In our study, we found that hereditary breast cancer patients had tumor with significantly lower estrogen and Her-2 receptor expression with no significant difference in progesterone receptors status when compared to non-hereditary breast cancer patients. This difference could be related to other non BRCA 1 gene mutations, BRCA2, ATM, NF, TP53, CHK-2, PALP2, and MUTYH gene, which might not have similar hormonal receptor status as BRCA1.
The limitations of our study included its retrospective nature, small number of women with non-BRCA mutated genes, and we could not evaluate the incidence of pregnancy and its outcome. However, to the best of our knowledge, this is the first study evaluating gamete collection outcome in breast cancer women with different mutated genes.
We conclude that over three quarters of positive mutated genes in women with breast cancer are BRCA. Despite concerns of poor ovarian reserve, compared to those with non-hereditary breast cancer, women with hereditary breast cancer undergoing fertility preservation prior to gonadotoxic therapy produced a similar response and in the current study yielded a higher number of cryopreserved embryos.
Acknowledgements
The author would like to thank Nancy Lamothe for managing the database, and all nurses, physicians, and medical health workers at the MUHC-Reproductive center.
Abbreviations
- AFC
Antral follicle count
- ATM
Ataxia-telangiectasia mutated
- BRCA
Breast cancer gene
- CP
Clinical pregnancy
- CHK2
Checkpoint kinase 2
- DOR
Diminish ovarian reserve
- ET
Endometrial thickness
- FET
Frozen embryo transfer
- FSH
Follicle stimulating hormone
- GnRH
Gonadotropin releasing hormone
- HRT
Hormonal replacement treatment
- HCG
Human chorionic gonadotropin
- IVF
In vitro fertilization
- IVM
In vitro maturation
- ICSI
Intracytoplasmic sperm injection
- LBR
Live birth rate
- NF1
Neurofibromin 1
- PALP2
Partner and localizer of BRCA 2
- PCOS
Polycystic ovarian syndrome
Author contribution
S. Arab was involved in study design, data collection, data analysis, and writing the manuscript; W. Buckett participated in study design, data analysis, editing the manuscript, and review; T. Tulandi was involved in data analysis, interpretation, and editing the manuscript.
Code availability
Not applicable.
Declarations
Ethical approval
Research and Ethics Board (MUHC REB) approved the study (REB #2020-6219).
Consent to participate
Not applicable.
Consent for publication
Not applicable.
Conflict of interests
The authors declare no competing interests.
Footnotes
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Data Availability Statement
Not applicable.