Patient acceptability of circulating tumour DNA testing in endometrial cancer follow- up

Objective: Circulating tumour DNA (ctDNA) is emerging as a potential option to detect disease recurrence in many cancer types, however, ensuring patient acceptability of changing clinical practice and the introduction of new technology is paramount. Methods: Patients enrolled in a non- intervention cohort study determining the ability of ctDNA to detect recurrent endometrial cancer (EC) were invited to participate in a semi- structured interview. Analysis was performed by Template Analysis. Results: Eighteen patients were interviewed. A ctDNA blood test was viewed by participants as more physically and psychologically acceptable than clinical examination to monitor for EC recurrence. In particular, participants expressed overwhelm ing preference for a blood test rather than pelvic examination. Although participants acknowledged that an abnormal ctDNA result could cause anxiety, they expressed a preference to be informed of their results, even if a recurrence was too small to detect radiologically. Explanations for these opinions were a desire for certainty whether their cancer would recur or not, and knowledge would help them be more aware of symptoms that should be reported to their clinician. Conclusions: ctDNA monitoring to identify EC recurrence appears to be acceptable to patients, and for many, it may be preferable to clinical examination.


| INTRODUC TI ON
The identification of circulating tumour DNA (ctDNA) is hailed as introducing a paradigm shift in cancer management, enabling a more personalised approach to treatment. One of the reported advantages of ctDNA is its high sensitivity and specificity in identifying patients who will experience disease relapse, often many months, or even years, before clinical signs/symptoms or detection on imaging (Coombes et al., 2019;Garcia-Murillas et al., 2019). Monitoring ctDNA levels to identify cancer recurrence before it is clinically or radiologically detectable has the potential to dramatically impact patient management by being used as the basis of remote monitoring schemes, as compared to the current standard management for most tumour sites of clinician-led hospital follow-up (HFU).
However, the issue of patient management and expectations with raised, or rising, ctDNA levels but no detectable site of recurrence does pose significant challenges, since earlier detection may not result in earlier oncological intervention or ultimately impact patients' overall survival. Despite the huge international effort focusing on the scientific and molecular aspects of ctDNA detection, very little work has been undertaken with the target patient groups to determine the acceptability of such developments and the potential on changing management.
Endometrial cancer (EC) is the fourth most common cancer in women in the USA with over 60,000 new cases diagnosed each year (Miller et al., 2016). It has a high overall survival, 69.1-76.5% 5-year failure-free survival for high-risk disease (de Boer et al., 2019), and for low-risk disease, the 10-year survival rate is over 94% (Ignatov et al., 2018). As a result, there is a high prevalence of EC survivors in the community, and this is projected to increase from 757,190 in 2016 to 942,670 in the USA over the next decade. The value of HFU for early-stage EC has been questioned given the low recurrence rate and that the majority of recurrences are associated with symptoms (Gadducci et al., 2000). This has led to the introduction of reduced schedule or alternative models of follow-up (Coleman & Newton, 2020), such as telephone (TFU) or patient-initiated follow-up (PIFU), which appear to be well tolerated (Beaver et al., 2017;Kumarakulasingam et al., 2019) and have cost savings for both the patient and the healthcare economy (Luqman et al., 2020).
Concerns, however, have been raised over the psychological impact on patients, with fear of recurrence reported to be higher with PIFU than with HFU (Jeppesen et al., 2018).
ctDNA is reported to have high sensitivity (100%) in detecting EC recurrence and a lead time of 10 months compared to CT scan and up to 18 months over patient symptoms . The high accuracy of ctDNA in identifying recurrence opens up the possibility of developing remote monitoring for EC by combining ctDNA monitoring with reduced schedule follow-up, such as a PIFU scheme.
This could enable the identification of women at high risk of recurrence for further investigation and close monitoring, whilst allowing ctDNA negative women to continue on PIFU.
Before trials, determining the utility of remote monitoring with ctDNA in EC can be undertaken, patient acceptability needs to be established. The aim of this study was to explore the views of study participants on the potential use of ctDNA in EC follow-up in the future.

| ME THODS
This research adopted a Critical Realist standpoint (Bhaskar, 1989) to gain insight into women's experiences of the ECctDNA blood test and to locate these experiences within the broader culture of preventative medicine. Critical Realism separates the real world from the observable world and, therefore, according to this thinking, social events (patient' experiences) can only be understood if we understand the social events with reference to causal mechanisms (preventative medicine) (Fletcher, 2017). A prospective cohort study aimed at determining the sensitivity of ctDNA to monitor EC activity (ECctDNA study) opened for recruitment in December 2017. Women attending follow-up ap-an accurate representation of themes present in the data. The transcripts were coded by the researcher, and a subset was independently coded by the senior authors. Themes and codes were developed and added into a final version of the template, with codes presented and ordered to represent the different themes, both broad and specific. Evidence of the template analysis process was recorded, by maintaining copies of each stage of analysis, from the complete transcripts to each version of the developing template and final interpretation (Nowell et al., 2017).

| RE SULTS
In total, 18 patients attended for an interview, 35% of the active ECctDNA study population. Three women declined to attend for an interview. The median age was 67.5 years, and two (11.1%) of the patients were of South Asian ethnicity (Table 1). There was a mix of clinical cases including early-stage high-risk cases, advanced disease at diagnosis and EC recurrence, to ensure a wide range of experiences. In three interviews, a friend or family member was also present. There were no repeat interviews.

| Motivations and experiences participating in the ctDNA monitoring study
Altruism was the leading motivation for study participation with a desire to help women in the future, even though they may not personally benefit from the results of the study. The participants shared their understanding of the purpose and potential role of the ctDNA blood test, the majority demonstrating sound understanding by discussing it as a new tool for cancer detection and how ctDNA blood testing could enable cancer recurrence to be detected earlier.
All participants regarded blood tests as having high patient acceptability, regardless of any possible discomfort. Even participants who had experienced minor discomfort as part of the blood testing process regarded that discomfort as acceptable and manageable, 'I don't mind it -I don't mind, no, even if she can't get the blood out [laughter], I just say 'that's alright, just try'…' -02. Multiple participants made reference to difficulties in administering the blood test in an understanding manner, viewing it as a minor inconvenience and not problematic.

| Patient perceived utility and acceptability of ctDNA
Participants did express apprehension in relation to the ctDNA blood test, but this was only in relation to the lead-time for blood test results to become available. A clinical examination gave an immediate result, and the apprehension expressed by participants may suggest that patients could feel concern or worry during the time between having blood taken for ctDNA testing and being given the results.

| PIFU and ctDNA as a potential follow-up tool
Participants gave mixed responses regarding PIFU as an alternative follow-up model to HFU, with some women expressing a preference for seeing a doctor face-to-face. Most participants, however, expressed confidence in their ability to phone for advice if using a scheme such as PIFU. A few stated that they may 'put off' calling, out of a desire to 'not bother' the team: 'I don't like to bother people, I'm one of those people that, 'well I'll leave it, I'll see how it goes…' -02.
Other potential positives of PIFU were discussed, including the reassurance of having direct access to their clinical team, as well as practical benefits in particular of saving time and travel to appointments.
One participant stated: 'it's time as well, I'm back at work part time… you've probably got to change your shift or whatever, you know so in that respect it would be easier.' -04.
Participants also stated that being trained on the red-flag symptoms to look for as part of PIFU could make them more confident, physically self-aware and more able to self-check. And a further participant stated: 'To be able to just go in and have a blood test, and them say 'yes you're alright, no you're not', that would be good. 'Less time wasted, confidence that you have got the backup and confidence that hopefully the blood test is accurate and could discover something earlier than a hospital visit, definitely.' -15.

| DISCUSS ION
In this study, we were able to explore the experiences and opinions from a diverse population in order to gain a wide breadth of experiences of women in active follow-up for EC. The results have identified new insights that can be used to inform the design of future trials incorporating ctDNA monitoring into clinical practice. The accuracy of ctDNA to detect EC recurrence in the pilot data from our study was 100% , and other studies support our results, including a lead time of over 6 months, high negative predictive value and 100% overall survival in gynaecological cancer cases with undetectable ctDNA (Pereira et al., 2015).
One of the main findings of this study was the high level of patient acceptability of ctDNA monitoring, with an overwhelming preference by participants, both early and advanced stage, for a blood test rather than a pelvic examination to monitor for recurrence. The level of distress that was reported to be associated with a pelvic examination was considerable in some participants and sheds new light on a routine aspect of gynaecological practice in this population. The use of a diagnostic examination that is associated with such high levels of anxiety in some women, can result in patients entering a passive status, leading to feelings of powerlessness and helplessness (Aujoulat et al., 2007). Feeling unable to control or influence their health status may result in decreased levels of self-efficacy, and an external locus of control (Cross et al., 2006;Wallston et al., 1978), thereby reducing a patient's ability to manage symptoms and perform maintenance behaviours (Cross et al., 2006). A pelvic examination was identified as the 'most personal' of examinations, and although the majority of women accepted that it was a necessary aspect of their follow-up examination, some did raise the issue of continuity in the clinician-patient relationship in improving its tolerability, as com- However, the majority of women who develop a local EC recurrence will present clinically, typically with vaginal bleeding (Aung et al., 2014). Direct access to the specialist team through a PIFU scheme (Kumarakulasingam et al., 2019) may expedite clinical review, rather than patients taking a more passive role in their care and waiting until their next HFU appointment to report symptoms, as happens with a proportion of patients, possibly leading to a delay in diagnosis (Aung et al., 2014).
The patients recruited to this interview study were already under HFU and participating in a cohort study determining the sensitivity of ctDNA to detect recurrence, but were blinded to their results, and therefore had previously received information on ctDNA monitoring as part of the ECctDNA study recruitment process. Despite patients acknowledging that early detection of recurrence would be associated with anxiety, great importance was placed on being informed of the result, rather than being blinded and only the clinician being aware. The concept of remote biomarker monitoring for cancer is well established in many solid tumours, for example, prostate and thyroid cancer, and has been shown to be well tolerated by patients (Frankland et al., 2019).
Significant cost savings to both the patient and the healthcare economy have been identified with PIFU for low-risk EC (Luqman et al., 2020), as compared to HFU, and extension of such schemes could be used to finance the addition of ctDNA monitoring for EC follow-up.
Fear of cancer recurrence (FCR) can have a very real psychological impact on cancer survivors (Crist & Grunfeld, 2013) and has been estimated to affect between 22% to 99% of all cancer survivors (Simard et al., 2010). In a systematic review (Simard et al., 2010), a number of factors were found to be strongly associated with FCR including cancer cues, including new symptoms, pain and follow-up appointments. Some participants in our study expressed feeling anxiety when attending for follow-up appointments, in keeping with the review findings. The theme of 'reassurance' was stated as the most important benefit of HFU, reducing fears of recurrence, and helping patients to feel 'looked after', mirroring findings that regular hospital check-ups can provide patients with psychological reassurance and relief (Brown et al., 2002). HFU was nevertheless associated with negative feelings in some women, linked to concerns over pelvic examination or the fear of disease recurrence, as well as practical issues of time and transport costs. The need for additional reassurance with PIFU was echoed in the views of our participants; however, the addition of ctDNA monitoring was felt to be highly acceptable since it fulfilled the wish for disease monitoring, avoided pelvic examination but also gave them a greater sense of self-efficacy with regard to their health.
ctDNA monitoring in endometrial cancer shows great promise; however, further work is needed before it can become an established test within standard clinical care. Currently, four companion