Management Strategies for Older Patients with Low-Risk Early-Stage Breast Cancer: A Physician Survey

When managing older patients with lower-risk hormone-receptor-positive (HR+), HER2 negative (HER2−) early-stage breast cancer (EBC), the harms and benefits of adjuvant therapies should be taken into consideration. A survey was conducted among Canadian oncologists on the definitions of “low risk” and “older”, practice patterns, and future trial designs. We contacted 254 physicians and 21% completed the survey (50/242). Most respondents (68%, 34/50) agreed with the definition of “low risk” HR+/HER2− EBC being node-negative and either: ≤3 cm and low histological grade, ≤2 cm and intermediate grade, or ≤1 cm and high grade. The most popular chronological and biological age definition for older patients was ≥70 (45%, 22/49; 45% 21/47). In patients ≥ 70 with low risk EBC, most radiation and medical oncologists would recommend post-lumpectomy radiotherapy (RT) and endocrine therapy (ET). Seventy-eight percent (38/49) felt that trials are needed to evaluate RT and ET’s role in patients ≥ 70. The favored design was ET alone, vs. RT plus ET (39%, 15/38). The preferred primary and secondary endpoints were disease-free survival and quality of life, respectively. Although oncologists recommended both RT and ET, there is interest in performing de-escalation trials in patients ≥ 70.


Introduction
Managing older patients with early-stage breast cancer (EBC) requires a careful evaluation of the potential risks and benefits of treatment, as well as the integration of competing risks of non-cancer-related mortality. Although current guidelines recommend adjuvant radiotherapy (RT) and endocrine therapy (ET) for all hormone-receptor-positive (HR+) EBC [1], there may be some older patients, such as those with comorbid medical conditions, where the potential harms of RT and/or ET may outweigh the benefits [2][3][4].
A few trials have been performed to identify older patients with a lower risk EBC, for whom it might be appropriate to de-escalate adjuvant therapies. These trials tend to focus mainly on omitting RT [5][6][7]. Indeed, a recent systematic review that included seven randomized controlled trials (RCT) evaluated the omission of RT [8][9][10][11][12]. This review showed that in patients treated with adjuvant ET, the addition of adjuvant RT reduced inbreast tumor recurrence (IBTR) at 5 years (summary risk ratio (SRR) 0.15, 95% CI 0.08-0.28), but had no effect on survival (SRR 0.97, 95% CI 0.79-1.2) [13]. Only one RCT compared adjuvant RT alone, to either adjuvant ET alone, or to the standard of care (i.e., RT plus ET), and showed that RT alone was superior in preventing IBTR, compared with ET alone [8]. Considering the body of evidence, more trials on the omission of ET are required to better inform treatment decisions. Indeed, a recent study evaluating the benefits of adjuvant ET for EBC has shown that when competing risks for death are taken into account, not only are disease-free survival (DFS) and distant recurrence-free survival (DRFS) events significantly reduced, but the overall benefits of ET become more modest, particularly for older patients and those with lower-risk disease [14].
Despite the fact that over 30% of EBC are diagnosed in patients ≥ 70 years, there is still controversy around what defines the terms "older" and "low risk" HR+/HER2− breast cancer, and how to properly counsel these older patients on the optimal adjuvant strategy (i.e., RT alone, ET alone or RT + ET) [15][16][17]. We therefore surveyed oncologists regarding their definitions of the terms "low risk" and "older", their current practice patterns, and their thoughts on potential future trial designs for older patients with lowrisk node-negative, HR+/HER2− EBC. The information obtained from these surveys could assist in the design of future pragmatic clinical trials to evaluate the risks and benefits of adjuvant RT and ET in older patients with lower-risk breast cancer, with findings that are clinically relevant, patient-centered and practice-changing.

Survey Development
The survey was designed by a multidisciplinary team with established expertise in survey development and performance [18][19][20]. The target population was Canadian oncology clinicians (i.e., medical oncologists, radiation oncologists, surgical oncologists and general practitioners in oncology/radiation) involved in the treatment of patients with HR+/HER2− lymph-node-negative EBC. The first section of the survey collected pertinent respondent demographic information (5 items). The second section collected information on how clinicians defined the terms "low risk" and "older" (19 items). This included querying the definition of low-clinical-risk disease, proposed by Sparano et al. [17] which defined node-negative low-risk breast cancer as: a tumor ≤ 3 cm with a low histological grade, a tumor ≤ 2 cm with intermediate grade, or a tumor ≤ 1 cm with high grade. In the third section, medical oncologist and radiation oncologists were asked about their personal practice regarding the use of RT and ET in older patients (15 items). Finally, respondents were presented with different scenarios for a potential clinical trial in older patients with node-negative HR+/HER2− low-risk breast cancer. They were also asked for their opinion on an acceptable primary study endpoint that could inform a change in their practice (16 items). The survey was pilot tested on three oncologists, a nurse practitioner and two research staff before launch. The survey is shown in the Supplementary Materials.

Survey Implementation
Canadian physicians treating breast cancer were identified through publicly available physician email addresses, which were used in previous surveys of this type [18][19][20]. The online survey was run using Microsoft Forms from the designated research coordinator's secure account, within the Ottawa Hospital Research Institute. The survey was initiated on 16 September 2020 and remained open until 23 November 2020. Physicians were sent an invitation to complete the survey, and a link to the electronic survey as well as an information sheet for the study. Completion of the survey implied consent to participate. A reminder notice was sent to participants 4 weeks later. The survey was approved by the Ontario Cancer Research Ethics Board (OCREB).

Data Analysis
All of the data was summarized descriptively. The frequency of each answer choice was tabulated as a proportion of the total number of respondents for that category. Data were analyzed using SPSS version 27 IBM (Armonk, NY, USA).

Definition of the Term "Low Risk" HR+/HER− EBC
When respondents were asked about their opinion regarding the definition of low-risk HR+/HER2− EBC, 68% (34/50) agreed with the definition of low-clinical-risk disease proposed by Sparano et al. [20] (Table 2). Among 14 respondents who did not agree with this definition or were unsure, some respondents agreed with a broader definition: two respondents suggested that a tumor ≤ 5 cm with low histologic grade could also be considered as low-clinical-risk disease; two respondents would consider a tumor ≤ 3 cm with intermediate histologic grade as low-clinical-risk disease and two respondents would consider a tumor ≤ 2 cm with high histologic grade as low-clinical-risk disease. Furthermore, seven respondents (7/50, 14%) would exclude patients with any grade tumor larger than 2 cm from the low-risk definition. When respondents were asked about multifocal EBC, 73% (36/49) suggested these EBC patients could still be considered low risk.
In regard to whether Ki-67 (protein expressed in the nucleus of cells during different phases of the cell cycle; principally used to evaluate prognosis) is required to define low-risk breast cancer, 56% (28/50) thought Ki-67 would improve their confidence in identifying low-risk breast cancer but that it was not absolutely necessary. When asked if one of the multigene profiling assays (MPA) such as Oncotype Dx Recurrence Score (RS), EndoPredict and Prosigna was required to define lower-risk breast cancer irrespective of tumor size and grade, 50% (25/50) indicated that MPA would improve their confidence in identifying low-risk breast cancer, but that it was not absolutely necessary, 20% (10/50) would not feel comfortable defining low risk without MPA, and 26% (13/50) did not think an MPA was necessary for identifying low-risk breast cancer. Regarding the preferred type of MPA, 74% (26/35) preferred using Oncotype Dx Recurrence Score (RS) to identify low-risk breast cancer.

Practice Regarding the Use of RT in Older Patients
All the physicians were asked at what age they would consider de-escalating (i.e., partial breast radiation, altered fractionation) and/or omitting RT and the majority (37% (15/41)) mentioned 70 years old (chronological or biological age) ( Table 3).

Impact of Axillary Surgery on Decision of Adjuvant RT and ET
For patients ≥ 70 years that were not receiving sentinel node biopsy or any form of axillary surgery, as per the Society of Surgical Oncology Guidelines [21], 45% (20/44) of respondents were more likely to give ET, whereas 55% (24/44) indicated that this did not affect their decision. With regards to RT, 50% (6/12) of respondents were more likely to give RT if surgical evaluation of axilla was not offered, whereas 42% (5/12) indicated that this did not affect their decision.

Potential Future De-Escalation Trials of Adjuvant RT and/or ET in Older Patients with Low-Risk ER+/HER2− EBC
Respondents were asked for their views on potential future de-escalation trials of adjuvant ET and/or RT, and the relevance of various study endpoints to facilitate the design of practice-changing trials. Three quarters (78% (38/49)]) of respondents felt trials to evaluate the risks and benefits of RT and ET in older patients with low-risk ER+/HER2− EBC are needed, whereas 12% (6/49) felt such trials are not needed, and 10% (5/49) were unsure (Table 4).
Respondents were offered three trial designs, to choose the most informative and impactful design based on their knowledge, experience and current practice. Thirtynine percent (15/38) suggested adjuvant ET alone vs. adjuvant RT plus ET, 32% (12/38) suggested adjuvant RT alone vs. adjuvant RT plus ET, and 29% (11/38) suggested adjuvant RT alone vs. adjuvant ET alone (Table 4). When respondents were asked if they felt comfortable offering one of the above trials to their older patients, 72% (34/47), 64% (29/45) and 54% (25/46) said they would feel comfortable offering the previously mentioned trials to their patients, respectively ( Figure 2). Table 4. Views on potential de-escalation studies.

Discussion
Developing evidence-based guidelines for the treatment of older patients with breast cancer can be challenging for a number of reasons. First is the broad spectrum of functional status and other health issues in this aging population. Second, older patients are often underrepresented in studies, as they have been excluded from many practice-changing clinical trials because of their age or co-morbidities [16]. Finally, some studies suggest the existence of a less aggressive breast cancer biology in most patients ≥ 70 years of age [14]. Therefore, it is not surprising that evidence-based guidelines regarding the optimal treatment of older patients with EBC are lacking [22][23][24].
This survey was devised to gain an understanding of current Canadian practice patterns in older patients with low-risk, ER+/HER2− EBC. Although the definition of low-risk HR+ HER2− EBC varies in studies, a majority of respondents agreed with the definition proposed by Sparano et al. [17], which defined low-risk breast cancer as: a tumor ≤ 3 cm with a low histological grade, a tumor ≤ 2 cm with an intermediate grade, or a tumor ≤ 1 cm with a high grade. The majority of respondents indicated the age of 70 as both the chronological and biological age for defining "older adults", with chronological age referring to the amount of time a person has lived, and biological age relating to the presence of diseases associated with old age and the decline of function [25]. In clinic, the concept of biological age is often used loosely. Recently, epigenetic changes and DNA-methylation has been used to calculate biological age, but its use remains limited in gerontology research and is not broadly applied in the clinical setting [26]. Therefore, as reflected by the wide range of answers, there is a lack of consensus regarding the definition of older adults and how to incorporate age as a de-escalation factor.
Although some studies have shown that the risk of a local recurrence is lower in older patients, and the benefits of RT following breast-conserving surgery decline with age [27,28], most clinicians in this survey tended to offer RT (80%). It is important to note that the small number of clinicians answering this question may limit our ability to extrapolate. However, some will take into account the life expectancy of the patient and whether or not they will receive ET in their decision-making. Indeed, Cancer and Leukemia Group B [CALGB] 9343 and PRIME-II have suggested that the omission of RT in this subset is an acceptable strategy, assuming that ET is administered [5,6] According to guidelines, adjuvant ET should be offered to all patients with HR+ breast tumors > 0.5 cm, regardless of age, provided they are candidates for medical therapy [1]. In this study, most respondents would offer ET (77%), and the majority of them would choose an AI. This is supported by the Early Breast Cancer Trialists' Group (EBCTCG) metaanalysis which showed that AIs are slightly superior for reducing relapse risk, compared with tamoxifen, even in patients aged 70 years or older [29]. Although some patients might be over-treated with ET, there is clearly a lack of data to suggest omitting ET. Indeed, older patients may have other health issues that impact their survival more than breast cancer, and therefore the benefit of ET is diminished [14].
In the last part of the survey, respondents were presented with a series of questions related to the design of a future clinical trials geared toward studying the clinical benefits of de-escalated adjuvant ET and/or RT, and the relevance of various potential study endpoints to facilitate the design of practice-changing trials. The results strongly suggest that the physicians surveyed were very interested in such trials. As most of the previous de-escalation trials studied the omission of RT, it is striking that a future trial comparing adjuvant ET vs. RT plus ET is deemed to be the most informative and impactful design for the majority of respondents. DFS and OS were the preferred primary study endpoints and quality of life was the most important secondary endpoint. Another de-escalation strategy for adjuvant therapy in older patients with low-risk breast cancer is to shorten the duration of ET. This was not questioned in this survey, but there is an ongoing phase 2 trial, comparing 5 versus 2 years of ET in low-risk patients aged > 50 (NCT03917082). There is a second ongoing Canadian trial on this topic, the REaCT-70 study, that is evaluating the harms and benefits of endocrine therapy in older patients with lower-risk breast cancer (NCT04921137).
The study received fewer responses than desired, but this is consistent with the response rates observed in many surveys. This antipathy to surveys is likely more pronounced due to the COVID-19 pandemic. As with all surveys, there is an inherent selection bias in those that are contacted and in those that respond. The physicians that completed this survey might be more involved in research and inclined to participate in studies. Therefore, the number of physicians that are willing to take part in de-escalation studies might be overestimated.

Conclusions
The results from this study highlight the clinical importance of evaluating the harms and benefits the adjuvant therapies in patients ≥ 70 years of age with low-risk HR+/HER2− EBC. It will serve as a useful guide in the design of future clinical trials and increase the likelihood that trial results will have a clinical impact. Given that there is no robust data supporting the optimal management (adjuvant RT alone vs. adjuvant ET alone vs. adjuvant RT plus ET) of older patients with low-risk HR+/HER2− EBC, this feedback from Canadian oncologists will be of great value [30].