Experiences and Perceptions of Older Adults with Lower-Risk Hormone Receptor-Positive Breast Cancer about Adjuvant Radiotherapy and Endocrine Therapy: A Patient Survey

Older patients with lower-risk hormone receptor-positive (HR+) breast cancer are frequently offered both radiotherapy (RT) and endocrine therapy (ET) after breast-conserving surgery (BCS). A survey was performed to assess older patients’ experiences and perceptions regarding RT and ET, and participation interest in de-escalation trials. Of the 130 patients approached, 102 eligible patients completed the survey (response rate 78%). The median age of respondents was 74 (interquartile range 71–76). Most participants (71%, 72/102) received both RT and ET. Patients felt the role of RT and ET, respectively, was to: reduce ipsilateral tumor recurrence (91%, 90/99 and 62%, 61/99) and improve survival (56%, 55/99 and 49%, 49/99). More patients had significant concerns regarding ET (66%, 65/99) than RT (39%, 37/95). When asked which treatment had the most negative effect on their quality of life, the results showed: ET (35%, 25/72), RT (14%, 10/72) or both (8%, 6/72). Participants would rather receive RT (57%, 41/72) than ET (43%, 31/72). Forty-four percent (44/100) of respondents were either, “not comfortable” or “not interested” in participating in potential de-escalation trials. Although most of the adjuvant therapy de-escalation trials evaluate the omission of RT, de-escalation studies of ET are warranted and patient centered.

Older patients with cancer tend to have more comorbid conditions, polypharmacy, poorer function and performance status, which all have implications on tolerance and compliance with treatment. Moreover, the competing risk of death in older adults with lower-risk HR+ BC render the adjuvant therapy benefits lesser than initially reported [9][10][11].
Prospective [12,13], retrospective [14,15], systematic review and meta-analysis [16][17][18] and computer modeling studies [19] have demonstrated that it is safe to omit either RT or ET without affecting distant metastasis and survival outcomes for older adults with lowerrisk HR+ BC. However, the randomized trials on adjuvant therapy de-escalation mainly evaluated the omission of RT [18]. However, this body of evidence has not changed broader clinical practice, as most patients continue to receive both treatment modalities [3,20,21]. Furthermore, it remains unclear whether the best de-escalation strategy is RT alone or ET alone [9,22].
We conducted a survey among patients aged ≥70 who were offered adjuvant RT and ET for a lower-risk HR+ BC to better understand their perceptions with respect to adjuvant RT/ET and their interest in participating in clinical studies evaluating treatment de-escalation. The results of this survey will inform the decision-making process, include the patient's voice in current clinical practice and align our research objectives with the patient's needs and priorities.

Study Population
The survey's target population was patients ≥70 years of age who were diagnosed with early-stage (node negative) HR+ breast cancer treated with BCS, and who had been offered both RT and ET by their treating team. Of note, in our health region, all patients who had a BCS or a mastectomy for an invasive breast cancer would be referred to both a medical oncologist and a radiation oncologist to discuss adjuvant therapies. The original study plan was to accrue 200 participants in 3 months to ensure a broad perspective on treatment. Furthermore, in order to capture a wide range of experience on the treatment and decision-making process, patients could be at any point in the course of their breast cancer treatment or surveillance from the time that both adjuvant therapies were discussed. On 1 November 2020, an amendment was approved to the protocol to include patients treated with a mastectomy to better reflect our institutional practice and improve recruitment (Supplementary Materials). In addition, we felt that these patients could present some valuable input on their perceptions of adjuvant therapies. Patients had to be able to provide verbal consent and complete the survey in English. Patients were accrued in two cancer centers: The Ottawa Hospital Cancer Center (TOH), including the General Campus and the Irving Greenberg Family Cancer Center (Ottawa, ON, CA), and The London Health Sciences Center (London, ON, CA).

Study Outcomes
The aim of this survey was to provide insight on the experiences, perspectives and expectations of older patients with regards to adjuvant ET and RT for lower-risk HR+ breast cancer. Furthermore, this survey sought to understand patient interests in participating in clinical trials evaluating the de-escalation of ET.

Survey Development
The patient survey was developed by a multidisciplinary team with demonstrated expertise in oncology, methodology and survey design [23,24], including medical oncologists (MC, MFS, TH), a radiation oncologist (LC), a surgical oncologist (AA), a nurse practitioner (GL) and a medical oncology resident (KC). It was also reviewed by non-healthcare professionals (DS, LV). The first part of the survey gathered information regarding patient demographics (age at diagnosis), health conditions (comorbidities, prescribed medications and self-rated health) and breast cancer medical context (type of adjuvant therapy received and the point at which they were in their breast cancer treatment) (8 items). The subsequent section evaluated the patients' understanding of the benefits and risks of ET and RT, as well as the expected benefit threshold at which they would accept treatment or not (10 items). Then, patients were asked to provide their views on participating in a theoretical de-escalation study looking at omitting ET (2 items). Finally, patients were asked to share their own experiences regarding ET and/or RT, including side effects and impact on quality of life, and to identify which of the two they would opt for given the choice (14 items) (the complete survey is available in the "Supplementary Materials" Section).

Survey Implementation
Patients meeting eligibility criteria were approached and recruited by members within their circle of care (e.g., medical oncologists, radiation oncologists, general practitioners in oncology, nursing staff) during their routine clinic visits. Once verbal permission was given, interested patients had the choice of receiving a hard copy or an electronic version of the information sheet and survey. The electronic version was sent by email with a link to the anonymous survey on Microsoft Forms (on the secure Ottawa Hospital SharePoint site). Reminders were not sent to patients. The clinical research study associates (DS, LV) assisted in contacting interested patients, collecting completed surveys and gathering data. In addition, patients discharged from the oncology clinic to their family physicians through the Wellness Beyond Cancer Program of The Ottawa Hospital Cancer Center were also contacted (DS, MFS). This survey was approved by the Ontario Cancer Research Ethics Board (OCREB).

Data Analysis
Data were reported using descriptive statistics and analyzed using Microsoft Excel. The answer choices were summarized with observed proportions.

Patient Characteristics
Between 29 July 2020 and 3 March 2021, 130 patients were approached: 114 in Ottawa and 16 in London. Among these, 27 (21%) declined participation (Ottawa 26, London 1) and 1 was deemed not eligible afterwards due to their age at diagnosis. Of the eligible candidates, 87 and 15 completed surveys were obtained from Ottawa and London, respectively. Patient characteristics are presented at Table 1. Among the 102 eligible respondents, the median age at BC diagnosis was 74 (interquartile range (IQR) 71-76). Forty-five percent (46/102) were ≥75. Most participants rated their health status as "good" (66%, 66/100). Excluding ET, the median and average number of prescribed medications taken per day by participants was three (IQR 2-4.75). The most commonly reported health problems were hypertension (49%, 50/102) and dyslipidemia (38%, 39/102). At the time that the survey was completed, 71% (72/102) were receiving or had received both RT and ET, 12% (12/102) were receiving or had received RT only and 9% (9/102) ET only.

RT vs. ET: Impact on QoL and Patients' Preferences
Among 72 respondents who had received both RT and ET, 43% (31/72) reported that neither RT nor ET affected their QoL, 35% (25/72) that ET affected their QoL more than RT, 14% (10/72) that RT affected their QoL more than ET, 8% (6/72) that RT and ET affected their QoL equally (Figure 1). When participants who received both RT and ET were asked which of RT or ET that they would rather receive, 57% (41/72) preferred RT over ET (Figure 1).

Patient's Perceptions and Expectations of RT and ET Benefits
Ninety-one percent (90/99) answered that RT would help reduce ipsilateral breast recurrence vs. 62% (61/99) for ET (

Patients' Attitudes towards Omitting RT or ET, and a Future De-Escalation Clinical Trial
Participants were asked how comfortable they would be if their oncologists did not offer RT or ET based on their health and lower-risk cancer status ( Figure 2): 45% (45/99) and 53% (54/102) would be comfortable to various degrees in omitting RT or ET, respectively.

Discussion
To our knowledge, this is the first survey on the perceptions of older adults with lower-risk HR+ BC towards RT and ET and de-escalation clinical trials. Although RT and ET are the two established adjuvant therapies for HR+ HER2-BC, evidence supporting their use in this population is based on extrapolation from studies that mainly accrued younger patients with higher risk BC. There is increasing interest in de-intensifying adjuvant therapies in older patients with biologically favorable BC defined as node-negative, small size, low-intermediate grade and HR+ BC [9]. To date, most of the prospective trials performed in older patients compared the omission of RT to standard of care, i.e., RT plus ET [25][26][27][28][29][30][31]. These studies demonstrated that while RT reduced the rate of ipsilateral breast tumor recurrence, neither the omission of RT nor ET impacts survival [14,17,18]. Limited data exist on ET omission [12,13,18] and clinical endpoints, such as QoL, safety and economics [9,18].
In this survey, almost half of the participants were aged 75 and older, providing a good representation of the elderly population. However, it is possible that highly educated and non-minority populations were over-represented, as we did not collect data on this. While many participants perceived themselves to be in good health, many reported comorbidities and most took several medications, as is common with aging. Notably, a substantial proportion of patients were taking four or more medications. For these patients, the addition of ET would result in polypharmacy [32], which can be associated with increased pill burden, increased likelihood of side effects and can have financial implications for patients. Thus, taking additional medication (ET) is not inconsequential for patients in this age category [33].

Discussion
To our knowledge, this is the first survey on the perceptions of older adults with lowerrisk HR+ BC towards RT and ET and de-escalation clinical trials. Although RT and ET are the two established adjuvant therapies for HR+ HER2-BC, evidence supporting their use in this population is based on extrapolation from studies that mainly accrued younger patients with higher risk BC. There is increasing interest in de-intensifying adjuvant therapies in older patients with biologically favorable BC defined as node-negative, small size, lowintermediate grade and HR+ BC [9]. To date, most of the prospective trials performed in older patients compared the omission of RT to standard of care, i.e., RT plus ET [25][26][27][28][29][30][31]. These studies demonstrated that while RT reduced the rate of ipsilateral breast tumor recurrence, neither the omission of RT nor ET impacts survival [14,17,18]. Limited data exist on ET omission [12,13,18] and clinical endpoints, such as QoL, safety and economics [9,18].
In this survey, almost half of the participants were aged 75 and older, providing a good representation of the elderly population. However, it is possible that highly educated and non-minority populations were over-represented, as we did not collect data on this. While many participants perceived themselves to be in good health, many reported comorbidities and most took several medications, as is common with aging. Notably, a substantial proportion of patients were taking four or more medications. For these patients, the addition of ET would result in polypharmacy [32], which can be associated with increased pill burden, increased likelihood of side effects and can have financial implications for patients. Thus, taking additional medication (ET) is not inconsequential for patients in this age category [33].
About 70% of the participants in this survey received or are planning to receive both RT and ET, which correlates with the most common adjuvant approach [3,20,21]. However, many appeared to misunderstand and/or overestimate the clinical benefits of RT and ET. For example, 44% believed that RT helps reduce metastatic recurrence and 25% felt it could reduce the risk of contralateral BC occurrence. Even though the survival benefit of RT and ET was not demonstrated [9,18,19], about 50% believed that it will improve their survival.
Surprisingly, while more than 50% would have taken RT/ET regardless of the magnitude of benefit, others would have taken RT/ET only if it yielded a level of efficacy that is much higher than what is demonstrated. One possible reason is that the concept of benefits relative to risks is difficult for physicians to explain and challenging for patients to grasp. This highlights a key aspect which must be accounted for and improved upon in order to help patients in their decision-making process. The relatively high proportion who would take adjuvant therapies regardless of the degree of benefit and the high ET compliance rate could also reflect the fact that a high proportion reported that treatments did not significantly impact their QoL, and/or could reflect a selection bias. These respondents may be fitter and are likely those who tolerated treatment. However, this remains an important finding, which points out that increased age does not always equate with a desire for less treatment or a shift in perception about what outcomes are important (e.g., overall survival vs. QoL), and emphasizes the importance of asking older patients about their values and preferences.
Participants preferred RT over ET in terms of side effects, expected benefits and QoL. Furthermore, a majority of patients treated with ET and RT would rather receive RT than ET and appeared to be more comfortable in omitting ET rather than RT. This may reflect technical and practical advances in RT, which have lessened late toxicities and reduced treatment numbers, rendering RT much more tolerable in recent years. This preference for RT over ET is also important, as it contrasts with the fact that almost all randomized controlled trials have focused on evaluating the omission of RT rather than ET [9], suggesting that studies evaluating the omission of ET are warranted. The necessity of such studies may be increasingly important with the adoption of 5-fraction RT courses, which were not standard at the time when participants received treatment [34] and may further skew patient preference towards ET omission.
Despite these findings and the interest from a medical perspective in minimizing harm due to over-treatment, up to 45% were not comfortable or did not want to participate in any kind of research study. A prior systematic review reported that 83% of the studies identified patient barriers as a major category that hindered the enrollment of older patients in clinical trials, of which 50% were due to patient concerns regarding the idea of experimentation [35]. This highlights the importance of both engaging patients during clinical study development and addressing their concerns to ensure that proposed studies are successful and inclusive of a wide range of older patients.
Our study has limitations. First, the COVID-19 pandemic directly affected our accrual. Fewer patients underwent surveillance mammography, and, therefore, a reduced number of new patients were seen. Furthermore, there were less opportunities for direct interactions as many patients were being seen virtually. In this survey, we included patients at different stages in their BC treatment journey to capture short-and long-term perspectives. This might be perceived as a limitation, since it makes the population less homogeneous and may introduce a recall bias if some were more than 5 years after their diagnosis. The survey only included patients who had been offered both ET and RT, and did not include patients who for whatever reason were not offered either modality. Furthermore, as most patients agreed to therapy, it is likely that these patients perceived a greater benefit to therapy and had a greater willingness to take therapy. Finally, this survey was completed without supervision and the treatments received could not be verified. In addition, some patients omitted answering certain questions. This might be due to inability to recall information, the length of the questionnaire or a lack of understanding.

Conclusions
Despite the paucity of data specifically addressing adjuvant therapy for older patients with lower-risk HR + BC, most participants surveyed received both RT and ET, and appeared to overestimate the clinical benefits of RT and ET. Older patients might be more interested in de-escalation clinical trials that omit ET, since they would rather receive RT than ET and were more comfortable in omitting ET. This patient survey will be a key instrument for including patient voices in the design of future clinical trials.