Improving Adherence to Adjuvant Hormonal Therapy Among Disadvantaged Women Diagnosed with Breast Cancer in South Carolina: Proposal for a Multimethod Study

Background Current clinical guidelines recommend that hormone receptor–positive breast cancer survivors take adjuvant hormonal therapy (AHT) for 5 to 10 years, following the end of definitive treatment. However, fewer than half of patients adhere to the guidelines, and suboptimal adherence to AHT is associated with an increased risk of breast cancer mortality. Research has extensively documented sociodemographic and disease-specific factors associated with adherence to AHT, but very little evidence exists on behavioral factors (eg, knowledge, patient-provider communication) that can be modified and targeted by interventions. Objective The goal of this study is to develop and test a theory-based, multilevel intervention to improve adherence to AHT among breast cancer survivors from racially and socioeconomically disadvantaged backgrounds (eg, Medicaid-insured). The specific aims are to (1) explore multilevel (eg, patient, health care system) factors that influence adherence to AHT; (2) develop a theory-based, multilevel intervention to improve adherence to AHT; and (3) pilot test and evaluate the intervention developed in Aim 2. Methods For Aim 1, we will recruit breast cancer survivors and health care professionals to participate in semistructured interviews to gain their perspectives about barriers and facilitators to AHT use. We will conduct a directed content analysis of the Aim 1 qualitative interview data. For Aim 2, we will integrate Aim 1 findings and current literature into the design of a multilevel intervention using an Intervention Mapping approach. For Aim 3, we will recruit Medicaid-insured breast cancer survivors to assess the feasibility of the pilot intervention. Results From May 2016 to July 2018, we completed interviews with 19 breast cancer survivors and 23 health care professionals in South Carolina. We will conduct a directed content analysis of the qualitative interview data. Results from this analysis will be used, in combination with current literature, to design (Aim 2) and pilot test a theory-based multilevel intervention (Aim 3) in Summer 2021. Results of the pilot are expected for Fall 2021. Conclusions This study will provide a deeper understanding of how to improve adherence to AHT, using a novel and multilevel approach, among socioeconomically disadvantaged breast cancer survivors who often experience disproportionate breast cancer mortality. International Registered Report Identifier (IRRID) DERR1-10.2196/17742

NCI-I FELDER, T extensively documented socio-demographic and disease-specific factors associated with adherence to AHT, but very little evidence exists on behavioral factors that can be modified (e.g., knowledge, patientprovider communication) and targeted by interventions. Identifying these modifiable intervention targets is critical to the development of efficacious strategies to improve adherence. Therefore, the overall goal of this study is to develop and test a theory-based, multi-level intervention to improve adherence to AHT among breast cancer survivors from racial and socioeconomically-disadvantaged backgrounds. The specific aims of this study are to: 1) explore multi-level (e.g., patient, healthcare system) factors that influence adherence to AHT; 2) develop a theory-based, multi-level intervention to improve adherence to AHT; and 3) pilot and evaluate a theory-based, multi-level intervention. The proposed studies will provide training, mentorship, and research experience that will provide the foundation for my career as an independent investigator committed to improving health outcomes and eliminating disparities among the growing cancer survivor population.

PUBLIC HEALTH RELEVANCE:
The proposed research will address a significant gap in our knowledge of the modifiable factors that influence breast cancer survivors' adherence to adjuvant hormonal therapy (AHT), and will result in the development of a theory-based, multi-level intervention that may improve AHT adherence among racial/ethnic and socio-economically-disadvantaged (eg, Medicaid-insured) survivors who experience excess rates of breast cancer mortality. This intervention will be the first of its kind and has the potential to improve AHT adherence in an underserved population known for poor AHT adherence rates and for being disproportionately affected by breast cancer disparities.
The written critiques of individual reviewers are provided in essentially unedited form in this section. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The "Resume and Summary of Discussion" section above summarizes the final opinions of the committee. This candidate proposes to develop and test a multi-level intervention to increase AHT adherence among disadvantaged patients. The candidate has considerable training in social policy, behavioral sciences, and outcome sciences. The candidate's limited record of first author research publications is a concern, as the plan for increased productivity is not adequate given other responsibilities and training. The career development plan is multidimensional and includes relevant training experiences, but the primary mentors are largely absent from training plan. There is minimal institutional support for the candidate without significant external support. An intervention like the one proposed may increase adherence, but the proposed data collection is inadequate. From the specific aims it is not clear whether the proposal is for disadvantaged populations or minorities; as such this research appears to overlap directly with Dr. Heiney"s research and this is not adequately addressed. Adequate details of the data analyses are not provided, beyond mention of the software package. All research aims are dependent and this is also not adequately addressed. A letter attesting to the eligibility of the candidate is missing.

Strengths
Candidate has MSW degree in Social policy and evaluation, PhD degree in Behavioral sciences, and several years of postdoctoral experience in outcomes sciences.
Currently research assistant professor in College of Nursing at USC Columbia.
Several research publications to date in the general area of disparities and cancer.

Weaknesses
Limited first author research publications since 2011, despite full time research support. Current funding is unrelated to cancer or disadvantaged populations.
Only one publication with previous postdoctoral advisor.

Strengths
Proposed career development does built on previous training and educational experience.
Plan does include interactions with mentors, didactic training, and training for professional success.

Weaknesses
The mentoring team is very large, and individuals with the most input to the training plan and the most relevant research background are not primary mentors.
Some of the activities/timeline are not well motivated. For example, research aim 1 is scheduled for year 1 at which time the candidate will have one short course in qualitative data, but plans to develop an interview guide, coding, analysis, and interpretation of interview data with only monthly meetings with co-mentors (not primary mentors).
There is limited input from the primary mentors in the training plan.
The plan to increase scholarly productivity is unconvincing, particularly with the plethora of training activities proposed for years 1-3.
A single cancer biology course in year 3 is insufficient.

Strengths
Multilevel multicomponent approach to intervention could address many factors related to medication adherence.
Involvement of SCOA and Dr. Heiney in patient recruitment is very positive.

Weaknesses
All three aims are dependent.
Sample size is not adequately supported and very small given the multiple factors involved in adherence and the broad definition of breast cancer survivor. Insufficient data to support Aim 2.
Insufficient consideration of pitfalls and limitations. Candidate states that studies show AHT significantly contributed to disparities in breast cancer mortality, but this is not adequately supported by her own research (see pg. 85).
Research is not well motivated; previous interventions were not successful and it is not clear how the proposed plan will overcome this obstacle.
Candidate suggests that pharmacists can lead intervention (see table 11.1) but a pharmacist is not involved in this proposal.

Strengths
Glowing letter of support from Mentors.
The primary mentors are well established and well funded in their respective fields.

Weaknesses
Dr. Felder"s appointment is in the College of Nursing, but the primary mentors' are not.
Dr. Skinner is not included in the letter of support, and her role appears to overlap with Dr. Ford. This confuses the distinction between consultants and collaborators.
This proposal has significant overlap with Dr. Heiney"s funded research; it is not clear why she does not have a larger role in this proposal.
Dr. Hebert lists Dr. Felder as one of his K05 protégés, but Dr. Felder is currently supported to conduct non-cancer research.
None of the previous trainees have completed their training and taken their research beyond the USC context.

Strengths
Institution will allow Dr. Felder to commit 75% of her time to the proposed award.

Weaknesses
Stated institutional resources are not being employed, such as statistical support. It is unclear what is meant by "other resources" that will be provided to support the proposed research as none are specifically mentioned.

Protections for Human Subjects:
Acceptable Risks and Adequate Protections acceptable risks and protections

Inclusion of Women, Minorities and Children:
Sex/Gender: Distribution justified scientifically Race/Ethnicity: Distribution justified scientifically Inclusion/Exclusion of Children under 21: Excluding ages < 21 justified scientifically acceptable inclusion of women, minorities, and children

Budget and Period of Support:
Recommended budget modifications or possible overlap identified: Full time GRA is not justified. These activities should be conducted by the applicant as part of the proposed training.
Travel to meet with Consultant is not justified.
Laptops are not justified, as applicant is not dedicating 100% effort to this proposal.
Funding for statistics licenses should be supported by stated institutional resources.
NIH Regional Seminar on Program Funding and Grants Admin only requires a single attendance, not annually.
Plan to compensate participants overvalues professionals and undervalues patient participation CRITIQUE 2: The candidate"s career goal is to develop expertise in the area of disparities and health applied to cancer survivors. Short term goals via the K01 award are to develop knowledge in qualitative research methods, the development and testing of behavioral interventions and health communication while increasing productivity in cancer disparity research. The proposed research project for the K01 program pertains to intervention research to improve adherence to adjuvant hormonal therapy (AHT) among racial and socioeconomically disadvantaged groups with high rates of mortality from breast cancer. Strengths of the proposal are the excellent candidate, the impeccable training plan, the important and overall well-developed research project, the well-structured and competent group of mentors, collaborators and consultants, and the superb environment for the research program to be developed by the candidate. Minor weaknesses are found in the research plan that would require more details for some aspects.

Candidate: Strengths
The candidate was trained in health services/outcomes research using secondary analytic approaches with a focus on disparities in pharmaceutical treatment in disadvantaged populations. She has a BA degree in Sociology from Wake Forest University and a Master"s in Social Work from University of Michigan in Social Policy & Evaluation, and a PhD degree in behavioral sciences from the UT School of Public Health and completed a postdoctoral training (2013) in the College of Pharmacy at USC.
She received a constant string of awards linked to scholarly activities (including a highly competitive Presidential Management Fellow award to attract individuals to public service) since the late 90s and she is first author on six out of the 13 publications listed.
She is a research assistant professor in the College of Nursing at USC. Excellent letters of support acknowledge the candidate"s research accomplishments, her quest for constant improvement via advice from senior colleagues, her drive and commitment to research on health disparities and her high quality work. They describe the candidate as an ideal scientist for a K01 award.

Weaknesses
None noted.

Strengths
The candidate clearly articulates the need for training in qualitative research methods, development of behavioral intervention and health communication as she spent training related to disparities so far on secondary analytic techniques. She also explains her journey towards health disparity research, notably via her exposure to NCI-related work early on and her 1 K01 CA193667-01 8 NCI-I FELDER, T realization that the field of cancer disparities lacks minority researchers. Since then she has had rich and diverse training activities related to cancer disparities. She justifies well the need to learn how to develop and test multilevel interventions that reflect the involvement of patients, healthcare systems, etc. She greatly justifies the need for qualitative methods that provide context and meaning to complex phenomena and also enable the vulnerable populations to be heard.
The training program is well organized and clearly presented with meeting schedules and role for each mentor.
For each of the three career objectives the candidate explains what will be hands-on and research experience, interaction with mentors, shadowing clinicians and courses or workshops. Rationale is given for each aspect of the training and what the candidate will gain for these phases of the training. It is a very well organized training plan.
Milestones are presented in terms of publications, presentations and grant applications with topics and expected years of achievement. Progress with the training plan will be evaluated by the mentoring committee four times per year; evaluation points are detailed. Cultural aspects of the training will be fulfilled via the candidate"s participation in the National Center for Faculty Development and Diversity"s Faculty Success Program.

Weaknesses
None noted.

Research Plan:
The rationale for the proposed research is that there is almost no information on the behavioral factors that could be modified to improve adherence to AHT, thus impairing targeted intervention. The goal of the candidate is to develop and test a theory-based multi-level intervention to remedy low adherence to AHT. Aims are to (1) explore multi-level (patient, healthcare system, etc.) factors influencing adherence to AHT, (2) develop an intervention to improve adherence to AHT, and (3) evaluate this intervention.

Strengths
The rationale and urgency to study factors that influence adherence to AHT in socioeconomically challenged populations in order to reduce disparity is well explained. The components and models to guide the project are identified. The candidate makes a point in justifying her choice for the specific study of AHT that goes beyond biologically-based differences among African American and Caucasian races. Choices for the different steps in the project are justified. The impact of this project on other interventions using medications is also discussed showing that the candidate has placed the specific analysis of adherence to AHT in the bigger context of intervention therapy with oral medications and survivorship. These aspects combined with the exploration of the impact of fashionable forms of communication also contribute to the innovative approach of the project.
The proposed research is built on the candidate"s own preliminary data.
Aim 1: the candidate will use in-depth semi-structured qualitative interviews with breast cancer survivors and healthcare professionals. Criteria for patients" and healthcare personnel selections are clear and complete; the involvement of each collaborator to help with recruitment is indicated. The data analysis process is detailed.
Aim 2: the candidate convincingly explains how models available and her attendance to courses such as "intervention mapping" as part of the training will inform decisions regarding the intervention design. NCI-I FELDER, T Aim 3: this will be the pilot study for intervention that will be assessed rigorously via quasiexperimental, pre/posttest design (no control group). Criteria for recruitment of patient participants are clear, including the fact that they should be non-adherent to AHT.

Weaknesses
Aim 1: The candidate does not adequately discuss how the type of drug used for AHT will be taken into account in the analysis. Yet, this might be an essential aspect of adherence to AHT since some of the drugs have very different levels of side effects and inconveniences that might differently impact adherence to their use.
Aim 2: The candidate did not adequately explain how strongly the results from the patients compared to those obtained from the healthcare personnel will weigh on the design of the intervention. There might be a possibility that the healthcare "point of views" undermine the information given by the patients. It is important that the candidate clearly describes her approach to reduce the risk of bias in her design from that standpoint. This is probably a question normally addressed in multi-level interventions but there is no adequate information regarding this issue in the proposal. Also the importance of the influence of family and friends in impacting the results should be adequately discussed.
Aim 3: it is not clear what we will be the timeframe for the post-interview.
The expectations, limitations and alternative section is not well developed; only one aspect is discussed: retention of participants. There are several other essential aspects to discuss, some of which were already suggested in the critique of the specific aims and others that pertain to more conceptual aspects of the project that, most likely, this competent candidate has in mind already. This section of the proposal is particularly important, since each aim is linked to the preceding one and thus, specific issues might profoundly affect the organization/conduct of the next aim.

Strengths
Co-primary mentor: Dr. Marvella Ford, Professor of biostatistics and epidemiology at the Medical University of South Carolina, Hollings Cancer Center. She is associate director of cancer disparities in the Cancer Center with the goal to increase the number of investigators in South Carolina who conduct research on cancer disparities. She has a record of external federal funding and a good list of publications. She is a behavioral scientist who has mentored 26 junior scientists (undergraduate to faculty level) since 2000. She will provide mentorship on intervention development in cancer disparity research.
Co-primary mentor: Dr. James Hebert, professor of epidemiology and biostatistics and a Health Sciences Distinguished Professor, Arnold School of Public Health. He is the director of the USC Cancer Prevention and Control Program. He is committed to transdisciplinary and communitybased participatory research (he has a K05 Established Investigator Award to develop this area of research). He has an extensive publication record (> 345 articles) and has an excellent track record of external funding. He will provide mentorship on intervention development and cancer epidemiology. He has described his mentorship track record and has provided information on his mentorship plan for the candidate and has listed her as one of the protégé on his K05 grant.
Co-mentor: Dr. Ronit Elk, research associate professor in the college of Nursing. She is an expert in health policy and disparities and has worked for 10 years to build the American Cancer Society program in health disparities before coming back to academia (since 2012). She will provide mentorship on career development. NCI-I FELDER, T Co-mentor: Dr. Daniela Friedman, Associate Professor of Health Promotion, Education & Behavior, Arnold School of Public Health. She is PI and co-PI on several projects related to dissemination, implementation and evaluation of evidence-based cancer prevention and control interventions. She lists a K01 awardee as a current mentee in addition to a few graduate students. She has an excellent publication track record. She will provide mentorship on qualitative research and health communication.
Co-mentor: Dr. Sue Heiney, Dunn-Shealy Research Professor in the College of Nursing, is the co-director of the Cancer Survivorship Center at USC. She has expertise in intervention studies with group approaches. She will provide mentorship on qualitative research, intervention development and study recruitment.
Collaborators and consultants will provide help with biostatistics, breast oncology care and multilevel intervention development.
The candidate has support letters from the president of the South Carolina Oncology Associates (to help recruit low-income individuals for the project) and from a consultant from UT Southwestern on multi-level initiatives in cancer care.

Weaknesses
Drs. Ford and Elk did not give sufficient details regarding the mentorship plan for the candidate.
It might have been helpful to have biosketches of the collaborators and consultant since they will participate in the training of the candidate.

Strengths
The environment at the University of South Carolina (USC) is excellent, commended by the Carnegie Foundation for "very high research activity", the only university in South Carolina in this category. It will provide access for the candidate to resources and facilities there and also at the NCI-designated Hollings Cancer Center since the candidate is an affiliate member of the cancer control program.
The college of nursing works in collaboration with other health disciplines (pharmacy, social work, public health, medicine) for health planning, grant writing, delivering services and developing educational programs.
The Cancer Survivorship Center will provide a network of clinical and academic experts available to the candidate for her research.
The candidate is also a core-faculty affiliate of the Statewide Cancer Prevention and Control Program housed in the School of Public Health that focuses on large cancer health disparities in African American populations.
There are also other centers focusing on health disparity in South Carolina, including the Institute for Partnerships to Eliminate Health Disparities and the South Carolina Rural Health Research Center, as well as the Palmetto Health not-for-profit healthcare system that is dedicated to working with individuals and centers to fight against health disparities.
The institutional letter of support is excellent; it indicates protected time as requested but also support towards a tenure track position based on external funding and scholarly publications.

Weaknesses
None noted. a different program every year for years 1 to 4, the frequency for each activity is not detailed.

Not Applicable (No Select Agents)
Budget and Period of Support:

Recommend as Requested
Recommended budget modifications or possible overlap identified: The budget justification does not seem to match the yearly forms; also there is no information on the FTE for a graduate student; based on the amount budgeted it does not seem to correspond to a full stipend. This is a new application from an African American behavioral scientist who is a Research Assistant Professor at the University of South Carolina School of Nursing/School of Public Health. The strengths of the application are the Candidate who has clearly dedicated herself to the study of disparities in cancer treatment, a strong Mentoring team, and an outstanding Career Development Plan. The subject of adherence to adjuvant hormonal therapy in breast cancer is highly significant, but the lack of an explicit hypothesis is considered at least a moderate weakness in the Research Plan. Track record of internal and foundation funding.

Weaknesses
None noted.

Strengths
Clearly defined new areas of development in qualitative research, behavioral intervention development, and health communication.
Exemplary career development plan -well-organized, detailed, including frequency of interactions and specific role of mentors/advisors in the project. 1 K01 CA193667-01   13 NCI-I FELDER, T None noted.

Strengths
There are large racial disparities in breast cancer so this is a significant problem, and South Carolina seems to be an ideal state to study this problem with greater than average disparities .
There are compelling data that adherence to adjuvant hormonal therapy (AHT) improves survival in HR+ breast cancers and that this may contribute to racial disparities.

Weaknesses
There is not an explicitly-stated hypothesis. For example, is it expected that lack of adherence is most commonly due to socioeconomic factors?
Candidate"s own prior data demonstrate that among Medicaid patients there is no difference in adherence based on race. Does limiting this study to Medicaid patients perhaps miss important non-socioeconomic factors that may contribute to racial disparities?

Strengths
Primary Mentor, Dr. Hebert (at USC) is an epidemiologist and Director of SC"s Cancer Prevention and Control Program and is expert in field of disparities. He has U54 and K05.
Co-Primary Mentor, Dr. Ford (at MUSC) is a behavior scientist with expertise in interventions to reduce disparities and track record of mentoring minority trainees.
Three additional "co-mentors", Drs. Friedman, Elk, Heiney plus three collaborators/consultants provide additional expertise, some seems complementary, some may be redundant, but overall it is a strong team with a very strong "team" letter of support for Candidate.

Weaknesses
Charleston is not that close to Columbia (2-3 hours drive). She clearly describes regular meetings with both her USC and MUSC mentors/co-mentors. Some acknowledgment of this geographic limitation is expected, and clarification as to whether she will be commuting back and forth or whether some meetings will be by phone.

Strengths
Currently in pre-tenure track position but with commitment to transition to tenure track with receipt of extramural funding.

Weaknesses
None noted.