Breast cancer and its treatment can cause physical (eg, loss of body part and vaginal dryness), psychological (eg, stress and body dissatisfaction), and relational concerns (eg, restricted communication and relational discord) that can lead to problems with sexual distress and dysfunction [1,2]. Therefore, approximately 70% of survivors of breast cancer report clinically relevant symptoms of sexual distress and dysfunction [2-5], which they rank among their most distressing cancer-related problems [6,7]. These sexual concerns are particularly severe among women who were premenopausal at diagnosis, as treatments can induce menopause with more severe symptoms [8-10]; take adjuvant endocrine therapy (AET; tamoxifen or aromatase inhibitors) as it blocks estrogen [11-13]; have comorbid depression and anxiety [14-16]; and have newer relationships or are generally more dissatisfied in their relationship [5,17-19]. Unlike psychological or informational needs that tend to remit naturally, survivors’ unmet sexual health needs increase over time [20]. Given the prevalence and profound impacts of cancer on sexual health, oncology care standards recommend that all survivors receive information, assessment, and care for sexual symptoms [21,22]. Despite these recommendations, <1 in 3 survivors of breast cancer recall ever discussing sexual health with their cancer care team [23]. Thus, there is an urgent need to develop highly scalable interventions to support survivors’ sexual health.

Commonly cited reasons for the lack of comprehensive sexual health care within oncology include limited access to specialty services, provider and patient discomfort in discussing sexual health, and appointment time constraints [24,25]. Delivering fully automated care via the internet can help alleviate these barriers to care by providing evidence-based education and behavioral strategies privately and on demand, anywhere an internet connection exists [26-28]. Comprehensive sexual health interventions have been demonstrated as effective when delivered remotely; however, the substantial time requirements of these multicomponent programs have been a leading barrier to enrolling and retaining survivors in care [28-30]. Maximizing the population-wide impact of sexual health interventions for survivors of breast cancer will require minimizing intervention requirements, without compromising the overall intervention efficacy. More efficient interventions may attract and retain more survivors to benefit from care.

A major gap in the literature regarding the efficacy of individual sexual health components has limited the development of more efficient sexual health treatments for survivors of breast cancer [29]. Because of the complex biopsychosocial nature of sexual health, interventions to improve sexual health after cancer typically include multiple therapeutic components. Leading clinical oncology organizations recommend that women are educated about the effects of cancer on their sexual response cycle, as well as interventions to improve intimacy and relationship concerns [21,31]. Communication skills training is critical to help survivors overcome the barriers of stigma to advocate for their sexual health needs [1]. Because interventions tested in this area to date have tended to test multiple components packaged together and in differing combinations across trials, it has been impossible to differentiate which components work, establish why those components work, or identify for whom different components work best. Addressing these gaps will help promote the development of more efficient, effective, and personalized interventions.

The overarching goal of our research is to develop a highly scalable and efficient breast cancer–related sexual health intervention with a strong potential for population-wide impact. Toward that goal, the primary aim of this trial is to identify the combination of the fewest intervention components likely to provide survivors of breast cancer with the greatest sexual health benefit. Intervention components to be tested are (1) level of education about the influence of breast cancer on sexual health, (2) communication skills training for discussing sexual concerns with one’s health care team, (3) communication skills training for discussing sexual concerns with one’s intimate partner, and (4) intimacy promotion skills training. These components, which address the complex biopsychosocial nature of sexual concerns after breast cancer, were selected based on the research team’s prior qualitative and intervention development research [32,33] and are consistent with survivorship care guidelines [21,22]. This aim will be achieved through evaluating the impact of each component, alone and in combination, on survivors’ sexual distress and functioning.

This trial will also evaluate the clinical mechanisms of the intervention components and whether different groups of survivors may need different combinations of intervention components. We hypothesize that the intervention components will influence sexual morbidity via mediators selected based on social cognitive theory [34], specifically, through increased knowledge about sexual concerns and self-efficacy to discuss them, as well as emotional intimacy with one’s partner (see Figure 1 for the trial conceptual model). We also hypothesize that a priori moderators, selected according to clinical and psychosocial characteristics known to influence sexual morbidity in survivors of breast cancer, will influence the components’ efficacy. Achieving these research objectives will improve cancer survivorship care by establishing the first internet intervention for breast cancer–related sexual morbidity that has been optimized for maximum impact, as well as clarifying how intervention components work and for whom they work best.

The study protocol has been reviewed and approved by the National Cancer Institute (NCI) Central Institutional Review Board (CIRB; WF-2202 initially approved on December 1, 2023). Study modifications will be reviewed and approved by the NCI CIRB. Participating study sites and their local institutional review boards will be notified of any modifications. Deidentified data sets used in primary publications will be transferred to the National Clinical Trials Network and NCI Community Oncology Research Program (NCORP) Data Archive in accordance with the agreement between Wake Forest (WF) NCORP Research Base (RB) and NCI. The internet intervention platform hosting the Sexual Health and Intimacy Enhancement (SHINE) intervention is managed by the University of Virginia (UVA) and was designed to support projects that contain protected health information that are subject to compliance with federal and state regulations. Access to data will be in accordance with the Health Care Financing Administration’s Internet Security Policy and the Health Insurance Portability and Accountability (HIPAA) Act of 1996. The database servers and web servers are backed up daily and are protected from threats by regular maintenance and the application of hotfix and security patches when released. Security policies are in place with UVA to ensure that access to database repositories and web application server environments is limited. On completion of the trial, summary results will be submitted to ClinicalTrials.gov in accordance with National Institutes of Health (NIH) policies [35]. No participant identifiers will be published.

During the informed consent process, potential participants are informed that this study aims to determine whether an internet-delivered program can help survivors of breast cancer manage cancer-related sexual concerns. Under a waiver of documentation of consent, participants will provide either signed informed consent or verbal informed consent that is documented by the enrolling research staff member. The NCI CIRB–approved informed consent form will be made available open-access with other study materials. Participants will receive a US $50 e-gift card for completing the 12-week assessment and a US $75 e-gift card for completing the 24-week assessment. On request at the end of the 24-week assessment, participants will be provided access to all the SHINE program components through the end of the grant period.

This factorial trial will enroll 320 adult survivors of breast cancer with sexual concerns to test the effects of 4 sexual health intervention components. The primary trial objective is to determine the optimal breast cancer–related sexual health intervention package. The secondary objective is to examine mediators and moderators of intervention component efficacy, and we will also explore survivors’ intervention engagement and acceptability. This manuscript reports the protocol for the WF-2202 SHINE trial following recommendations from the 2013 SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) [36,37]; Table 1 provides the World Health Organization trial registration data set. The study protocol was revised following the NIH peer review process (see Multimedia Appendix 1 for reviews).

Our study aims will be achieved via a factorial trial within the optimization phase of the multiphase optimization strategy (MOST) framework. The MOST methodological framework directly addresses our goal of optimizing a multicomponent intervention to improve sexual health after breast cancer [39,40]. In an optimization trial, the effects of intervention components are tested independently and in combination, which allows the identification of an efficient intervention package that only includes components shown to improve survivors’ sexual health. Components may also be evaluated to determine whether effects vary systematically across survivors, guiding future treatment tailoring. These insights directly address major research gaps regarding how sexual health intervention components work and for which survivors they work best [29].

In this factorial trial, participants will be randomized to 1 of 16 conditions in a factorial design involving 4 intervention components, each with 2 levels (2⁴; Figure 2). Participants may continue to receive standard care during the trial. The trial will be conducted via the WF NCORP RB, which has 42 affiliated health system sites, each with its own research infrastructure and dedicated research staff to identify, screen, consent, and enroll survivors for this trial. Only 10% of the affiliated sites are connected with an academic medical center, and 25% of sites are safety-net hospitals, serving patient populations that are commonly neglected in intervention development research [41]. The use of this oncology practice–based research network is important because it will both enhance the generalizability of results to diverse survivors treated in community settings and encourage the eventual translation of the optimized intervention into clinical practice. As required by the NCORP trials, the NCI CIRB serves as the institutional review board of record for this trial.

This trial will enroll 320 survivors of breast cancer meeting the following inclusion criteria (see Table 1 for details): (1) history of stage 0 to III breast cancer diagnosis (history of other cancer diagnoses is permitted); (2) ≥12 weeks from last primary cancer treatment (eg, chemotherapy, surgery, or radiation therapy); (3) ≥18 years of age; (4) cisgender female; (5) in an intimate relationship with a person of any sex and gender; (6 and 7) endorse at least 1 bothersome sexual symptom that they attribute to their breast cancer; and (8) willing to receive emails from the study. Survivors will be excluded if they (1) have cancer treatment planned within the study period; (2) cannot read English; (3) do not have reliable internet access (and are not willing to participate in a study tablet loan program); (4) have had a recent episode of serious mental illness; (5) are in current couple, marital, or sex therapy; or (6) are currently pregnant. These eligibility criteria are in keeping with our prior breast cancer–related sexual health intervention research (eg, [42]) and support the evaluation of isolated intervention effects with less risk of contamination or confounding from other interventions or treatments.

All study procedures, namely, recruitment, consenting, assessment, and intervention, can be completed remotely (eg, via the internet; see Figure 3 for a schematic of procedures). Potential participants’ medical records will be screened by research staff at the participating NCORP sites; this process may be initiated by the staff at the site or by a potentially interested participant contacting the site after learning of the trial via social media, other advertisement, or the NCI Clinical Trials page [43] (Figure 3, steps 0-1). Individuals who meet medical eligibility criteria will be contacted (step 2); those who are interested will complete a self-reported web-based screener regarding the remaining eligibility criteria (step 3). This screener will be completed through REDCap (Research Electronic Data Capture; Vanderbilt University), a HIPAA-compliant, web-based survey and research management platform. Individuals not meeting the eligibility criteria will be notified that they are ineligible for the trial, while those who are eligible will be contacted by the NCORP site staff to answer any remaining questions about the trial and obtain informed consent (step 4). Participants who do not have reliable access to the internet via computer, smartphone, or tablet will be offered a cellular data–enabled tablet to use for the full 24-week study period.

After enrollment, participants will be invited to complete the web-based baseline assessment via REDCap (step 5). On completion of the baseline assessment, participants will be automatically randomized to 1 of the 16 study conditions via REDCap (step 6). Block randomization will be used to help maintain balance across conditions, with varying block sizes of 16, 32, and 48 [44,45]. A participant’s randomized condition will not be revealed to the local NCORP study staff; only the UVA research coordinator (who implements participants’ conditions in the SHINE intervention system) and a WF NCORP RB data manager will have access to participants’ randomized condition information. Participants cannot be blinded to their condition. Participants will receive a welcome email directing them to set a password and log into their SHINE program (ie, the set of components assigned to them in their randomized condition; step 7).

After baseline, participants will be asked to complete their SHINE program within the following 12 weeks and to complete follow-up assessments through REDCap at 12 and 24 weeks (steps 8 and 9). A protocol of stepped reminder emails via REDCap and contacts by NCORP site research staff will encourage participants to complete all study assessments.

Intervention components are delivered fully automated as a Core, or lesson, of content. Components (and component levels) to be tested are (1) education about the influence of breast cancer on sexual health, either with limited information in a static web page format in the Sexual Health Essentials-Standard Core or more comprehensive information through an interactive web program in the Sexual Health Essentials-Enhanced Core; (2) communication skills training for discussing sexual concerns with one’s health care team in the Health Care Discussions Core; (3) communication skills training for discussing sexual concerns with one’s intimate partner in the Partner Conversations Core; and (4) intimacy promotion skills training in the Intimacy Insights Core. All participants will receive 1 of 2 Sexual Health Essentials Cores (ie, standard [component level=low] or enhanced [component level=high]) given that survivorship care guidelines recommend that all survivors receive education about the influence of cancer treatment on sexual health [21]. For the 3 remaining components, participants will either receive the Core (component level=on) or not receive the Core (component level=off; see Figure 2 for factorial design and Multimedia Appendix 2 for additional Core details).

The Sexual Health Essentials-Enhanced, Health Care Discussions, Partner Conversations, and Intimacy Enhancement Cores each deliver content as stand-alone, web-based programs. These Cores were developed following the Model for Internet Interventions [46] and user-centered design practices to be highly engaging, using interactive elements, audiovisuals, and tailoring. Cores were developed with a team of software engineers and consultants in user interface, user experience, and instructional design. Core content was refined through iterative feedback from survivors of breast cancer. The Sexual Health Essentials-Standard Core provides education via a traditional web page with no tailoring or interactive elements.

Cores take about 20-45 minutes to complete, which participants may do at their convenience and own pace (ie, Cores do not need to be completed in 1 sitting). Participants must complete their Sexual Health Essentials Core (enhanced or standard) before any remaining Cores in their randomized condition are made available. These remaining Cores may be completed in any order. Completed Cores may be revisited and reviewed as often as desired. While technical support is available from the UVA research coordinator, no clinical support will be provided. All Cores were written to an eighth-grade reading level (Flesch-Kincaid Grade Level) [47] or lower.

Participants will access their SHINE program via a password-protected website by computer, tablet, or smartphone. Participants will be monitored by the UVA research coordinator to ensure that they set up a password and can successfully log into the program. The goal of this monitoring is to ensure that the participants can access the intervention. Participants who do not complete their first log-in within a day of receiving the welcome email will receive daily automated reminder emails from the program. If the participant still has not logged in after 3 automated reminder emails, contacts will escalate to reminders by phone call and personal email by the UVA research coordinator and then by the local NCORP site research staff.

There are also automated email prompts to support participant engagement with the SHINE program after participants have successfully logged into the program. Participants who do not initiate Cores within 3 days of initial access will receive a reminder prompt. All participants will receive weekly progress emails regarding their progress through each of their assigned Cores. After participants complete their assigned SHINE program, email prompts will remind them that they may continue to access their SHINE program and review their Cores as desired.

We will examine survivors’ intervention engagement and acceptability. Means and SDs or frequencies, as appropriate, of user engagement metrics will be reported. Whether log-ins differ by components will be tested using the GLM approach as described for the primary objective analyses. The influence of engagement on the change in sexual morbidity outcomes will also be tested by extending GLM models from the primary objective analyses to include the interaction effects between intervention components and engagement. Users’ ratings of Core usability and satisfaction will also be reported.

Findings will be used to identify a breast cancer–related sexual health intervention package optimized for maximum impact by providing the greatest expected improvement with the fewest (and least-intensive) intervention components. This will be achieved by evaluating which sexual health intervention components meaningfully improve survivors’ sexual health either on their own or in combination with other components. Ensuring that only beneficial components are included in a resulting intervention eliminates unnecessary user effort. Minimizing the time burden to complete the resulting intervention is expected to limit a critical engagement barrier [28,30], permitting more survivors of breast cancer to benefit from this care.

More broadly, the factorial trial design will permit a rigorous evaluation of mechanisms of action for sexual health intervention components and suggest whether certain survivors may need distinct sexual health intervention approaches. These findings from our mediation and moderation analyses will fill a key gap in the literature regarding what specific intervention techniques work and for whom those techniques work best [29]. Furthermore, the results from this optimization trial could accelerate cancer-related sexual health intervention research by demonstrating which therapeutic components may best meet the specific needs, constraints, and characteristics of other target populations [70]. Indeed, the NIH recognizes rigorous testing of the mechanisms of behavioral intervention components as necessary to develop the next generation of more effective and efficient interventions [71].

Delivering the optimized and fully automated intervention via the internet promotes its potential impact through greater accessibility, as internet interventions are scalable and overcome many barriers to sexual health care in standard oncology practice. Although prior internet interventions for cancer-related sexual morbidity tested to date have included care delivered by a clinician [28,72-76], delivering such care without the need for clinician involvement would dramatically increase scalability and reduce long-term costs [77]. The fully automated delivery of care also has the advantage of being private, thereby removing the barrier of stigma related to discussing sex and giving women more control over their access to sexual health care after cancer [26,27,30]. Finally, fully automated interventions can be delivered with complete treatment integrity [78], ensuring each survivor using the program has a consistent experience.

Future research steps are planned to address the limitations of this trial. In this trial, SHINE intervention components are only available in English. To increase the reach of this intervention, future transcreation work with Latina survivors of breast cancer is planned to both translate and culturally adapt the intervention to be appropriate for Spanish-speaking survivors [79-81]. In addition, this intervention only targets survivors of breast cancer and does not have content directed specifically for their partners. Future studies should evaluate whether providing companion educational materials to survivors’ partners may enhance intervention outcomes for couples. Finally, as our factorial trial is part of the optimization phase of the MOST research framework, a follow-on randomized controlled trial of the optimized intervention package will be needed to test the efficacy of this program.

In summary, this novel optimization trial holds significant potential to address the critically undertreated and distressing breast cancer survivorship concern of sexual morbidity. The factorial trial design will begin to identify which sexual health intervention components work, for whom, and how. These data are directly responsive to calls from leaders in cancer control to advance intervention science through systematically testing intervention components and their mechanisms. By identifying the combination of the fewest and least-intensive intervention components that are likely to provide survivors the greatest benefit, this study will result in the first breast cancer–related sexual health internet intervention optimized for maximum population health impact.