Female Fertility Following Chemotherapy for Breast Cancer: A Descriptive Study of 265 Cases Treated in Yaounde

Context: In Cameroon, breast cancer (BC) is usually diagnosed late in the disease course. About a third of women affected are aged less than 40 years. Chemotherapy (CT) could alter ovarian function and thereby compromise future fertility in these women. We therefore described the fertility of women following CT for BC in women treated at the Yaounde General Hospital (YGH). Methods: It was a retrospective, descriptive, cross-sectional study conducted over 8 months, from January to August 2017. We used the files of patients managed for BC from January 2011 to December 2015 in the medical oncology unit of the YGH. Results: We included 265 patients for the study following at least one year of CT. The mean age at the onset of CT was 35.9 ± 6.9 years. Most of the patients had fewer than 2 deliveries (68.3%). Intraductal carcinoma was the most frequent histological lesion (90.6%) and most often diagnosed in advanced stages (73.5%). As per CT, the FAC protocol was the most used (44.5%). The menstrual cycles of the patients were more regular prior to the onset of chemotherapy (89.4% vs. 58.9%), while the mean period of resumption of menstrual activity following cessation of chemotherapy was 6.3 ± 2.0 months. Chemotherapy-related amenorrhoea was observed in 29.1% of patients after 12 months of treatment. More than half of these women (51.3%) complained of a drop in libido and 6.4% achieved pregnancy within 13 months following cessation of chemotherapy. Conclusion: Following chemotherapy for BC, menstrual cycle disorders are more frequent and this can affect the patients’ reproductive potential. Fertility consultations should be integrated into the management plan of such patients.


Introduction
Breast cancer is the first female cancer in Cameroon [1], with a significant number of young women amongst those affected [2] [3]. Many studies suggest the occurrence of more aggressive forms of breast cancer in young women [4] [5] [6]. The absence of screening in young people, associated to the low levels of knowledge on the condition is responsible for the late diagnosis of breast cancer [3] [7]. As a result, practitioners resort to more aggressive treatment protocols to ensure survival and/or remission.
In addition to its aesthetic and psychological complications, the management of breast cancer in women of childbearing age could decrease their fertility potential. Because of their young ages, advanced disease, and the aggressive nature of the tumours, chemotherapy constitutes the mainstay of conservative management plans. According to Rudra et al. in the United States, a higher proportion of women under 40 years of age require chemotherapy when compared to older women [8]. Chemotherapy is based on antimitotic regimens with well described effects on ovarian function. These drugs act through multiple mechanisms such as decreased blood flow to the ovaries, the destruction of the ovarian cortical vasculature with ensuing cortical fibrosis associated to the disappearance of primordial follicles [9] [10]. Chemotherapy accelerates physiological ovarian aging, and therefore significantly compromises the fertility of women. Improvements in treatment options and a better codification of the management of breast cancers have significantly increased the survival of patients. There is a need to address the desire for childbearing in women after breast cancer treatment, because the recovery of ovarian function and fertility becomes an important goal for their post-treatment quality and hence the need to perform fertility assessments while managing young women for breast cancer [11].
In this study, we aimed to describe the characteristics of reproductive life as well as the fertility of women following treatment for breast cancer with chemotherapy. Alterations in ovarian function following chemotherapy, raise the need to resort to the increasingly available and accessible gamete conservation techniques.

Materials and Methods
We conducted a descriptive cross-sectional study of a population of women of  The study took place from January 2017 to August 2017 (8   months). We collected the contact details of the patients followed up for breast cancer from the database of the medical oncology unit. Then, using these, we searched for and consulted their medical files at the hospital archives. The medical records granted us access to the patients' telephone numbers via which we contacted them. All those residing in Yaounde, and who granted their consent were invited to the service for an interview. The date and time were determined according to the availability of the patients. In some cases, and following patient authorisation we obtained the information by phone call. Similarly, for all patients living outside Yaoundé and wishing to participate in the study, the interview was carried out on the telephone. Data on diagnosis and chemotherapy protocols were collected from the patients' medical records. For the study, we selected women following a post-chemotherapy interval of at least 12 months.
We excluded from our study all patients with a known history of hysterectomy, chemotherapy, ovarian failure or those who had a recurrence of breast cancer or died before or during our study.
Our variables of interest were socio-demographic (age, age at onset of chemotherapy, level of education, marital status), clinical (clinical stage, histological type, therapeutic modalities, chemotherapy protocol used and the number of sessions) and the characteristics of reproductive life (parity, history of infertility, contraception, menstrual cycle's pattern before and after chemotherapy, delay of menstruation after chemotherapy, desire for pregnancy, libido, occurrence of pregnancy).
We defined post-chemotherapy amenorrhoea as the absence of menses following 12 months or more of treatment cessation, and oligomenorrhoea as too few menses or bleeds lasting less than 2 days. Regular menstrual cycles are cycles occurring every 21 -35 days. Patients were staged for breast cancer as per the TNM classification. Any histologically proven metastases in distant organs; or if in non-regional nodes, metastases greater than 0 At the medical Oncology service of the Yaoundé General Hospital, chemotherapy is administered in cycles every 21 days. The most commonly used protocols were: Protocols Description

Results
Between who had incomplete or absent records, 5 who had a history of hysterectomy before the diagnosis of breast cancer, and 1 who had a history of chemotherapy prior to the diagnosis of breast cancer. In the end, 265 patients were included for the study (Figure 1). Sociodemographic characteristics The average age of the patients at the time of the study was 39.2 ± 6.8 years, while the average age of patients at the onset of chemotherapy was 35.9 ± 6.6 years. Higher and secondary education levels were the most represented, representing 37% and 36.2% of cases respectively. Half of these were married ( Table 1).
Clinical and histopathological characteristics  Table 3 represents the therapeutic aspects. The most common management plan for patients involved chemotherapy, surgery and radiotherapy in 70.6% (187/265) of cases. The FAC and AC60-Taxotere protocols were the most commonly used, in 44.5% (118/265) and 35.5% (94/265) of cases respectively.    Reproductive life variables Table 4 and Table 5 (Table 6) and all age groups before 40 years were concerned (Table 7).      Figure 2. Distribution of pregnancy desire by age range (N = 265).

Discussion
The occurrence of amenorrhea following chemotherapy reveals its toxicity to the ovaries. Several authors have echoed this in many studies [10] [11] [12] [13] [14]. The possibility of premature ovarian failure caused by chemotherapy, is potentially invalidating for women of childbearing age treated for breast cancer.
According to Kemfang [12], unlike in industrialized countries where the diagnosis is made earlier [13]. The late discovery of the disease is associated with poor survival rates [2], ultimately leading to aggressive treatments, especially in young women [14]. These treatments are likely to be more toxic to the ovaries.
In addition, young age is a poor prognostic factor [15] for breast cancer. The average age in our study population was 35.9 years.
Many authors have evaluated the toxicity of the chemotherapeutic agents used in the management of breast cancers, with evidence that treatment protocols affect ovarian function differently. The toxicity depends on the age of the patient, the agent used, including the dose and the protocol [16]. Cyclophosphamide-based protocols induce the highest rates of chemotherapy-induced ovarian  [17]. Long JP et al. [18] had found that although both CAF and DPT affected ovarian function, alterations with the CAF protocol was less pronounced. The FAC protocol (44.5%) was the most used in our study, a fact not consistent with recent literature, which increasingly recommends a sequence-based protocol with Anthracyclines and Taxanes, known to be less toxic to ovaries [19] [20]. The reason for this is that many chemotherapeutic agents remain unavailable in our setting, and their relatively high cost makes them inaccessible for the majority of these patients who have limited resources in the absence of a Universal health coverage scheme.
Age is a determining factor in the occurrence of menstrual disorders following chemotherapy. The average age of women in our study was young at 35.9 years.
This is probably why only 41.1% of our patients had cycle disorders such as amenorrhoea or oligomenorrhoea after chemotherapy. In the study by Tiong et al. [21], 93.1% of women reported amenorrhea at the end of treatment and 77.9% reported same 12 months after chemotherapy in a female population in which the average age was 43.3 years. These authors also found that age was the most important risk factor for the occurrence of chemotherapy-induced amenorrhoea because the rate of amenorrhoea increased with increasing age. This finding was further corroborated by the work of Ben-Aharon et al. [22], which showed that women under 35 years of age recovered from alterations in chemotherapy-induced ovarian circulation faster than their older counterparts. Menstrual disorders are likely to occur in women who already have some degree of aging ovarian function [23] [24]. Amongst the women who complained of amenorrhea, 37% had a resumption of menstrual activity after 6 months. This rate was higher than those described in literature with different treatment protocols [21]. We observed 17 (6.4%) cases of spontaneous pregnancies 13 months after chemotherapy, and a 10.4% pregnancy rate among women under 40 years of age. Despite the return to normal of the menstrual cycle, young women survivors of chemotherapy will undergo varying degrees of altered ovarian function that will interfere with their fertility [25].
The pregnancy rate amongst women over 40 years of age was extremely low at 0.9% with Gerber B et al. [26] reporting a 3% spontaneous pregnancy rate amongst women over 40 years of age, suggesting a more severe alteration in fertility in women over 40 years of age, even if their menstrual cycle remains intact. Literature findings estimate that 70% of patients under 45 years of age who are treated for breast cancer would desire a child after the end of their treatment [27], however we found a lower proportion in our study. This could be explained by the fact that most of our patients already had at least one child. In order to avoid the residual teratogenic risk of chemotherapy, a minimum of at least 1 year following the last course of chemotherapy is recommended (at least 3 months after stopping Tamoxifen) [28]. Unfortunately safety time is not often taken into consideration.
Our study presented some limits. First, we studied overall female fertility fol-Open Journal of Obstetrics and Gynecology lowing chemotherapy regardless of the protocol used. Also, the size of our sample did not allow us to isolate the protocol favorable to fertility, or better still to identify the molecule most toxic to the ovaries. In addition, data obtained by telephone posed the risk of information bias. Finally, we evaluated the fertility of women and not that of the couple, with the risk of missing potential male partner infertility as the sole cause for childlessness.

Conclusion
Chemotherapy alters the fertility of women treated for breast cancer. Cycle disorders are more frequent after chemotherapy. The resumption of normal menstrual cycle activity does not guarantee future childbearing. The high proportions of patients wanting pregnancy after chemotherapy suggest the need to integrate fertility consultations into the management of breast cancer patients and to look out for factors associated with fertility potential following chemotherapy.

Data Availability Statement
The data used to support the findings of this study are included within the article.

Funding Statement
This article was not funded.