Stromal lymphocytes are associated with upgrade of B3 breast lesions.

Various histopathological, clinical and imaging parameters have been evaluated to identify a subset of women diagnosed with lesions with uncertain malignant potential (B3 or BIRADS 3/4A lesions) who could safely be observed rather than being treated with surgical excision, with little impact on clinical practice. The primary reason for surgery is to rule out an upgrade to either ductal carcinoma in situ or invasive breast cancer, which occurs in up to 30% of patients. We hypothesised that the stromal immune microenvironment could indicate the presence of carcinoma associated with a ductal B3 lesion and that this could be detected in biopsies by counting lymphocytes as a predictive biomarker for upgrade. A higher number of lymphocytes in the surrounding specialised stroma was observed in upgraded ductal and papillary B3 lesions than non-upgraded (p < 0.01, negative binomial model, n = 307). We developed a model using lymphocytes combined with age and the type of lesion, which was predictive of upgrade with an area under the curve of 0.82 [95% confidence interval 0.77-0.87]. The model can identify some patients at risk of upgrade with high sensitivity, but with limited specificity. Assessing the tumour microenvironment including stromal lymphocytes may contribute to reducing unnecessary surgeries in the clinic, but additional predictive features are needed.

Supervised, structured and individualized exercise in metastatic breast cancer: a randomized controlled trial.

Physical exercise both during and after curative cancer treatment has been shown to reduce side effects. Evidence in the metastatic cancer setting is scarce, and interventions that improve health-related quality of life (HRQOL) are much needed for patients with metastatic breast cancer (MBC). The multinational randomized controlled PREFERABLE-EFFECT trial assessed the effects of exercise on fatigue and HRQOL in patients with MBC. In total, 357 patients with MBC and a life expectancy of ≥6 months but without unstable bone metastases were recruited at eight study centers across five European countries and Australia. Participants were randomly assigned (1:1) to usual care (control group, n = 179) or a 9-month supervised exercise program (exercise group, n = 178). Intervention effects on physical fatigue (European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-FA12 scale) and HRQOL (EORTC QLQ-C30 summary score) were determined by comparing the change from baseline to 3, 6 (primary timepoint) and 9 months between groups using mixed models for repeated measures, adjusted for baseline values of the outcome, line of treatment (first or second versus third or higher) and study center. Exercise resulted in significant positive effects on both primary outcomes. Physical fatigue was significantly lower (-5.3 (95% confidence interval (CI), -10.0 to -0.6), Bonferroni-Holm-adjusted P = 0.027; Cohen's effect size, 0.22) and HRQOL significantly higher (4.8 (95% CI, 2.2-7.4), Bonferroni-Holm-adjusted P = 0.0003; effect size, 0.33) in the exercise group than in the control group at 6 months. Two serious adverse events occurred (that is, fractures), but both were not related to bone metastases. These results demonstrate that supervised exercise has positive effects on physical fatigue and HRQOL in patients with MBC and should be recommended as part of supportive care.ClinicalTrials.gov Identifier: NCT04120298 .

Contrast-Enhanced Mammography in Local Staging of Screen-Detected Breast Cancer.

BACKGROUND: BreastScreen Australia, the population mammographic screening program for breast cancer, uses two-view digital screening mammography ± ultrasound followed by percutaneous biopsy to detect breast cancer. Secondary breast imaging for further local staging, not performed at BreastScreen, may identify additional clinically significant breast lesions. Staging options include further mammography, bilateral ultrasound, and/or contrast-based imaging (CBI) [magnetic resonance imaging (MRI) or contrast-enhanced mammography (CEM)]. CBI for local staging of screen-detected cancer was introduced at an academic hospital breast service in Melbourne, VIC, Australia. We report findings for otherwise occult disease and resulting treatment changes. MATERIAL AND METHODS: Patients staged using CEM between November 2018 and April 2022 were identified from hospital records. Data were extracted from radiology, pathology, and breast unit databases. CEM-detected abnormalities were documented as true positive (TP) for invasive cancer or ductal carcinoma in situ (DCIS), or otherwise false positive (FP). The impact on surgical decisions was assessed. RESULTS: Of 202 patients aged 44-84 years, 60 (30%) had 74 additional findings [34 (46%) TP, 40 (54%) FP]. These were malignant in 29/202 (14%) patients (79% invasive cancers, 21% DCIS). CEM resulted in surgical changes in 43/202 (21%) patients: wider resection (24/43), conversion to mastectomy (6/43), contralateral breast surgery (6/43), additional ipsilateral excision (5/43), and bracketing (2/43). Additional findings were more common for patients with larger index lesions and for invasive cancer, but there was no significant variation by age, breast density, or index lesion grade. CONCLUSIONS: CEM for local staging of screen-detected breast cancers identified occult malignancy in 14% of patients. CEM improves local staging and may facilitate appropriate management of screen-detected breast cancers.

Quality of Life Outcomes Associated With Optimization of Treatment by Omitting Radiotherapy in Early Breast Cancer.

PURPOSE: Improved prognosis of early breast cancer (EBC) has created opportunities for treatment optimization but reducing morbidity should not inadvertently compromise quality of life (QoL). PROSPECT1 used pre-operative MRI and pathology findings to identify women suitable for radiotherapy (RT) omission following breast conserving surgery. We retrospectively explored the association between de-escalation by omission of RT and QoL in women with EBC. MATERIALS AND METHODS: Three groups were recruited: PROSPECT participants who omitted RT following preoperative MRI (A); participants who received RT following preoperative MRI (B); and women who received usual care - No MRI, received RT (C). Measures included the EORTC QLQ-C30 and BR23, BCTOS, DASS-21 and a measure of decision regret. Between group differences were assessed using ANOVA or nonparametric equivalents. Semi-structured interviews were analyzed with qualitative description (n = 44). RESULTS: Data from 400 women were analyzed (125A, 102B, 173C). Group A had fewer symptoms and better body image (breast symptoms: A-B P = .003, A-C P = <.001; arm symptoms: A-B P = .004, A-C P = .011; body image: A-C P = .041) and fewer differences between the treated and untreated breasts (cosmetic: A-B P < .001, A-C P < .001; functional: A-C P = .011; breast specific pain: A-B P < .001, A-C P < .001). Two qualitative themes were found: Treatment with the biggest impact on QoL, and Specific impact of RT on QoL. CONCLUSIONS: Omission of RT was associated with better QoL and functional and cosmetic outcomes. It was highly acceptable to patients. Clinicians should consider the potential for preserved QoL associated with treatment optimization via omission of RT in treatment planning for patients with EBC.

Autologous Fat Grafting in Breast Augmentation: A Systematic Review Highlighting the Need for Clinical Caution.

BACKGROUND: Autologous fat grafting (AFG) is a breast augmentation method for treating volume and contour abnormalities. This systematic review aims to summarize complications, radiologic safety, volume retention, and patient satisfaction associated with AFG. METHODS: The PubMed, Embase, Google Scholar, Cochrane Central Register of Controlled Trials, Wiley library, clinical key/Elsevier, and EBSCO databases were searched for relevant studies from January of 2009 to March of 2022. Articles describing AFG for breast augmentation were selected based on predetermined inclusion and exclusion criteria. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were adhered to, and the study was registered on the International Prospective Register of Systematic Reviews. The Risk of Bias in Nonrandomized Studies of Interventions assessment was used to assess the quality of studies and the risk of bias was measured using the Cochrane Risk of Bias Assessment Tool for Nonrandomized Studies of Interventions. RESULTS: A total of 35 studies comprising 3757 women were included. The average follow-up duration was 24.5 months (range, 1 to 372 months). The overall complication rate was 27.8%, with fat necrosis making up 43.7% of all complications. Average fat volume injected was 300 mL (range, 134 to 610 mL), and average volume retention was 58% (range, 44% to 83%). Volume retention was greater with supplementation of fat with platelet-rich plasma and stromal vascular fraction. The most common radiologic changes were fat necrosis (9.4%) and calcification (1.2%). After 1 year of follow-up, patient satisfaction was, on average, 92% (range, 83.2% to 97.5%). The included studies were of good quality and consisted of a moderate risk of bias. CONCLUSIONS: AFG was associated with an overall complication rate of 27.8%. Additional supplementation of fat with platelet-rich plasma and stromal vascular fraction may improve graft survival. Despite poor volume retention being a persistent drawback, patient satisfaction remains high.

Outcome of different radiotherapy strategies after breast conserving surgery in patients with ductal carcinoma in situ (DCIS).

BACKGROUND: Adjuvant radiotherapy (RT) after breast-conserving surgery for DCIS lowers the relative local recurrence risk by half. To identify a low-risk group with the minimal benefit of RT could avoid side effects and spare costs. In this study, the outcome was compared for different RT-strategies using data from the randomized SweDCIS trial. MATERIAL AND METHODS: Five strategies were compared in a Swedish setting: RT-to-none or all, RT to high-risk women defined by DCISionRT, modified Radiation Therapy Oncology Group (RTOG) 9804 criteria, and Swedish Guidelines. Ten-year recurrence risks and cost including adjuvant RT and local recurrence treatment cost were calculated. RESULTS: The mean age at recurrence was 64.4 years (36-90) and the mean cost for treating a recurrence was $21,104. In the SweDCIS cohort (n = 504), 59 women developed DCIS, and 31 invasive recurrence. Ten-year absolute local recurrence risk (invasive and DCIS) according to different strategies varied between 18.6% (12.5-23.6%) and 7.8% (5.0-12.6%) for RT-to-none or to-all, with an additional cost of $2614 US dollars per women and $24,201 per prevented recurrence for RT-to-all. The risk differences between other strategies were not statistically significant, but the larger proportion receiving RT, the fewer recurrences. DCISionRT spared 48% from RT with 8.1% less recurrences compared to RT-to-none, and a cost of $10,534 per prevented recurrence with additional cost depending on the price of the test. RTOG 9804 spared 39% from RT, with 9.7% less recurrences, $9525 per prevented recurrence and Swedish Guidelines spared 13% from RT, with 10.0% less recurrences, and $21,521 per prevented recurrence. CONCLUSION: It seems reasonable to omit RT in pre-specified low-risk groups with minimal effect on recurrence risk. Costs per prevented recurrence varied more than two-fold but which strategy that could be considered most cost-effective needs to be further evaluated, including the DCISionRT-test price.

Is de-escalation of treatment by omission of radiotherapy associated with fear of cancer recurrence in women with early breast cancer? An exploratory study.

PURPOSE: Safe de-intensification of adjuvant radiotherapy (RT) for early breast cancer (BC) is currently under evaluation. Little is known about the patient experience of de-escalation or its association with fear of cancer recurrence (FCR), a key issue in survivorship. We conducted a cross-sectional study to explore this association. METHODS: Psychometrically validated measures including the Fear of Cancer Recurrence Inventory-Short Form were completed by three groups of women with early BC: Women in the PROSPECT clinical trial who underwent pre-surgical MRI and omitted RT (A), women who underwent pre-surgical MRI and received RT (B); and women who received usual care (no MRI, received RT; C). Between group differences were analysed with non-parametric tests. A subset from each group participated in a semi-structured interview. These data (n = 44) were analysed with directed content analysis. RESULTS: Questionnaires from 400 women were analysed. Significantly lower FCR was observed in Group A (n = 125) than in Group B (n = 102; p = .002) or Group C (n = 173; p = .001), and when participants were categorized by RT status (omitted RT vs received RT; p < .001). The proportion of women with normal FCR was significantly (p < .05) larger in Group A (62%) than in Group B (35%) or Group C (40%). Two qualitative themes emerged: 'What I had was best' and 'Coping with FCR'. CONCLUSIONS: Omitting RT in the setting of the PROSPECT trial was not associated with higher FCR than receiving RT. Positive perceptions about tailored care, lower treatment burden, and trust in clinicians appear to be protective against FCR.

A modelled evaluation of the impact of COVID-19 on breast, bowel, and cervical cancer screening programmes in Australia.

Australia introduced COVID-19 infection prevention and control measures in early 2020. To help prepare health services, the Australian Government Department of Health commissioned a modelled evaluation of the impact of disruptions to population breast, bowel, and cervical cancer screening programmes on cancer outcomes and cancer services. We used the Policy1 modelling platforms to predict outcomes for potential disruptions to cancer screening participation, covering periods of 3, 6, 9, and 12 mo. We estimated missed screens, clinical outcomes (cancer incidence, tumour staging), and various diagnostic service impacts. We found that a 12-mo screening disruption would reduce breast cancer diagnoses (9.3% population-level reduction over 2020-2021) and colorectal cancer (up to 12.1% reduction over 2020-21), and increase cervical cancer diagnoses (up to 3.6% over 2020-2022), with upstaging expected for these cancer types (2, 1.4, and 6.8% for breast, cervical, and colorectal cancers, respectively). Findings for 6-12-mo disruption scenarios illustrate that maintaining screening participation is critical to preventing an increase in the burden of cancer at a population level. We provide programme-specific insights into which outcomes are expected to change, when changes are likely to become apparent, and likely downstream impacts. This evaluation provided evidence to guide decision-making for screening programmes and emphasises the ongoing benefits of maintaining screening in the face of potential future disruptions.

Universal genetic testing for women with newly diagnosed breast cancer in the context of multidisciplinary team care.

OBJECTIVE: To determine the feasibility of universal genetic testing of women with newly diagnosed breast cancer, to estimate the incidence of pathogenic gene variants and their impact on patient management, and to evaluate patient and clinician acceptance of universal testing. DESIGN, SETTING, PARTICIPANTS: Prospective study of women with invasive or high grade in situ breast cancer and unknown germline status discussed at the Parkville Breast Service (Melbourne) multidisciplinary team meeting. Women were recruited to the pilot (12 June 2020 - 22 March 2021) and expansion phases (17 October 2021 - 8 November 2022) of the Mutational Assessment of newly diagnosed breast cancer using Germline and tumour genomICs (MAGIC) study. MAIN OUTCOME MEASURES: Germline testing by DNA sequencing, filtered for nineteen hereditary breast and ovarian cancer genes that could be classified as actionable; only pathogenic variants were reported. Surveys before and after genetic testing assessed pilot phase participants' perceptions of genetic testing, and psychological distress and cancer-specific worry. A separate survey assessed clinicians' views on universal testing. RESULTS: Pathogenic germline variants were identified in 31 of 474 expanded study phase participants (6.5%), including 28 of 429 women with invasive breast cancer (6.5%). Eighteen of the 31 did not meet current genetic testing eligibility guidelines (probability of a germline pathogenic variant ≥ 10%, based on CanRisk, or Manchester score ≥ 15). Clinical management was changed for 24 of 31 women after identification of a pathogenic variant. Including 68 further women who underwent genetic testing outside the study, 44 of 542 women carried pathogenic variants (8.1%). Acceptance of universal testing was high among both patients (90 of 103, 87%) and clinicians; no decision regret or adverse impact on psychological distress or cancer-specific worry were reported. CONCLUSION: Universal genetic testing following the diagnosis of breast cancer detects clinically significant germline pathogenic variants that might otherwise be missed because of testing guidelines. Routine testing and reporting of pathogenic variants is feasible and acceptable for both patients and clinicians.

Neoadjuvant chemotherapy in non-metastatic breast cancer: The surgeon's perspective.

Breast cancer is the most common non-skin cancer in Australia, affecting 1 in 7 women by the age of 85 years. Current management of early breast cancer is becoming increasingly variable and complex. The typical range of treatments include some combination of surgery, chemotherapy and targeted therapy, immunotherapy, radiotherapy, and endocrine therapy. Neoadjuvant chemotherapy (NACT) in carefully selected patients can facilitate increased rates of breast conservation therapy, and when successful, offers improved cosmesis due to less extensive resection of tissue. A neoadjuvant approach also provides biological insight into a patient's tumour, prognostication based on a patient's response to therapy, as well as enabling their treating oncologist to personalise adjuvant strategies based on the presence or absence of residual cancer at surgery. Neoadjuvant chemotherapy has become an integral element in the provision of breast conserving surgery to selected early-stage breast cancer patients. Appreciating the indications and understanding the likely outcomes from NACT in select situations, can result in significant improvements in patient tailored care.

Breast Cancer Risk Assessment Tools for Stratifying Women into Risk Groups: A Systematic Review.

BACKGROUND: The benefits and harms of breast screening may be better balanced through a risk-stratified approach. We conducted a systematic review assessing the accuracy of questionnaire-based risk assessment tools for this purpose. METHODS: Population: asymptomatic women aged ≥40 years; Intervention: questionnaire-based risk assessment tool (incorporating breast density and polygenic risk where available); Comparison: different tool applied to the same population; Primary outcome: breast cancer incidence; Scope: external validation studies identified from databases including Medline and Embase (period 1 January 2008-20 July 2021). We assessed calibration (goodness-of-fit) between expected and observed cancers and compared observed cancer rates by risk group. Risk of bias was assessed with PROBAST. RESULTS: Of 5124 records, 13 were included examining 11 tools across 15 cohorts. The Gail tool was most represented (n = 11), followed by Tyrer-Cuzick (n = 5), BRCAPRO and iCARE-Lit (n = 3). No tool was consistently well-calibrated across multiple studies and breast density or polygenic risk scores did not improve calibration. Most tools identified a risk group with higher rates of observed cancers, but few tools identified lower-risk groups across different settings. All tools demonstrated a high risk of bias. CONCLUSION: Some risk tools can identify groups of women at higher or lower breast cancer risk, but this is highly dependent on the setting and population.

A Novel Biosignature Identifies Patients With DCIS With High Risk of Local Recurrence After Breast Conserving Surgery and Radiation Therapy.

PURPOSE: There is an unmet need to identify women diagnosed with ductal carcinoma in situ (DCIS) with a low risk of in-breast recurrence (IBR) after breast conserving surgery (BCS), which could omit radiation therapy (RT), and also to identify those with elevated IBR risk remaining after BCS plus RT. We evaluated a novel biosignature for a residual risk subtype (RRt) to help identify patients with elevated IBR risk after BCS plus RT. METHODS AND MATERIALS: Women with DCIS treated with BCS with or without RT at centers in the US, Australia, and Sweden (n = 926) were evaluated. Patients were classified into 3 biosignature risk groups using the decision score (DS) and the RRt category: (1) Low Risk (DS ≤2.8 without RRt), (2) Elevated Risk (DS >2.8 without RRt), and (3) Residual Risk (DS >2.8 with RRt). Total and invasive IBR rates were assessed by risk group and treatment. RESULTS: In patients at low risk, there was no significant difference in IBR rates with or without RT (total, P = .8; invasive IBR, P = .7), and there were low overall 10-year rates (total, 5.1%; invasive, 2.7%). In patients with elevated risk, IBR rates were decreased with RT (total: hazard ratio [HR], 0.25; P < .001; invasive: HR, 0.28; P = .005); 10-year rates were 20.6% versus 4.9% (total) and 10.9% versus 3.1% (invasive). In patients with residual risk, although IBR rates decreased with RT after BCS (total: HR, 0.21; P < .001; invasive: HR, 0.29; P = .028), IBR rates remained significantly higher after RT compared with patients with elevated risk (HR, 2.5; 95% CI, 1.2-5.4; P = .018), with 10-year rates of 42.1% versus 14.7% (total) and 18.3% versus 6.5% (invasive). CONCLUSIONS: The novel biosignature identified patients with 3 distinct risk profiles: Low Risk patients with a low recurrence risk with or without adjuvant RT, Elevated Risk patients with excellent outcomes after BCS plus RT, and Residual Risk patients with an elevated recurrence risk remaining after BCS plus RT, warranting potential intensified or alternative treatment approaches.

Dataset for pathology reporting of ductal carcinoma in situ, variants of lobular carcinoma in situ and low-grade lesions: recommendations from the International Collaboration on Cancer Reporting (ICCR).

AIMS: To describe a new international dataset for pathology reporting of ductal carcinoma in situ (DCIS), variants of lobular carcinoma in situ (LCIS) and low-grade lesions (encapsulated papillary carcinoma, solid papillary carcinoma in situ, Paget's disease) produced by the International Collaboration on Cancer Reporting (ICCR). METHODS AND RESULTS: The ICCR, a global alliance of pathology bodies, uses a rigorous and efficient process for the development of evidence-based, structured datasets for pathology reporting of common cancers. Their aim is to support quality pathology reporting and engender understanding between the breast surgeon, pathologist, and oncologist for optimal and uniform patient management globally. Here we describe the dataset for DCIS, some variants of LCIS (namely the pleomorphic and the florid variants), and low-grade lesions by a multidisciplinary panel of internationally recognized experts. The agreed dataset comprises 12 core (required) and five noncore (recommended) elements suitable for both developed and low-income jurisdictions, derived from a review of current evidence. Areas of contention were addressed using a pragmatic approach in the absence of evidence. Use of all core elements is the minimum reporting standard for any individual case. Commentary is provided, explaining each element's clinical relevance, definitions to be applied where appropriate for the agreed list of value options and the rationale for considering the element as core or noncore. CONCLUSION: This first internationally agreed dataset for DCIS, variants of LCIS, and low-grade lesions reporting will enable their standardization of pathology reporting and enhance clinicopathological communication leading to improved patient outcomes. Widespread adoption will also facilitate international comparisons, multinational clinical trials, and help to improve the management of breast disease globally.

Impact of the EndoPredict genomic assay on treatment decisions for oestrogen receptor-positive early breast cancer patients: benefits of physician selective testing.

PURPOSE: Genomic tests improve accuracy of risk prediction for early breast cancers but these are expensive. This study evaluated the clinical utility of EndoPredict®, in terms of impact on adjuvant therapy recommendations and identification of parameters to guide selective application. METHODS: Patients with ER-positive, HER2-negative, and early-stage invasive breast cancer were tested with EndoPredict®. Two cohorts were recruited: one consecutively and another at clinical team discretion. Systemic treatment recommendations were recorded before and after EndoPredict® results were revealed to the multidisciplinary team. RESULTS: 233 patients were recruited across five sites: 123 consecutive and 110 at clinical team discretion. In the consecutive cohort 50.6% (62/123) cases were classified high risk of recurrence by EndoPredict®, compared with 62.7% (69/110) in the selective cohort. A change in treatment recommendation was significantly more likely (p < 0.0001) in the selective cohort (43/110, 39.1%) compared to the consecutive group (11/123, 8.9%). The strongest driver of selective recruitment was intermediate grade histology, whilst logistic regression modelling demonstrated that nodal status (p < 0.001), proliferative rate (p = 0.001), and progesterone receptor positivity (p < 0.001) were the strongest discriminators of risk. CONCLUSION: Whilst molecular risk can be predicted by traditional variables in a high proportion of cases, EndoPredict® had a greater impact on treatment decisions in those cases selected for testing at team discretion. This is indicative of the robust ability of the clinical team to identify cases most likely to benefit from testing, underscoring the value of genomic tests in the oncologists' tool kit.

POSNOC-POsitive Sentinel NOde: adjuvant therapy alone versus adjuvant therapy plus Clearance or axillary radiotherapy: a randomised controlled trial of axillary treatment in women with early-stage breast cancer who have metastases in one or two sentinel nodes.

INTRODUCTION: ACOSOG-Z0011(Z11) trial showed that axillary node clearance (ANC) may be omitted in women with ≤2 positive nodes undergoing breast conserving surgery (BCS) and whole breast radiotherapy (RT). A confirmatory study is needed to clarify the role of axillary treatment in women with ≤2 macrometastases undergoing BCS and groups that were not included in Z11 for example, mastectomy and those with microscopic extranodal invasion. The primary objective of POsitive Sentinel NOde: adjuvant therapy alone versus adjuvant therapy plus Clearance or axillary radiotherapy (POSNOC) is to evaluate whether for women with breast cancer and 1 or 2 macrometastases, adjuvant therapy alone is non-inferior to adjuvant therapy plus axillary treatment, in terms of 5-year axillary recurrence. METHODS AND ANALYSIS: POSNOC is a pragmatic, multicentre, non-inferiority, international trial with participants randomised in a 1:1 ratio. Women are eligible if they have T1/T2, unifocal or multifocal invasive breast cancer, and 1 or 2 macrometastases at sentinel node biopsy, with or without extranodal extension. In the intervention group women receive adjuvant therapy alone, in the standard care group they receive ANC or axillary RT. In both groups women receive adjuvant therapy, according to local guidelines. This includes systemic therapy and, if indicated, RT to breast or chest wall. The UK Radiotherapy Trials Quality Assurance Group manages the in-built radiotherapy quality assurance programme. Primary endpoint is 5-year axillary recurrence. Secondary outcomes are arm morbidity assessed by Lymphoedema and Breast Cancer Questionnaire and QuickDASH questionnaires; quality of life and anxiety as assessed with FACT B+4 and State/Trait Anxiety Inventory questionnaires, respectively; other oncological outcomes; economic evaluation using EQ-5D-5L. Target sample size is 1900. Primary analysis is per protocol. Recruitment started on 1 August 2014 and as of 9 June 2021, 1866 participants have been randomised. ETHICS AND DISSEMINATION: Protocol was approved by the National Research Ethics Service Committee East Midlands-Nottingham 2 (REC reference: 13/EM/0459). Results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN54765244; NCT0240168Cite Now.