Sexual dysfunction and reproductive concerns in young women with breast cancer: Type, prevalence, and predictors of problems

Abstract Objective A dearth of studies focusing on young women (<40 years) with breast cancer have hampered the understanding of the type, prevalence, and predictors of sexual dysfunction and reproductive concerns in this population. Methods Data were collected from 181 women (response rate = 60%) diagnosed with breast cancer approximately 2 years previously (age 21‐39) using the Swedish National Quality Registry for Breast Cancer and a survey including standardized measures of sexual dysfunction, reproductive concerns, body image, and health‐related quality of life. Multivariable logistic binary regression analyses were used to identify predictors of sexual dysfunction and reproductive concerns. Results Sexual dysfunction in at least one domain was reported by 68% of the women, and a high level of reproductive concerns in at least one dimension was reported by 58%. Model results showed that current endocrine treatment was a significant predictor of dysfunction related to lubrication (OR 3.8, 95% CI 1.2‐12.1) and vaginal discomfort (OR 8.7, 95% CI 1.5‐51.5). Negative body image was related to satisfaction with sex life (OR 1.1, 95% CI 1.0‐1.2). A high level of reproductive concerns was predicted by a wish for (additional) children in the future (OR 3.4, 95% CI 1.1‐10.2) and by previous chemotherapy (OR 2.5, 95% CI 1.1‐5.9). Conclusions Sexual dysfunction and reproductive concerns are common in young women with breast cancer. Current endocrine treatment, previous chemotherapy, a negative body image, and a wish for children in the future predict higher level of problems.


| INTRODUCTION
Women diagnosed with breast cancer at a young age face unique challenges and demands. First, young age at diagnosis (<40 years) is linked to genetically more aggressive tumors, 1 poorer prognosis with increased mortality, and more extensive treatments. 2 Second, a diagnosis of breast cancer during one's reproductive years may interfere with important life goals such as building intimate relationships and having children. 3 Also, young women may be at particular risk of sexual problems due to a higher vulnerability to hormonal changes caused by cancer treatment and more concerns about body image after, eg, breast cancer surgery. 4,5 Few studies have however investigated these important issues, resulting in a lack of knowledge regarding sexual function and reproductive concerns in young women with breast cancer.
Common breast cancer treatments such as chemotherapy and endocrine treatments may have a negative impact on fertility. Chemotherapy directly induces a risk of infertility via temporary or permanent ovarian failure and amenorrhea. 6,7 The dominating endocrine treatment used in this age group (tamoxifen) on the other hand is mainly indirectly linked to inability to conceive due to its feto-toxicity, imposing women to avoid pregnancy during this often lengthy treatment. 8 Reproductive concerns in the context of cancer extend beyond the biological fertility potential and include concerns about recurrence, living long enough to raise children, discussing fertility problems with a partner, acceptance of possible infertility, and concerns regarding the child's health. 9,10 This multidimensional concept was developed based on young female survivors' identification of important aspects related to reproduction and thus includes a range of concerns related to fertility and parenthood after cancer. 9 Reproductive concerns have been associated with decreased quality of life (QoL) 3,11 and long-term depressive symptoms in women with cancer. 12 A wish for children, low number of prior pregnancies, prior difficulty conceiving, and being nulliparous at diagnosis have been reported to increase the risk of high levels of reproductive concerns. 10,12 Sexual dysfunction, such as a reduction in desire, lubrication difficulties, and vaginal pain and discomfort, has been reported by women with breast cancer. 4,[13][14][15] These symptoms have in previous studies been related to a premature menopause induced by chemotherapy, which can be transient or permanent. 4,15 Results regarding the effects of endocrine treatment on sexual function have been somewhat contentious 15 with some studies reporting no clear relationship with sexual dysfunction, [16][17][18] whilst others have reported that women on endocrine treatment complain about pain, burning or discomfort during intercourse, vaginal tightness, and hot flashes. [19][20][21] Recent evidence suggests ovarian suppression, which is achieved with GNRH analogues, to be particularly related to sexual dysfunction, whereas tamoxifen alone may not be related to these issues. 22,23 Importantly, few studies have examined sexual problems exclusively in young women (<40 years) with breast cancer.
Both biological factors (including hormonal alterations, pain, and fatigue) and psychological factors (such as negative body image, depression, and anxiety) have been suggested as mechanisms involved in sexual dysfunction in women with breast cancer (eg, the biopsychosocial model by Bober and Sanchez Varela, 2012). Negative body image has been reported to mediate the relationship between mastectomy and low interest in sexual activities. 4 Similar results have been reported for young adults (<40 years) with different types of cancers where a negative perception of one's physical appearance was shown to predict sexual problems. 24 Canada and Schover (2012) have furthermore reported that women who view themselves as infertile experience lower sexual satisfaction than women who believe they have normal fertility, pointing to the potential intricate interdependence between these issues. 25 The overall aim of the current study was to investigate sexual dysfunction and reproductive concerns in women under the age of 40 at breast cancer diagnosis. The study also aimed to identify predictors of high levels of problems and the potential interdependence between sexual dysfunction and reproductive concerns.

| Participants and procedure
Participants were identified using the Swedish National Quality Registry for Breast Cancer which is a high-quality registry with almost complete coverage. 26 Identification criteria included women diagnosed with invasive breast cancer at the age of 18 to 39 in Sweden Information about the study was sent by post to potential participants together with a survey and a pre-paid envelope for questionnaire return. Two reminders were sent to non-responders.
By responding to the survey, participants consented to participate in the study. Ethical approval was obtained by the Regional Ethical

| Clinical variables
Clinical data obtained from the registry included date of diagnosis, distant metastases, planned adjuvant cancer treatment (chemotherapy, radiation therapy, endocrine treatment, targeted therapy), and type of surgery (breast conserving vs mastectomy). Information about current cancer treatment, fertility preservation, and menstruation status was collected in the survey.

| Socio-demographic variables
Study specific questions were used to assess socio-demographic information including birth country, education, employment, family situation (partner, children), and wish for (additional) children.

| Sexual function
Sexual function was assessed using the Patient-Reported Outcomes Measurement Information System® Sexual Function and Satisfaction measure version 2.0 (SexFS). 27 The following five domains were selected: vaginal lubrication (two items), vaginal discomfort (four items), vulvar discomfort-clitoral (one item), vulvar discomfort-labial (1 item), and satisfaction with sex life (two items). Scores were transformed to a T-score metric with 50 corresponding to the mean of the population of US adults who have been sexually active in the past 30 days. 27 We considered one standard deviation (10 points on the T-scale) under/above 50 as indicative of dysfunction. For "Satisfaction with sex life" and "Lubrication," lower scores indicate more problems and in the three discomfort domains higher scores indicate more problems. One question concerning reasons for not having had sexual activity with a partner during the past 30 days was also included. The SexFS has shown adequate content and construct validity and test-retest reliability. 27,28 We translated the SexFS-v2 into Swedish and linguistically validated it in accordance with the procedure developed by FACITrans and PROMIS. 29

| Reproductive concerns
Reproductive concerns were assessed using the Reproductive Concerns After Cancer scale (RCAC). 9 The RCAC is a multidimensional scale assessing a range of reproductive and parenthood concerns developed and evaluated for young adult female cancer survivors. 9 The scale encompasses 18 items scored on a five-point scale ranging from 1 = "Strongly disagree" to 5 = "Strongly agree", and includes the six dimensions: "Fertility potential," "Partner disclosure," "Child's health," "Personal health," "Acceptance," and "Becoming pregnant." For each dimension, a mean value of >4 indicates a high level of reproductive concern. 9 The RCAC has demonstrated satisfactory internal consistency and construct validity. 30 The scale was independently translated into Swedish by two bilingual researchers, evaluated by two lay panels (n = 7) and one patient panel (n = 12), and in cognitive interviews with three young cancer patients.

| Body image
Body image was assessed using the Body Image Scale (BIS) which assesses body image discomfort associated with cancer. 31 The BIS consists of 10 items, and responses are given on a 4-point scale, from "not at all" (0) to "very much" (3) with higher scores indicating a positive body image. The BIS has shown high test-retest reliability and internal consistency (Cronbach's Alpha 0.93) in a sample of cancer patients. 31 Cronbach's Alpha for the BIS in the current study was 0.91.

| Health-related quality of life
Health-related QoL was measured using the EORTC QLQ-C30 version 3.0 (QLQ-30-v3.0), which is a 30-item questionnaire developed to assess the QoL of cancer patients. 32

| Statistical analyses
Fisher's exact test was used to analyze differences between responders and non-responders. Prevalence of sexual dysfunction and reproductive concerns was calculated using descriptive statistics.
The relationships between the domains of the SexFS and the dimensions of the RCAC were analyzed by Pearson's correlation coefficient.
Predictors for sexual dysfunction and reproductive concerns were identified using multivariable binary logistic regression with effects expressed as odds ratios (OR) using 95% confidence intervals (CI).

| Participants
Of the 301 individuals matching the inclusion criteria, 181 returned the questionnaire representing a response rate of 60%. There were no statistically significant differences between responders and nonresponders with regard to age or previous treatment modalities. Please see Table 1 for demographics and clinical variables.

| Sexual function
Sexual dysfunction in at least one domain was reported by 68%, and dysfunction in at least two domains was reported by 38% ( Table 2).
The most common problem was vulvar discomfort of the labia, reported by 40%. The most common reasons why participants had not had sex with a partner during the past 30 days were "Feeling unattractive" (51%), "Too tired" (49%), and "Dryness or pain in the vagina" (36%) ( Table 3).

| Reproductive concerns
At least one dimension of high level of reproductive concerns was reported by 58%, and at least two dimensions of high levels were reported by 22% ( Table 2). The most common areas of concern were "Child's health" and "Personal health," reported by 38% and 21%, respectively.

| Relation between sexual function and reproductive concerns
Correlations between the domains of sexual function and dimensions of reproductive concerns were small, ranging from 0.01 to −0.21.

| Predictors of sexual dysfunction and reproductive concerns
Model results showed that endocrine treatment was a significant predictor of dysfunction related to lubrication (OR 3.8, 95% CI 1.  (Table 4).

| DISCUSSION
The current study shows that sexual problems and reproductive concerns are common approximately 2 years post diagnosis in young women diagnosed with breast cancer. Two in three women reported at least one domain of sexual dysfunction. This is a much higher number compared with women in the general population where 10% report having sexual problem. 35 The prevalence of problems in this study is also higher compared with older women with breast cancer. 36,37 Our results underscore that women with breast cancer face increased risk of sexual dysfunction, and furthermore, that younger women endorse even more problems than older women with breast cancer.
Predictors of sexual dysfunction varied between the more biological/physical aspects, such as vaginal discomfort and problems with lubrication, and the psycho-social aspects, such as satisfaction with sex life. Endocrine treatment turned out as a significant predictor of both vaginal discomfort and lubrication dysfunction, which is an important finding. Furthermore, negative body image was a significant predictor of low satisfaction with sex life. This result relates to "Feeling unattractive" being the most common reason not to have had sex with a partner. Negative body image thus seems to be a concept of relevance to sexual function in young women with breast cancer and should be considered a target for interventions aiming at improving sexual health in this population.
A high level of reproductive concerns (at least one domain) was reported by 58% of the women which is comparable to previous findings (eg, Ganz 6 ). The most common areas of concern were "Child health" and "Personal health." These figures however diverse some from previous findings reporting "Fertility potential" to be a more common concern. 30 Our results should be seen in the context of the high degree of participants who already had children (77%), and the rather low number of participants who wished for (additional) children in the future (36%) which implies a lower level of concerns regarding ability to become pregnant. Still, the overall prevalence of reproductive concerns in our study is high pointing to the relevance of this concept also for women who already are mothers.
The predictor of reproductive concerns with the highest OR (3.5) was "a wish for (additional) children." This is an expected finding that supports previous research in women with breast cancer 10 and underscores the relevance of inquiring about patients' reproductive intentions in connection with oncological treatment as well as after end of initial treatment and surgery. Chemotherapy was also a significant predictor of reproductive concerns, which may reflect participants' awareness of the negative impact chemotherapy has on fertility. 38 There was a weak relationship between sexual dysfunction and reproductive concerns, and few shared predictors, suggesting separate mechanisms to be involved in these issues. Reproductive concerns

| Clinical implications
The current study shows that sexual dysfunction and reproductive