What Are Young Women Living Conditions after Breast Cancer? Health-Related Quality of Life, Sexual and Fertility Issues, Professional Reinsertion

In recent decades, the living conditions of young breast cancer (BC) survivors have garnered increasing attention. This population-based study aimed to identify the clinical, social and economic determinants of Health-Related Quality of Life (HRQoL), and to describe other living conditions of young long-term BC survivors. Women with non-metastatic BC diagnosed between 2006 and 2015, aged 45 years and younger at the time of diagnosis, were identified through the Breast and Gynecologic Cancer Registry of the Côte d’Or, France. Participants completed self-report questionnaires including standardized measures of HRQoL, anxiety, depression, social deprivation, social support and sexuality. Fertility and professional reintegration issues were also assessed. The determinants of HRQoL were identified using mixed regression model. In total, 218 BC survivors participated in the survey. The main determinants of poor HRQoL were anxiety, depression, comorbidities, social deprivation and menopausal status. Among 72% of women who did not receive information about fertility preservation, 38% of them would have liked to have been informed. Finally, 39% of survivors reported a negative impact of BC on their professional activity. This study showed that BC stage or treatments did not have an impact on HRQOL of young long-term BC survivors. Fertility, sexuality and professional reintegration remained the main concerns for survivors. Specific interventions in these population should focus on these issues.


Introduction
Breast cancer (BC) is the most common cancer and the leading cause of death by cancer in women in France and around the world [1]. In France, the incidence of BC for women under 40 years of age is increasing with an average annual variation of +0.9 [2]. Concurrently, this increase in incidence is associated with a decrease in mortality, with an average annual variation of −1.6 [2]. Survival after BC varies from one country to another [3], with the highest survival rate (87%) being observed in France, from 2005 to 2010, compared to other European countries [4,5]. Improved survival raises the question of improved living conditions for survivors. In this regard, increasing attention has been focused on health-related quality of life (HRQoL) [6] in recent decades, as well as on issues related to fertility and socio-professional reintegration, particularly among young women. Indeed, cancer is affecting increasing numbers of working individuals, who have a long professional life ahead of them. A return to work is generally perceived by this population as important for recovery [7]. Therefore, it is necessary to focus on the professional reintegration of young women who have had a BC. Moreover, Meneses et al. reported that difficulties linked to maternity and fertility were the main factors hindering HRQoL in young BC survivors, due to the side effects of treatment, such as chemotherapy, on ovarian function [8]. The sexuality of women with BC can also be perturbed, for both physical and psychological reasons. To the best of our knowledge, few population-based studies have encompassed all these post-cancer issues among young women with BC in France.
Using data from the specialized Côte d'Or Breast and Gynaecologic Cancer Registry, this study aimed to identify the clinical, social and economic determinants of HRQoL among young BC survivors. Secondarily, we describe the living conditions of BC survivors, with regard to fertility, sexual function, psychological distress and professional reinsertion.

Patients
This cross-sectional study was conducted using data from the specialized Breast and Gynaecologic Cancer Registry of the Côte d'Or Department in France, the only registry in France to focus on breast and gynecological cancers. The registry catchment area has approximately 500,000 inhabitants, of whom 270,000 are women. The population is predominantly rural, with low migration. The registry has been collecting comprehensive population-based data at the time of diagnosis for all cases of breast and gynecological cancer occurring in Côte d'Or residents since 1982. The Côte-d'Or is one of the eight French departments in the region of Burgundy Franche-Comté, in northeast France. Its prefecture, Dijon, is also the regional capital. The department's economic activity is 70% tertiary, 25% industry and 5% agriculture. Previous studies have been published using data from the French Côte d'Or Breast and Gynaecologic Cancer Registry [9,10]. Female BC survivors, aged 45 and younger at the time of diagnosis, diagnosed with non-metastatic BC between 1st January 2006 and 31st December 2015 were identified. Patients who died or relapsed before January 2019 were excluded. In February 2019, eligible participants were sent a study information pack by post that included an information letter, the study questionnaires and a stamped return envelope. Patient's referring physicians were provided with information about the study and were informed that their patients would be approached for participation. For patients who did not respond within one month, a reminder was sent.
Ethics approval: this study was performed in accordance with the declaration of Helsinki. The study was approved by the French national data protection authority (CNIL-MR003 N°1989764-v0) and by the Committee for the Protection of Persons South-East I (2018-A03431-54).

Outcome Variables
The main outcome of this study was HRQoL, as assessed by the validated Medical Outcome Study 12-item Short Form health survey questionnaire (SF-12) [11,12]. Through its 12 items, this questionnaire generates eight scales: physical functioning, role physical, bodily pain, role emotional, vitality, social functioning, mental health and general health. All scales were scored according to the standard scoring method of the SF-12 scoring manual. Each score ranges from 0 to 100, with higher scores representing a better level of HRQoL.

Predictor Variables
The Hospital Anxiety and Depression Scale (HADS) questionnaire, validated and adapted in French by Lepine et al. [13] was used to detect anxiety and depressive disorders. This scale has 14 items (7 each for anxiety and depression), all rated from 0 to 3. Total scores range from 0 to 21, and a subscale score of 11 or more indicates presence of anxiety or depression.
Social support was assessed by Sarason's social support questionnaire (SSQ6), validated and adapted in French by Rascle et al. [14]. This 6-item questionnaire measures the availability of social support and the satisfaction with the perceived support. Availability scores range from 0 to 54, and satisfaction scores range from 6 to 36. A higher satisfaction score represents better perceived social support. Scores were categorized into 2 classes, using the respective median value.
Socio-economic deprivation was assessed using the French Evaluation de le Précarité et des Inégalités de santé pour les Centres d'Examen de Santé (EPICES) [15]. This questionnaire, developed specially for the French context, contains 11 items that take into account the overall living conditions and generate an overall deprivation score. Scores vary from 0 to 100, and allow classification of patients as deprived or not deprived (>30 and ≤30, respectively).
The Female Sexual Function Index (FSFI) is a self-administrated questionnaire specific to sexual function in women. It was developed by Raymond Rosen and has been validated in French [16,17]. Through its 19 items, it explores six scales (desire, excitement, lubrication, orgasm, satisfaction and pain) of sexual function. Global score ranges from 2 to 36; an overall score <26.5 indicates sexual dysfunction. For each scale, a score <3.9 is considered as a deterioration on that scale.
Fertility concerns after BC were assessed using a specific questionnaire, developed in conjunction with clinicians and surgeons. Data collected included the number of pregnancies before and after diagnosis, information on treatment effects and fertility preservation before treatment, fertility preservation techniques, adoption, number of abortions and number of spontaneous miscarriages after treatment end.
Professional reinsertion was assessed using another study-specific questionnaire developed in conjunction with sociologists and psychologists. Data collected were problems obtaining loans, income since diagnosis, ability to work (after treatment and at the time of survey), impact of cancer and perceived discrimination in professional life.
Patient and tumor characteristics, including age at diagnosis (categorized as ≤35 and >35 years), age at the time of the survey (categorized as ≤45 and >45 years), Charlson's comorbidity index, tumor stage, tumor grade, hormone status, human epidermal growth factor receptor 2 (HER2) status and treatments were extracted from the Côte d'Or Breast and Gynaecologic Cancer Registry database. Time since diagnosis was categorized in two classes according to the median (≤86 and >86 months). body mass index (BMI) was classified as underweight and normal weight (BMI ≤25 kg/m 2 ) and overweight (BMI >25 kg/m 2 ). Tumor stage was categorized according to the 8 th edition of the Tumor Nodes Metastasis (TNM)-American Joint Commission of Cancer (AJCC) classification [18].

Statistical Analysis
We compared clinical characteristics and treatments between respondents and non-respondents using the chi-square or Fischer's exact test for categorical variables and the Mann-Whitney test for continuous variables. HRQoL, anxiety and depression, social support, deprivation and sexual function scores were generated, categorized and described, in addition to the other quantitative variables as mean (standard deviation, SD) or median (range). Clinical and social characteristics, treatment and all qualitative variables are described as number and percentage. A mixed regression model was built to identify the determinants of the 8 domains of HRQoL. The variables eligible for multivariate analysis were those with a p value < 0.10 by univariate analysis (for the eight dimensions of SF-12). Correlations and interactions were tested for eligible variables. Results are reported as multivariate analysis coefficients, SDs and p values.
Bonferroni's correction was used to adjust the α-risk in the eight multivariate models (α' = α/n with n corresponding to the number of comparisons made). The significance level for the multivariate analyses was therefore set at p < 0.00625.
All analyses were performed using SAS software version 9.4 (SAS Institute Inc., Cary, NC, USA).

Results
Four hundred and thirty-one patients with BC were eligible for this study. For 23 of these, the return address was no longer in use. The questionnaire was thus mailed to 408 participants, of whom 218 completed the questionnaire (response rate 53.4%). The details are shown in Figure 1. Respondents and non-respondents did not differ significantly in terms of clinical characteristics or treatments: age at diagnosis (p = 0.0490); age at time of survey (p = 0.1015); time since diagnosis (p = 0.7607); AJCC stage (p = 0.2673); tumor grade (p = 0.3391); hormone receptor status (p = 0.1408); HER2 status (p = 0.5709); tumor triple negative status (p = 0.2479); menopausal status at diagnosis (p = 0.8060); Charlson comorbidity index (p = 0.2336); chemotherapy (p = 0.1477); radiotherapy (p = 0.4795); endocrine therapy (p = 0.5772). The details of comparisons between respondents and nonrespondents are shown in Table S1.

Demographic and Clinical Characteristics of Participants
Mean age of study participants was 40.1 (SD = 4.4) years at the time of diagnosis and 47.4 (SD = 5.1) at the time of the survey. Mean BMI was 24.3 (SD = 4.5). Median time since diagnosis was 86 months (range, . At the time of diagnosis, 90.3% of women were married or living maritally. This proportion decreased to 60.9% at the time of survey. Other main characteristics were AJCC stage 1 (42%), no comorbidities (90%), menopaused at time of survey (53%), no deprivation (81%) and employed at the time of the survey (87%). All patients underwent surgery and the majority were treated by chemotherapy (77%), radiotherapy (85%) and endocrine therapy (71%). The demographic and clinical characteristics of the participants are shown in Table 1.

HRQoL Scores
The highest average score was in the physical functioning scale (80.8), and the lowest was in vitality (50.7). There were less than 3% of missing values in each of SF-12 dimensions (see Table 2). a : Scores range from 0 to 100 with higher scores representing better HRQoL. b : Global score ranges from 2 to 36; an overall score <26.5 corresponds to sexual dysfunction. For each scale, a score <3.9 is considered as an alteration on that scale. c : Availability scores range from 0 to 54 and satisfaction scores range from 6 to 36. A higher social support satisfaction score represents better perceived social support. d : Both the anxiety and depression subscores range from 0 to 21, with a score of 11 or higher indicating the probable presence of mood disorder.

Sexual Function Scores
Mean global FSFI score was 22.1 (SD = 10.5). Using the threshold of 26.5 to define the presence of sexual dysfunction, approximately 55% of women reported sexual dysfunction. Moreover, a deterioration was seen for each subscale (desire, arousal, pain, lubrication, orgasm), except satisfaction (see Table 2).

Social Support Scores
The median social support availability score was 19 (range, 0-54) and the median social support satisfaction score was 31 (range, 6-36) (see Table 2). A higher social support satisfaction score represents better perceived social support.

Anxiety and Depression Scores
Using the threshold of 11 to define the presence of mood disorders, 29% of women had anxiety, and less than 10% had depression (see Table 2).

Fertility Data and Concerns
Before treatment, 65.1% of women had regular menstrual cycles. This rate decreased significantly after treatment to 17%. Forty-nine (22.8%) women had no menstrual cycles before treatment, and this increased to 121 (57.1%) after treatment. Seventy women (33%) reported that they did not receive information before treatment about the impact of cancer treatment on fertility and ovarian function, and 150 (72%) reported that they did not receive information about fertility preservation. Among these, 55 (38%) would have liked to have been informed.
Eighty-five percent of the study participants already had children at the time of diagnosis. Twenty-one (9.8%) had a pregnancy project at time of diagnosis and 66 women (33.2%) gave up a pregnancy project after the diagnosis. Three out of these 21 women had a medically assisted procreation (MAP) consultation before treatment, of whom two agreed with the proposed fertility preservation and one woman became pregnant with MAP after treatment. Two of these 21 women had a spontaneous pregnancy after treatment. The fertility data of the study population are shown in Table 4.

Professional Reinsertion
The full details of professional reinsertion are shown in Table 5. Sixty women (27%) declared that their income had decreased since diagnosis, and 154 (70%) patients had a bank loan in progress. Among 62 women who had sought a home loan since diagnosis, 47 (81%) reported difficulties (exclusion and/or increased insurance premium and refusal) with insurance. Eighty-two women (38%) reported a negative impact of cancer on their professional life and 160 women (73%) reported a decreased ability to work after treatment and at the time of the survey (59%). The main reason for the reduced ability to work was fatigue in 84% of women at the end of treatment, and 75% at the time of the survey. Thirty-seven percent of women reported the occurrence of one of the following events: retirement, stopped working, made redundant, bankruptcy, sale or cessation of an independent professional activity, resignation, different position and transfer within the same company; among whom 60% specified that the events occurred due to BC.

Discussion
This population-based study assessed the medical and socioeconomic determinants of HRQoL among young women with BC identified through the French Côte d'Or Breast and Gynaecologic Cancer Registry. One of the main strengths of this study was the use of a specialized registry database, which has the advantage of being representative of regionally treated patients, enabling us to assess long-term HRQoL. We also used validated instruments to assess HRQoL and psychological outcomes. Moreover, this study encompassed all aspects of post-cancer life in young women with BC (HRQoL, fertility, sexuality, professional reintegration).
The response rate (53.4%) in this survey was similar to that of previous population-based studies in this geographical area [19][20][21]. Indeed, Chu et al. and Dialla et al. reported a response rate of 59% and 62%, respectively, in studies including women of all ages at diagnosis of BC [20,21]. There was no significant difference between respondents and non-respondents in terms of clinical characteristics and treatments in our study, and therefore, no potential selection bias in our results.
The limitations of this study included the cross-sectional design. Indeed, the time since diagnosis ranged from 36 to 155 months in our study, with a median time since diagnosis of 86 months. This raises concerns about recall bias, given the questions about fertility and return to work events at diagnosis or during the time of treatment.
Our results showed that anxiety, depression, social support satisfaction, deprivation, comorbidities and menopause were significant determinants of HRQoL for long-term young BC survivors, as may also be the case in a population of young women without BC [22][23][24][25].
In this study, approximately half of the women had sexual dysfunction. Cobo-Cuenca et al. and Abril-Requena et al. also found similar results in a population of Spanish women with BC [26,27]. Sexual function is an important component of HRQoL among BC survivors. The effects of BC on sexuality depend on treatment, disease severity and how patients experienced their relationship and sexuality before cancer [28,29].
In our study, the participants reported disturbed menstrual cycles after treatment. This could be attributable to the side effects of BC treatment on ovarian function, such as adjuvant chemotherapy [8]. Jacobson et al. reported similar results in a population of women with BC treated by chemotherapy with or without radiotherapy in the United States [30]. We noted that among women who did not receive information about fertility preservation, more than a third would have liked to have been informed. This underlines the unmet need for fertility preservation information among this age group, as shown by our study. Young women need access to high-quality health information to support their involvement in medical decision-making concerning fertility preservation [31][32][33]. These results may be useful for clinical practice, in terms of counseling on fertility preservation as part of BC treatment. The very low rate of access to fertility preservation observed in our study should be interpreted in light of the period of diagnosis. Today, fertility preservation is accessible to larger numbers. Few women became pregnant after treatment in our study. Anderson et al. found that the chance of achieving a first pregnancy was lower for women >5 years after diagnosis of all cancer types, with a marked reduction in women with BC [34]. Nevertheless, we cannot rule out the possibility that the low number of pregnancies after treatment may also depend on the structure of the questionnaire used or some unexplored specificity of the population under study. Indeed, in our study, few women were interested in having children after diagnosis, and for that reason, the number of pregnancies and miscarriages were indeed very low.
Another important finding was that for half of the women in our study, their income was unchanged since the BC diagnosis. Saito et al. found a lower rate than in the present study [35]. One explanation could be that approximately 50% of our sample had a higher level of education. However, Jensen et al. found that, overall, after seven years, BC did not have any effect on income but the negative effect of BC on income lasted longer among women with a higher educational level [36]. In our study, about one-third of women with BC reported a negative impact of BC on their professional life. These results are consistent with previous studies on the influence of cancer on work-related issues among Japanese BC survivors aged 20 years and older and Korean BC survivors at working age [35,37]. The women in our study also reported a decreased ability to work after treatment, as well as difficulties obtaining loans. In women with BC, the main reason for the impaired ability to work was fatigue, both before (84%) and after treatment (75%). One explanation for this reduced ability to work due to fatigue in women with BC might be the treatment strategies [38]. Abrahams et al. found that cancer-related fatigue was reported in up to 90% of persons with cancer during adjuvant treatment [39]. Moreover, Jones et al. reported the persistence of fatigue up to 6 years post-treatment in approximately one-third of cancer survivors [40].

Conclusions
In conclusion, the results of this study show that the main determinants of HRQoL in long-term young BC survivors are anxiety, depression, social deprivation, social support satisfaction and menopausal status. Other main issues highlighted by this study are the negative impact of BC on professional reintegration and sexual function, the unmet need for information about the impact of cancer treatment on fertility, and for information about fertility preservation. Specific interventions in this population should therefore focus on the promotion of professional reintegration and information about the impact of cancer treatment on fertility, as well as fertility preservation.