In this prospective clinic-based cohort of women with early-stage HR + breast cancer receiving adjuvant endocrine therapy, sexual function problems were common, with 55% of patients reporting at least one sexual function problem during study participation and 45.7% experiencing clinically significant worsening sexual function exceeding the MID compared to baseline. Worsening endocrine symptoms and worsening physical function were associated with worsening sexual function. For every 5-point worsening in Endocrine Symptom Subscale FACT-ES score, participants were 34% more likely to experience a clinically significant worsening in MOS-SP score. For every 4-point worsening in PROMIS physical function score, participants were 8% more likely to experience a clinically significant worsening in MOS-SP score. Worsening of endocrine symptoms and decline in physical function were common, with 53% of patients experiencing at least a 5-point worsening in Endocrine Symptom Subscale FACT-ES score and 36% experiencing at least a 4-point worsening in PROMIS physical function T-score. In addition, participants who had undergone a mastectomy were 45% more likely to experience a clinically significant worsening in MOS-SP score.
Our findings are consistent with prior studies that have demonstrated an association between worsening endocrine symptoms and sexual problems during adjuvant endocrine therapy. Hot flashes and vaginal dryness are among the most common endocrine symptoms patients experience during adjuvant endocrine therapy.[9, 18, 55, 56] In their conceptual framework for predictors of sexual health among breast cancer survivors, Ganz et al identify treatment-related menopausal symptoms, including hot flashes and vaginal dryness, as predictors of sexual health outcomes.[27] Multiple other studies have also identified an association between hot flashes, vaginal dryness, and sexual function problems in this population.[1, 11, 24, 25, 27, 29] Vaginal dryness often leads to dyspareunia, which may cause problems in multiple domains on the MOS-SP, including difficulties relaxing and enjoying sex and difficulty achieving orgasm.[9] The relationship between hot flashes and sexual function problems has not previously been well described; however, hot flashes have been associated with mood disturbance and disruption in sleep, which may in turn lead to sexual function problems.[1, 7, 21, 22, 24, 29, 57, 58] In a recent large cross-sectional study, sleep problems and fatigue were associated with sexual function problems, supporting this hypothesis.[59]
We also found that worsening physical function was associated with worsening sexual function during adjuvant endocrine therapy. The link between poor physical function and sexual function problems has previously been reported, although not consistently; however, prior studies were limited by cross-sectional design.[17, 22, 26, 59] It is possible that physical function limitations are attributable to joint discomfort in the setting of endocrine therapy, which we hypothesize may, in turn, affect multiple domains on the MOS-SP, such as sexual interest and ability to relax and enjoy sex; however, further study is needed to confirm this association and assess the mechanism by which physical function impairment during endocrine therapy impacts sexual function.
Our study also confirmed the previously demonstrated association between prior mastectomy and sexual function problems during adjuvant endocrine therapy.[2, 8, 10, 12, 19] Patients who undergo mastectomy may experience body image concerns that, based on the Ganz framework, predict adverse sexual health outcomes.[8, 10–13, 27]
We found that patients of low SES, defined by residence in a zip code with NP rate > 15%, were less likely to experience worsening sexual function during adjuvant endocrine therapy. The explanation for this finding is unclear and should be interpreted with caution. NP rate is not a precise measure of SES and only a relatively small percentage of our cohort was low SES.[51, 60] Additional research in diverse populations is needed to clarify the association between SES and sexual function problems.
Our study, like others, confirmed that sexual function problems are common during adjuvant endocrine therapy.[1–8] Despite being common and distressing for patients, sexual problems are often under-reported and under-treated in routine clinical care.[2, 28, 30, 31] Approximately 60% of breast cancer patients experiencing a sexual function problem who feel a need for intervention do not consult a healthcare professional.[2] Common patient-reported barriers to accessing support for sexual function problems include embarrassment or discomfort in bringing up sexual concerns.[31] Many patients report a desire for these discussions to be initiated by clinicians, while clinicians may be reluctant to initiate these discussions due to time constraints, lack of knowledge and training, and concerns about causing offense.[31, 61]
Multiple evidence-based interventions have been shown to improve sexual function during adjuvant endocrine therapy.[32–38] Vaginal moisturizers, tablets, suppositories, gels, oils, topical vitamin D or E, and hyaluronic acid can help alleviate vaginal dryness, and lubricants can be used during sexual activity for dyspareunia associated with vaginal dryness.[32–34] Topical lidocaine has also been shown to improve dyspareunia in this population.[36] Local hormonal treatments, including vaginal estrogen or dihydroepiandrosterone (DHEA), can also be used; however, there is some concern about systemic absorption of estrogen, and not all patients and clinicians are comfortable with the use of these products in this setting.[32–34, 38] Additionally, pelvic floor muscle training can improve sexual function in survivors of gynecologic cancers, and vaginal dilators can improve dyspareunia secondary to vaginal atrophy.[32, 33, 37]
Given the availability of evidence-based interventions to address sexual function problems, routine assessment of sexual function in breast cancer patients receiving adjuvant endocrine therapy is critical. Based on the associations we identified, patients who experience worsening endocrine symptoms or worsening physical function during endocrine therapy are at particular risk for worsening sexual function, as are those who have had a mastectomy. The use of PROs during adjuvant endocrine therapy may facilitate monitoring of patients for sexual function problems and may guide clinicians in identifying those at greatest risk for worsening sexual function. Because the extent of symptoms identified by PROs is greater than that reported by clinicians, PROs may be particularly informative in this setting, as both patients and clinicians may otherwise hesitate to initiate discussions about sexual health.[30, 31, 61]
A strength of this study is that we evaluated the association between worsening sexual function and other symptoms from the time of endocrine therapy initiation and throughout five years of therapy rather than at a single time point. Many prior studies evaluating factors associated with sexual function problems in patients with early breast cancer have been retrospective or cross-sectional and, of the few prior prospective studies, most have had much shorter follow-up.[1, 2, 7, 8, 10–12, 17, 19–29, 59] Additional strengths include our real-world population and inclusion of both pre- and post-menopausal women. Finally, we used validated PRO measures assessing a broad range of symptoms common during endocrine therapy and used MIDs to identify changes in scores on PROs that are clinically meaningful.
Our study has several limitations. Few participants received OFS, limiting generalizability of our findings to this population, a group at particular risk for sexual problems.[1, 62] Additionally, our study cohort was predominantly White and of high SES. Some participants may have also been on medications that can affect sexual function, such as selective serotonin reuptake inhibitors, and this was not accounted for as we did not collect data on specific concomitant medications. In addition, the proportion of participants who completed each PRO measure declined over time, and participants with complete data during the first 24 months reported slightly less fatigue and better physical function at baseline than those with missing measures, thus it is possible that missing data could have resulted in an underestimation of the strength of the association of these symptoms with worsening sexual function. Additionally, on the MOS-SP measure, respondents do not have the option to report sexual activity status; instead, those who are not sexually active indicate “not applicable” and this is recoded as “not a problem,” which may underestimate the prevalence of sexual function problems.[1, 42] Future studies investigating sexual problems in this population should include an assessment of sexual activity. Furthermore, the MOS-SP and the Endocrine Symptom Subscale of the FACT-ES questionnaires both contain an item regarding sexual interest; however, in a sensitivity analysis that excluded this item when calculating the Endocrine Symptom Subscale FACT-ES score, our findings remained robust. Finally, given that we evaluated the association of worsening symptoms by at least the MID at any time during adjuvant endocrine therapy with co-occurring worsening of sexual function during this timeframe, we were not able to demonstrate causality.
In conclusion, in this prospective clinic-based cohort of women with early-stage HR + breast cancer receiving adjuvant endocrine therapy, we confirmed that sexual function problems are common. Worsening endocrine symptoms, worsening physical function, and prior mastectomy are associated with worsening of sexual function. Routine assessment for symptoms including sexual function problems in these patients using PROs may reduce under-detection and identify patients who can benefit from interventions to reduce distressing sexual symptoms.