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| REVIEW ARTICLE |
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| Year : 2018 | Volume
: 1
| Issue : 1 | Page : 9-16 |
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Breast cancer and fertility: A Review - Part 1
Nalini Mahajan
Department of Reproductive Medicine, Mother and Child Hospital, New Delhi, India
| Date of Web Publication | 13-Feb-2018 |
Correspondence Address:
Nalini Mahajan
Mother and Child Hospital, D-59, Defence Colony, New Delhi - 110 024
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/tofj.tofj_6_17
Breast cancer (BC) treatment leads to a reduction in reproductive lifespan due to the use of gonadotoxic agents and prolonged hormonal treatment. With an increasing incidence of BC in the young and better survival rates, fertility issues have come into focus. Pregnancy does not appear to have a detrimental effect and may even improve survival rates. Fertility counseling and offering fertility preservation (FP), therefore, is the standard of care. Among the FP procedures, oocyte freezing is preferred as it allows reproductive autonomy. Ovarian stimulation required for oocyte recruitment does not worsen BC prognosis. Reproductive outcome using cryopreserved gametes gives live birth rates similar to nononcological patients though studies are limited in this aspect. Ovarian tissue cryopreservation can be safely offered if neoadjuvant therapy is required. Fertility issues are extremely relevant in BRCA mutation carriers and FP should be offered to them. Co-administration of gonadotropin-releasing hormone agonist with chemotherapy is recommended in patients wishing to preserve ovarian function.
Keywords: BRCA mutation, breast cancer, fertility preservation, gonadotropin-releasing hormone agonist, infertility
How to cite this article:
Mahajan N. Breast cancer and fertility: A Review - Part 1. Onco Fertil J 2018;1:9-16 |
| Introduction | |  |
Breast cancer (BC) is the most frequently diagnosed female cancer worldwide, with a higher incidence in developed nations.[1] Though common after the fifth decade of life, approximately 20% of cases are diagnosed below the age of 49 years and 12% between the ages of 20 and 44 years.[2],[3] In India, BC incidence in women under 40 years has risen from 10% to 20% in the last two decades.[4] Multimodality treatment has improved survival rates, and attention is now being focused on "quality-of-life" issues in survivors. Life-preserving therapies unfortunately lead to ovarian dysfunction, sexual dysfunction, and other systemic and psychosocial issues, that threaten fertility.[5] Fertility preservation (FP) counseling has been advocated by all oncological societies as a part of the initial workup in cancer patients.
Improved survival rates coupled with a rising incidence of BC in the reproductive age group and a trend to delay motherhood have led to an increasing number of women who need to start or complete their families.[6] Fortunately, disease-free survival (DFS) and overall survival in patients conceiving after BC has not shown any deterioration, encouraging BC survivors to seek advice on the prospect and safety of parenthood after completion of cancer therapy. This article (part 1) aims to provide a comprehensive look at the need and possibility of FP after BC. Part 2 of the article will address concerns regarding pregnancy during and after BC.
| Methods | | |
This review uses the published articles in the field of BC and FP. Cited articles were found by a literature search using PubMed for articles published until August 2017. In addition, relevant professional society guidelines were searched. The following key words were used: breast cancer, chemotherapy (CT), gonadotropin analog, ovarian reserve (OR), fertility, BRCA mutations, premature menopause, fertility preservation, ovarian stimulation (OS).
| Breast Cancer in Reproductive Years | | |
Though hormone receptor-positive (HR+ve) cancers are the most common, younger women have a higher incidence of triple receptor-negative, HER2/neu-positive, poorly differentiated, aggressive tumors.[7] BC in young women is frequently associated with a positive family history and gene mutations. Multimodality treatments include surgery, radiotherapy, adjuvant systemic endocrine or CT, and tumor-reducing neoadjuvant therapy before surgery, when indicated. CT with gonadotoxic alkylating agents and anthracyclines or taxanes forms the standard of care. HR+ve tumors are managed with prolonged hormonal treatment for up to 10 years to reduce the risk of recurrence and improve survival rates.[6]
| Effect of Chemotherapy and Endocrine Therapy on Fertility | | |
Chemotherapeutic drugs cause damage to the oocyte-granulosa cell complex, stroma, and blood vessels within the ovary. This leads to apoptosis of the growing follicles and activation of dormant follicles with subsequent apoptosis, culminating in a reduction of the OR.[8] Depending on the extent of follicular damage, the fall out can be infertility, premature menopause, or permanent amenorrhea.[9],[10] Type and dose of cytotoxic drug and age and OR of the woman at the time of cancer diagnosis are important determining factors for the associated complications.[11],[12] Gonadotoxicity is highest with alkylating agents such as cyclophosphamide, a drug commonly used in the treatment of BC.[13],[14],[15] Alkylating agents are responsible for the highest age-adjusted odds ratio (OR) of ovarian failure followed by other drug families.[16] The importance of a woman's age lies in the fact the she has a finite number of oocytes which deplete with age, thus the risk of developing permanent amenorrhea increases the older the woman is, at the time of receiving CT.[17] Endocrine therapies (tamoxifen, aromatase inhibitors, and gonadotropin (GT)-releasing hormone analogs [GnRH-a]) are not gonadotoxic but have a prolonged duration of administration, and by the time treatment is completed, a woman is well past her reproductive prime.
Chemotherapy-induced amenorrhea
Chemotherapy induced amenorrhea with CT regimens has been used as a marker of gonadotoxicity however resumption of menses is not an index of fertility.[18] In a systemic review and meta-analysis of 75 studies, evaluation of 23,673 patients revealed a pooled rate of chemotherapy-induced amenorrhea (CIA) to be 55% (95% confidence interval [CI]: 50%–60%). Age distribution revealed CIA to be 26% (95% CI: 12%–43%) for women <35, 39% (95% CI: 31%–58%) for women 35–40, and 77% (95% CI: 71%–83%) in >40 years' age group. Strong level of evidence existed for two risk factors for CIA – age over 40 years and use of tamoxifen. Taxanes were not found to be associated with higher risk for CIA, but the level of evidence was weak. There was inconclusive evidence for other potential risk factors such as trastuzumab, dose-dense therapy, duration of CT, smoking, educational level, and nulliparity.[15] Evaluation of the effect of the newer targeted therapies on CIA is not available in literature. [Table 1] summarizes the common CT regimens used in BC and the risk of treatment-induced amenorrhea.[19] | Table 1: The rate of chemotherapy-induced amenorrhea in breast cancer patients
Click here to view |
Tamoxifen
Treatment is the mainstay of hormone-positive BC. It is a selective estrogen receptor modulator (SERM) and competes with estrogen for binding sites in the estrogen receptor in target tissues such as breast. It prevents proper binding of estrogen and the subsequent transcription of DNA to mRNA. Tamoxifen is an endocrine disruptor which is cytostatic rather than cytotoxic. Long-term administration of tamoxifen for 10 years has shown to increase survival rates.[20] It is teratogenic, so contraception is advised during administration and a washout period of 2 months is recommended before attempting conception.[21] A recent study suggests that tamoxifen use does not reduce OR in BC patients. Tamoxifen users were found to have a higher OR than non-users.[22]
| Markers of Ovarian Reserve | | |
Anti-Mullerian hormone (AMH) is currently the marker of choice for assessing OR, being secreted by the pre- and early-ovarian antral follicles. In contrast to follicle-stimulating hormone, the traditional OR marker, AMH can be estimated on any day of the cycle, its value is not affected by tamoxifen use and it is proving useful even in prepubertal girls.[23] Follicular loss induced by CT results in a fall of AMH levels in serum,[24] indicating a decrease in OR. Immediately after CT, AMH levels drop drastically, recovering partially within 3–12 months. A study by Dillon et al., 2013, in cancer survivors suggested that pretreatment AMH levels were associated with the rate of recovery of AMH posttreatment.[25] In adjusted models, participants with a pretreatment AMH level >2 ng/mL recovered at a rate of 11.9%/month after CT, while those with AMH levels ≤2 ng/mL recovered at a rate of 2.6%/month after therapy (P = 0.003). AMH levels are useful for counseling patients for FP and assisted reproductive technologies (ARTs); however, their use for prediction of pregnancy is questionable as women with very low AMH are found to conceive spontaneously.[26]
| Medical Therapy for Fertility Protection | | |
There is an urgent need to develop drugs to protect the ovaries from the onslaught of life-preserving gonadotoxic agents. FP techniques are invasive and costly and cannot prevent the systemic effects of hormone depletion resulting from premature menopause. Though many drugs are under consideration, the only one in clinical use is the long-acting GnRH-a. Ovarian protection is thought to be conferred by pituitary downregulation which suppresses GTs and suppresses the ovary to a prepubertal state.[13] Decreased blood flow to the ovaries and a direct action on the ovary have also been postulated as GnRH receptors are found on preovulatory follicles and corpus luteum.[8] The initial flare-up effect of the drug necessitates its administration at least 7–10 days prior to CT and it should be continued till 2 weeks after completion of therapy.
Numerous studies including many systemic reviews and meta-analysis have been published on the use of GnRH-a as an ovoprotective agent, but a clear-cut direction is not forthcoming [Table 2].[5],[27],[28],[29],[30],[31],[32],[33] Studies done on BC patients suggest that GnRH-a use protects ovarian function (prevents premature ovarian failure [POF]) as estimated by a return of menses, but fertility protection is debatable. Protection of ovarian function in the young may give a small window to consider FP with pooling of embryos, if required. | Table 2: Trials and meta-analysis studies that investigated the efficacy of gonadotropin-releasing hormone analog during chemotherapy in breast cancer patients
Click here to view |
A retrospective cohort study on 286 patients reported that the OR for preserving ovarian function was 6.87 (95% CI, 3.4–13.4) for the patients who received GnRH-a.[27] Overall, 60% of the survivors conceived: 69.3% in the GnRH-a group compared with 42.4% in the control group (P = 0.006). One of the major trials impacting treatment decision was the POEMS trial in 2015.[29] POEMS study on 257 patients with hormone receptor-negative (HR-ve) disease concluded that concomitant use of GnRH-a was associated with a significant reduced rate of treatment-induced POF (8% vs. 22%; OR, 0.30; 95% CI, 0.09–0.97; P = 0.04) and an increased number of patients with subsequent pregnancy (22 vs. 12; OR, 2.45; 95% CI, 1.09–5.51; P = 0.03). The PROMISE-GIM6 trial included HR+ve patients and reported a reduced rate of POF in this group as well (8.9% vs. 25.9%; OR 0.28; 95% CI, 0.14–0.59; P < 0.001).[34] The number of patients achieving pregnancy subsequently was higher but did not reach statistical significance. A subsequent meta-analysis of 12 randomized trials in 1231 young BC women done by the same author confirmed these findings.[28]
In a recent large systemic review and meta-analysis of seven randomized clinical trial including 856 patients of early BC, use of GnRH-a was associated with a higher rate of recovery of regular menses after 6 months (OR, 2.41; 95% CI, 1.40–4.15; P = 0. 002) that maximized further at 12 months (OR, 1.85; 95% CI, 1.33–2.59; P = 0.0003) following last CT cycle.[5] The use of GnRH-a was also associated with a higher number of pregnancies (OR, 1.85; 95% CI, 1.02–3.36; P = 0.04), although this outcome was not uniformly reported.
Can we avoid fertility preservation using gonadotropin-releasing hormone analog protection?
Unfortunately, most trials did not have pregnancy outcome as their primary outcome, and so at this point in time, temporary ovarian suppression with GnRH-a during CT should not be considered as an alternative to embryo/oocyte cryopreservation.[35]
Safety of gonadotropin-releasing hormone analog co-administration
Concerns have been raised regarding the return of ovarian function, especially in HR+ve BC patients. The POEMS trial reported longer DFS and overall survival (HR = 0.49, P = 0.04; HR = 0.43, P = 0.05, respectively) in HR-ve patients receiving GnRH-a. The PROMISE trial which included 81% HR+ve patients reported no differences in 5-year DFS rates (83.7% in CT alone arm versus 80.5% in CT plus GnRH-a; P = 0.519) (HR = 0.96; 95% CI, 0.55–1.70; P = 0.19). The ASCO guidelines however recommend suppression of ovarian function in HR+ve patients who resume menses.[36]
Recommendations on the use of gonadotropin-releasing hormone analogs in breast cancer
The National Comprehensive Cancer Network guidelines, the 2nd International Consensus Guidelines for Breast Cancer in Young Women, and the Italian Association of Medical Oncology support the use of GnRH-a in all premenopausal BC patients who have to undergo CT and are interested in ovarian function and/or FP irrespective of the HR status of their disease.[37],[38],[39] The ASCO guidelines 2013 state that there is insufficient evidence to recommend use.[40]
| Fertility Preservation | | |
Cancer therapy leads to a significant reduction in the reproductive lifespan of a woman; hence, there is a consensus on advising FP to young BC patients desirous of pregnancy after treatment.[6],[40],[41]
Fertility preservation techniques
Embryo and oocyte cryopreservation
Embryo and oocyte cryopreservation are the standard procedures used for FP. Since these procedures require OS and oocyte retrieval, a period of approximately 12–14 days is required before CT. The time available between surgery and CT (~4–6 weeks) can be utilized for this. Embryo freezing is a well-established technique, it requires oocytes to be fertilized, so the woman needs to have a partner or use donor semen.
Mature oocyte cryopreservation offers reproductive autonomy and is advisable to avoid future ethical, religious, and legal concerns. Successful oocyte freezing requires a skilled embryologist as human oocytes are highly prone to ice crystal formation and damage by cryoprotectants. Vitrification is superior to slow freezing and remains the method of choice. An overall survival rate of 85.2% (95% CI, 83.2–87.2) has been reported.[42] Cryopreservation of immature oocytes and in vitro maturation after thawing is still not very efficient.
Cryopreservation of ovarian tissue
Cryopreservation of ovarian tissue (OTC) can be considered in BC patients if urgent neoadjuvant CT is required since it avoids delay of treatment. OTC also offers the advantage of preservation of gonadal function. Collection of ovarian tissue and re-transplantation require a surgical procedure that can be performed laparoscopically. Reports of pregnancies achieved after transplantation of preserved ovarian tissue are increasing and a live birth rate (LVB) of 30% has been achieved.[43] The success of OTC depends on the patient's age, baseline OR, and expertize of the surgeon and scientist performing the procedure. The procedure is no longer considered experimental in Europe and Israel. In women with BRCA mutations, there are safety concerns because of increased risk of ovarian cancer.[44]
| Ovarian Stimulation Regimens | | |
The OS protocols used preferentially in in vitro fertilization (IVF) are the long (luteal start) GnRH agonist or antagonist and OS with gonadotrophins (GT). Availability of time (between surgery and CT) in BC patients allows either one to be used. If time constraint is an issue, a random start protocol can be used. This protocol allows GTs to be started on any day of the cycle by recruiting a second wave of developing follicles, without compromising outcome. GnRH antagonist is started when the second wave of follicles reaches 12 mm in size, the dominating follicle in the follicular phase or the corpus luteum in luteal phase is discounted [Figure 1].[45] Use of natural cycle IVF or mild IVF is not a good option in FP as there is generally a single chance at collecting oocytes and maximizing the yield, which gives a better chance of pregnancy subsequently. Antagonist protocol with GnRH agonist trigger is preferred as it reduces the risk of ovarian hyperstimulation syndrome. Addition of letrozole significantly lowers estradiol (E2 level) throughout the cycle. It is given at a dose of 2.5–5 mg from cycle day 2 till E2 levels drop after oocyte pick-up. Though oocyte numbers and fertilization rate reported are similar to noncancer patients, a lower number of mature oocytes are retrieved.[46] Tamoxifen, a breast protective agent used in HR+ve BC, is added during controlled OS (COS) from day 4–5 of stimulation once the E2 levels start rising and is continued after oocyte retrieval. Its use does not compromise IVF results [Figure 2].[47] | Figure 1: Random start protocol–late follicular phase *D: Day; Sec wave of foll: Second wave of follicles; OS: Ovarian stimulation; GT: Gonadotropin; LH: Luteinizing hormone
Click here to view |
 | Figure 2: Ovarian stimulation protocols for women with breast cancer *OPU: Oocyte pickup; D: Day; GT: Gonadotropin; E2: Estradiol 2; GnRH: Gonadotropin-releasing hormone; HR+: Hormone receptor positive
Click here to view |
| Reproductive Outcome With Preserved Embryos/oocytes | | |
An oocyte-to-baby rate of 6.5% is projected, the probability of achieving a baby increases progressively with the number of vitrified oocytes used, a plateau being reached at 25.[42] A study done by Martinez et al., 2014, looked at the obstetric outcome using vitrified thawed oocytes in women treated for cancer.[48] The oocyte survival rate was 92.3%, fertilization rate was 76.6%, mean number of embryos transferred was 1.8 ± 0.7, and pregnancy was achieved in 63% (7/11) of patients. Oktay et al., 2015, reported a LBR of 45% in BC survivors using their frozen embryos, similar to nononcological women.[49] Dolmans et al. reported a LBR per patient of 44% in 54 women with cancer using cryopreserved embryos; the cumulative LBR was similar to that achieved with fresh embryos in noncancer patients.[50]
| Safety of Controlled Ovarian Stimulation | | |
One of the major worries in HR+ve BC is the rise in estradiol levels with COS. Tamoxifen, a SERM, and letrozole, an aromatase inhibitor, have been introduced into OS regimens to improve safety. Concerns on an increased recurrence or decreased survival have been addressed in two recent studies. First, a Swedish register-based, matched cohort study looked at the safety of hormonal stimulation in BC patients undergoing FP and concluded that it was safe to practice FP in young women with BC. Results showed that women who received hormone stimulation did not have a higher relapse rate than unexposed controls adjusted for age and calendar period of diagnosis (incidence rate ratio [IRR], 0.59; 95% CI, 0.34–1.04). Results remained unchanged after adjustment for tumor size, ER status, affected lymph nodes, and CT treatment (IRR, 0.66; 95% CI, 0.37–1.17).[51] A systematic review and meta-analysis looking at the safety of COS in BC also reported no decline in relapse-free survival rates in women receiving letrozole with GTs compared with women who did not undergo FP procedures (mean follow-up, 5.0 vs. 6.9 years; HR for recurrence, 0.77; 95% CI, 0.28–2.13). Insufficient data precluded the possibility of making any conclusion on the use of tamoxifen with GT; however, an earlier study done on the efficacy of tamoxifen in BC reported no long-term recurrence in a 10-year follow-up.[47],[52]
| Women With Brca Mutations | | |
BRCA1 mutation carriers are at a 50%–80% lifetime risk of BC, 40%–50% risk of developing a second primary BC, and 40%–60% risk of ovarian cancer. Women with BRCA2 mutations also present a high risk of BC, although the risk of ovarian cancer is lower (10%–20%). Fertility issues are extremely relevant as BRCA mutation carriers may require cancer treatment at a young age and prophylactic bilateral salpingo-oophorectomy could be advised. Deficient DNA repair may make oocytes more susceptible to CT-induced OR loss.[44] Literature also suggests a higher risk of POF, earlier menopause, and poorer response to OS among women with BRCA1/2 mutation [Figure 3].[53] | Figure 3: Options of fertility preservation in women with breast cancer *BC: Breast cancer; CT: Chemotherapy; FP: Fertility preservation; PGD: Preimplantation genetic diagnosis; GnRH: Gonadotropin-releasing hormone; HR+: Hormone receptor positive; rAMH: Recombinant anti-Mullerian hormone; eIVFG: Encapsulated in vitro follicle growth; OR: Ovarian reserve
Click here to view |
Concern over an increased risk of ovarian cancer after fertility treatment in BRCA carriers was addressed in two studies. Perri et al., 2014, found that fertility treatment was not associated with increased intraepithelial ovarian cancer risk (age-adjusted OR, 0.63; 95% CI, 0.38–1.05) regardless of treatment type (clomiphene citrate-OR, 0.87; 95% CI, 0.46–1.63; GT-OR, 0.59; 95% CI, 0.26–1.31; and IVF-OR, 1.08, 95% CI, 0.57–2.06).[54] Gronwald et al., 2016, reported that there was no significant relationship between the use of any fertility medication or IVF treatment (OR, 0.66; 95% CI, 0.18–2.33) and subsequent risk of ovarian cancer.[55] FP option of choice is oocyte freezing, preimplantation genetic diagnosis for mutation screening before transfer should be considered. For OTC, transplantation under the forearm skin has been proposed for easy monitoring of tissue.[44]
| Conclusion | | |
BC treatment leads to a reduction in reproductive lifespan due to the use of gonadotoxic agents and prolonged hormonal treatment. With the increasing incidence of BC in the young and better survival rates, fertility issues have come into focus. Pregnancy does not appear to have a detrimental effect and may even improve survival rates. Fertility counseling and offering FP therefore is the standard of care. Among the FP procedures, oocyte freezing is preferred as it allows reproductive autonomy. OS required for oocyte recruitment does not worsen BC prognosis. Reproductive outcomes using cryopreserved gametes (limited studies) give LVBs similar to nononcological patients. OTC can be safely offered if neoadjuvant therapy is required. Fertility issues are extremely relevant in BRCA mutation carriers and FP should be offered to them. Co-administration of GnRH analog with CT is recommended in patients wishing to preserve ovarian function.
Acknowledgment
I would like to acknowledge the contribution of Dr. Jasneet Kaur and Dr. Priya Bhardwaj for helping with preparation of manuscript.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]
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