Patterns of Post-Mastectomy Radiotherapy in Immediate Breast Reconstruction – Results from the iBRA-2 Cohort Study

doi:10.21203/rs.3.rs-1108079/v1

Purpose

Long-term data indicates that post-mastectomy radiotherapy (PMRT) is associated with improved overall survival in all node-positive breast cancer patients. Immediate breast reconstruction (IBR) remains controversial in the context of planned PMRT, but rates of IBR are increasing. The aim of this study was to examine current practice of PMRT in patients undergoing mastectomy +/- IBR.

Methods

Data were collected from 2,526 patients enrolled in the iBRA-2 prospective cohort study undergoing mastectomy +/- IBR between 1^st July and 31^st December 2016, recruited consecutively at 71 centres across the United Kingdom, Ireland, and five international centres.

Results

Of a total of 2,590 breast procedures included in the analysis, 696 were implant-based, 105 pedicled flap and 230 free-flap reconstruction. 31.4% of implant-based, 34.3% of pedicled, and 32.5% of free-flap reconstructions were recommended for PMRT. PMRT recommendation by cancer stage was 21% for T1-2 N0, 65% for T1-2 N1, and 89% for T_any N2 and T3 N_any disease. On multivariate analysis, patients undergoing IBR were no less likely to be recommended for PMRT than patients having mastectomy only. However, patients in Northern Ireland/Ireland, the North of England, and Scotland were less likely to be recommended for PMRT.

Conclusion

Although IBR was more likely to be performed for lower stage cancers and younger patients with fewer co-morbidities, patients undergoing IBR were no less likely to be recommended for PMRT, irrespective of reconstruction technique. This study also highlighted regional variation in PMRT practice within the UK which merits further investigation.

General Biochemistry

Molecular Biology

Immediate breast reconstruction

breast cancer

radiotherapy

cohort study

trainee collaborative.

Breast cancer is the most common female cancer in Europe with 562,000 new cases diagnosed in 2018 [1]. Despite advances in treatment and early diagnosis, almost 40% of women undergo mastectomy as their primary surgery [2, 3]. After surgery, radiotherapy is the second most commonly used treatment for breast cancer. Long-term data combining a number of previous randomised-controlled trials demonstrates that post-mastectomy radiotherapy (PMRT) reduces recurrence rate and improves survival in all node-positive breast cancer patients [4]. As a result, the indications for PMRT in women with breast cancer are widening. Population-based data from the US shows that use of PMRT in patients with 1-3 positive lymph nodes increased significantly between 2003 and 2012 [5, 6]. Several national treatment guidelines now recommend that radiotherapy be considered for all patients with node-positive disease after mastectomy [7–9].

Women undergoing mastectomy are offered immediate breast reconstruction (IBR) with the aim of improving quality of life [10]. IBR remains controversial in the context of planned PMRT [11]. However, an analysis of the US Surveillance, Epidemiology, and End Results (SEER) database indicates that an increase in PMRT amongst women with stage I to III breast cancer undergoing mastectomy did not lead to a concomitant decrease in IBR [6]. In fact, data from the US Mastectomy Reconstruction Outcomes Consortium (MROC) for >2,000 patients demonstrates that around 25% of implant-based and half of autologous reconstructions received PMRT [12]. The UK National Institute of Health and Care Excellence (NICE) recently reviewed 23 observational studies and concluded that there was insufficient evidence to indicate worse patient outcomes from PMRT in the setting of IBR, and that IBR should be offered even if adjuvant RT is anticipated [13].

Currently, high quality evidence for the use of PMRT in intermediate-risk breast cancer (defined as pT1–2N1; pT3N0; or pT2N0 if also grade III or with lympho-vascular invasion) is lacking and the results of a large European randomized-controlled trial are awaited [14]. At the same time, rates of IBR in the UK, in particular implant-based reconstruction, are increasing [15], yet large scale population-based data on the use of PMRT in patients undergoing IBR has not been published to date. In reconstructive breast surgery, the trainee research collaborative model has recently emerged as a time and cost-effective method for delivering large-scale prospective studies [16, 17].

This Breast Reconstruction Research Collaborative of breast and plastic surgeons was utilized to deliver the iBRA-2 study to determine the impact of IBR on the delivery of adjuvant treatment [18]. The present study was undertaken to analyse patterns of PMRT amongst patients undergoing mastectomy with and without IBR enrolled in the iBRA-2 cohort.

The methods of the iBRA-2 cohort study have been reported elsewhere [18, 19]. Briefly, all breast and plastic surgical units performing mastectomy with and without IBR were invited to participate in the study via the professional associations (Association of Breast Surgery [ABS] and British Association of Plastic Reconstructive and Aesthetic Surgeons [BAPRAS] and the breast and plastic surgery collaborative research networks (Reconstructive Surgery Trials Network [RSTN] and the Mammary Fold Academic and Research Collaborative [MFAC]). Of 90 centres, who expressed an initial interest, 76 centres enrolled 2,526 consecutive patients between 1st July and 31st December 2016. The study sample covered approximately half of all UK breast units as well as five centres in Ireland (recruiting n=103), four centres in Italy and one in Egypt (recruiting n=145).

Consecutive women aged 18 or over undergoing mastectomy with or without IBR using any technique for invasive or pre-invasive (ductal carcinoma in situ, DCIS) breast cancer with curative intent were included. Patients were identified from multidisciplinary team (MDT) meetings; unit operating records and clinics. Excluded were patients undergoing risk-reducing surgery (without a therapeutic mastectomy for breast cancer), partial mastectomy including wide local excision with volume replacement (latissimus dorsi mini-flaps; lateral intercostal perforator (LICAP) or thoracodorsal artery perforator (TDAP) flaps) or displacement techniques (therapeutic mammaplasty), and those with distant metastatic disease.

The iBRA-2 study was classified as service evaluation according to the NHS Health Research Authority online decision tool http://www.hra-decisiontools.org.uk/research/, so ethical approval was not required. Each participating centre obtained local governance approvals prior to entering patients into the study. Data were collected prospectively, including baseline demographic and operative data. Oncological data and adjuvant treatment recommendations were collected from post-operative MDT meeting records. Pilot data collected at a number of participating sites between 1st May and 30th June 2016 suggested that adjuvant therapy was unlikely to commence earlier than six weeks post-operatively. Data collection in patients not requiring adjuvant treatment therefore continued from the last definitive cancer surgery until six weeks following surgery.

Study data were collected and managed using REDCap (Research Electronic Data Capture) electronic data capture tools hosted at the Kennedy Institute of Rheumatology, University of Oxford [20, 21]. REDCap is a secure, web-based software platform designed to support data capture for research studies, providing 1) an intuitive interface for validated data capture; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to common statistical packages; and 4) procedures for data integration and interoperability with external sources. For quality assurance purposes, the lead investigator at each site was asked to independently validate 5-10% of the data. If concordance between the data entered on REDCap and that independently-validated was <90%, the unit’s data were excluded from the analysis, consistent with the QA procedure used in other collaborative projects.

Study definitions and endpoints

Primary and secondary outcomes in iBRA-2 were selected based on current best practice [22] and national breast cancer guidelines [23]. The endpoint in the present study was use of adjuvant radiotherapy, defined as the recorded post-operative MDT outcome “radiotherapy recommended” or “radiotherapy to be discussed”. For analysis purposes, patients in iBRA-2 were categorised into four groups according to the most complex surgical procedure received as: i) mastectomy only (no reconstruction), ii) mastectomy and IBR with implant-only techniques, iii) mastectomy and IBR with pedicled flaps, and iv) mastectomy and IBR with free-flap techniques.

Implant-based procedures included any reconstruction in which only expanders/implants were used to reconstruct the breast, either with or without biological (e.g. acellular dermal matrix) or synthetic (e.g titanium-coated polypropylene) mesh irrespective of whether the implant/expander was placed in a pre or sub-pectoral position. Pedicled-flap procedures included any pedicled-flap used to reconstruct the breast with or without an implant/expander, including latissimus dorsi (LD) and transverse rectus abdominus myocutaneous (TRAM) flaps. Free-flap procedures included any technique in which a microvascular free-flap was used for IBR, including deep inferior epigastric perforator (DIEP), superficial inferior epigastric perforator (SIEA), superior and inferior gluteal artery perforator (SGAP and IGAP), and transverse upper gracilis (TUG) flaps. All complications were defined a priori [19]. Major complications were defined as any complication requiring re-admission or re-operation. Minor complications were defined as those managed conservatively. An analysis of short-term complications is described elsewhere [18].

Statistical analysis

Descriptive summary statistics were calculated for each variable in the whole cohort and sub-divided by procedure type (mastectomy only; implant-based reconstruction; pedicled reconstruction; and free-flap reconstruction). Categorical data were summarised by counts and percentages, and continuous data by median, interquartile range (IQR), and range. Procedure groups were compared using appropriate non-parametric statistics. Univariable and multivariable logistic regression were used to explore associations between clinico-pathological variables and use of PMRT, including patient and procedure-related factors, namely, age, body mass index (BMI), smoking status, American Society of Anaesthesiologists’ (ASA) grade; diabetes, ischaemic heart disease (IHD); other comorbidities, chemotherapy, ER- and HER-2 status, lymphovascular invasion, tumour grade, multi-focality, and procedure type.

To assess selection bias, correlation between proportions of patients undergoing PMRT and IBR was determined by region using Pearson’s r. Regional trends in PMRT across the United Kingdom and Ireland were further assessed in multivariable logistic regression, adjusted for BMI, co-morbidities, smoking status, ASA, ER- and HER2-status, lymphovascular invasion, multi-focality and tumour grade, and including clustering by centre. All analyses were performed in STATA 15 (STATA Inc, Texas).

Of 2,526 patients recruited into the iBRA-2 study, 666 underwent implant-based reconstruction, 105 received pedicled flaps, and 227 underwent free-flap reconstruction. The remainder of patients underwent mastectomy only without reconstruction. As 80 patients had bilateral cancer surgery and there were 16 procedures with missing outcome data, a total of 2,590 breast procedures were included in the analysis. On a per breast basis, Table 1 summarises patient demographics and adjuvant therapy decisions by procedure type. Patients undergoing mastectomy alone (n=1,559 breast procedures) were older than those undergoing IBR and were more likely to have co-morbidities as indicated by ASA grade. Patients undergoing IBR were more likely to have lower stage cancers. Adjuvant chemotherapy was more likely to be recommended after mastectomy-only than after IBR. Adjuvant radiotherapy was recommended or for discussion in 44.9% of mastectomies, 31.4% of implant-based reconstructions, and in 34.3% and 32.5% of pedicled and free-flap reconstructions, respectively (p<0.001).

Table 1

Patient demographics and proportion of patients offered adjuvant radiotherapy in the iBRA-2 study by type of surgical procedure.
Per breast data	Mastectomy only		Implant reconstruction		Pedicled flap reconstruction		Free flap reconstruction		p-value
	(n=1559)		(n=696)		(n=105)		(n=230)
Age (median, IQR)	65	54-75	50	43-57	52	47-60	50	45-56	<0.001
ASA grade (n, %)
1	333	21.4%	273	39.2%	40	38.1%	59	25.7%	<0.001
2	906	58.1%	379	54.5%	61	58.1%	160	69.6%
3	279	17.9%	23	3.3%	3	2.9%	8	3.5%
Missing data	72	4.6%	21	3.0%	1	1.0%	3	1.3%
T stage (n, %)
Tis	141	9.0%	161	23.1%	26	24.8%	57	24.8%	<0.001
T1-2	1199	76.9%	448	64.4%	64	61.0%	139	76.9%
T3	189	12.1%	53	7.6%	9	8.6%	18	12.1%
Missing data	30	1.9%	34	4.9%	6	5.7%	16	1.9%
N stage (n, %)
N0	910	58.4%	524	75.3%	71	67.6%	158	68.7%	<0.001
N1	372	23.9%	110	15.8%	16	15.2%	42	18.3%
N2	247	15.8%	41	5.9%	12	11.4%	14	6.1%
Missing data	30	1.9%	21	3.0%	6	5.7%	16	7.0%
Chemotherapy (n, %)
Recommended	421	27.0%	154	22.1%	28	26.7%	46	20.0%	0.001
For discussion	138	8.9%	36	5.2%	5	4.8%	9	3.9%
For Oncotype DX™	95	6.1%	64	6.1%	5	4.8%	17	7.4%
Missing data	6	0.4%	6	0.9%	0	0%	0	0%
Radiotherapy (n, %)
Recommended	614	39.4%	198	28.4%	35	33.3%	62	27.0%	<0.001
For discussion	86	5.5%	19	2.7%	1	1.0%	19	5.5%
Missing data	4	0.3%	9	1.3%	0	0%	0	0%

PMRT recommendation by tumour and nodal stage

Figure 1 shows the proportion of patients on a per-breast basis (n=2,590) recommended for PMRT by tumour stage. Out of all patients with T3, N2 or N3 stage disease, 89% were recommended for radiotherapy, while 64.7% of patients with N1 stage disease were recommended for radiotherapy. Interestingly, 13.2% of Tis and 21.1% of N0 stage patients were also recommended for radiotherapy. When sub-divided by tumour and nodal stage, there were no differences between surgical procedure types (see Supplementary Table).

Table 2 shows the patient and tumour variables associated with PMRT recommendation. In multivariable analysis, patients with larger tumours and more advanced lymph node state were more likely to receive a recommendation for PMRT. However, patients undergoing IBR were as likely as those having simple mastectomy to be recommended for PMRT, although there was evidence of a trend for women receiving implant-based reconstruction to be less likely to be offered PMRT compared to patients undergoing mastectomy only (OR 0.56, CI 0.44-0.73, p<0.001 univariable; OR 0.69, 0.45-1.04, p=0.08 multivariable).

Table 2. Predictors of PMRT recommendation. MVA also included age, body mass index, co-morbidities (ischaemic heart disease, diabetes, other), smoking status, chemotherapy recommendation, ASA grade, ER and HER-2 status, lymphovascular invasion, multi-focality, and tumour grade (CI = confidence interval). Full results are shown in Supplementary Tables.

Per breast data

Univariable analysis

Multivariable analysis

(n=2,000)

Odds ratio

95% CI

p value

Odds ratio

95% CI

p value

Tumour size (invasive)

0-9 mm

10-20 mm

20-50 mm

>50 mm

1

0.74

1.91

14.07

Comparator

0.57-0.95

1.48-2.46

8.91-22.24

0.02

<0.001

1

0.75

1.44

18.45

Comparator

0.51-1.08

1.01-2.06

8.45-40.26

0.12

0.046

<0.001

Lymph nodes

N0

N1

N2

1

8.02

31.37

Comparator

6.10-10.54

19.87-49.50

<0.001

1

4.86

15.54

Comparator

3.40-6.96

8.53-28.33

<0.001

Type of surgery

Mastecomy only

Implant

Pedicled flap

Free flap

1

0.56

0.61

0.65

Comparator

0.44-0.73

0.35-1.08

0.42-1.00

<0.001

0.09

0.05

1

0.69

0.63

Comparator

0.45-1.04

0.33-1.19

0.30-1.33

0.08

0.15

0.23

Impact of PMRT use on IBR

Excluding patients from five centres outside the United Kingdom and Ireland, Figure 2 shows no clear correlation between the proportion of patients recommended for PMRT and of the proportion receiving IBR across the 14 regions (r=-0.23, p=0.41).

Regional variation in PMRT

Table 3 shows the proportion of patients recommended for PMRT subdivided by regions, excluding 145 patients from centres outside the UK and Ireland. Complete datasets for multivariable analysis were available for 2,010 breast procedures. Adjusting for patient, tumour and other treatment co-variates, women undergoing mastectomy in Northern Ireland/Ireland (OR 0.37, 0.18-0.76, p=0.007), the North of England (0.38, 0.17-0.83, p=0.016), West Midlands (0.43, 0.20-0.92, p=0.029), and Scotland (0.36, 0.18-0.75, p=0.006) were less likely to be recommended for PMRT than in London and the Southeast. For patients undergoing IBR, the regional numbers were too small to subdivide further by procedure type. Nevertheless, women undergoing IBR in Yorkshire/Humberside were less likely to be recommended for PMRT (OR 0.25, 0.09-0.69, p=0.007) than in London and the Southeast.

Table 3. Rates of PMRT by region in patients undergoing mastectomy only and those undergoing IBR. Multivariable analysis (MVA) also included age, body mass index, co-morbidities (ischaemic heart disease, diabetes, other) smoking status, chemotherapy recommendation, ASA grade, ER and HER-2 status, lymphovascular invasion, multi-focality, lymph node status, and tumour size and grade (CI = confidence interval, NI = Northern Ireland). Full results are shown in Supplementary Tables.

Per breast data	Mastectomy only (n=1,184)			Breast reconstruction (any) (n=816)
Per breast data	Percentage RT recommended	OR (95% CI) MVA	p value MVA	Percentage RT recommended	OR (95% CI) MVA	p value MVA
London/Southeast	53 %	1		39 %	1
East	48 %	0.73 (0.35, 1.49)	0.381	39 %	0.54 (0.20, 1.45)	0.221
East Midlands	49 %	0.85 (0.38, 1.94)	0.704	24 %	0.47 (0.17, 1.30)	0.145
Yorkshire/Humber	37 %	0.50 (0.20, 1.22)	0.129	24%	0.25 (0.09, 0.69)	0.007
NI/Ireland	52 %	0.37 (0.18, 0.76)	0.007	47 %	1.23 (0.41, 3.65)	0.708
North	41 %	0.38 (0.17, 0.83)	0.016	25 %	0.38 (0.15, 0.95)	0.038
Scotland	44 %	0.36 (0.18, 0.75)	0.006	48 %	1.03 (0.38, 2.82)	0.952
Wales/Southwest	47 %	0.76 (0.35, 1.67)	0.493	34 %	1.43 (0.46, 4.47)	0.542
West Midlands	47 %	0.43 (0.20, 0.92)	0.029	37 %	1.24 (0.29, 5.25)	0.773

The aim of this study was to analyse patterns of PMRT amongst patients undergoing mastectomy with and without IBR. The short-term outcomes and rates of complications in the iBRA-2 patient cohort have been reported elsewhere [18]. In relation to PMRT, the present study found that between 31.4% and 34.3% of women undergoing IBR were recommended for or for discussion of radiotherapy compared to 44.9% of those receiving simple mastectomy. These figures are in keeping with several previously published observational studies showing that between 29% and 43% of patients with IBR are irradiated [12, 17, 24, 25]. Although IBR was more likely to be performed for lower stage cancers and in younger patients with fewer co-morbidities, women undergoing IBR were no less likely to be recommended for radiotherapy after adjusting for patient and tumour variables. This adds to a growing body of evidence that in the setting of PMRT, IBR is becoming an acceptable option for women requiring PMRT [26–28] and that PMRT is only one of many factors in the decision for/against IBR which include consideration of patient and oncological factors as well as surgeon and patient preferences. Indeed, it has been shown that breast cancer multi-disciplinary teams (MDTs) cannot predict with certainty whether a patient will require adjuvant PMRT [29].

We found no clear correlation between higher proportions of patients recommended for PMRT and lower proportions of IBR across different UK regions. This suggests that participating centres offered all types of IBR irrespective of whether PMRT was likely to be needed in the adjuvant setting, in keeping with findings from a similar US population-based study [6] and current clinical guidelines [13]. The individual choice of IBR technique is likely to depend on several patient and surgical factors as well as locally available expertise and access to immediate free-flap reconstruction. However, in patients requiring PMRT, implant-only IBR is generally associated with more complications compared to autologous IBR [12, 17]. Early follow-up data from two prospective cohort studies shows lower satisfaction among patients with irradiated implant-only reconstruction [30, 31]. Nevertheless, further work is required to establish the impact of PMRT on the long-term outcomes of IBR to provide high-quality data to inform practice. Initial results from non-randomised studies comparing neoadjuvant versus adjuvant radiotherapy in patients scheduled for IBR are promising and demonstrate the feasibility and safety of this approach [32] but the results of randomized trials will take some years to mature.

Compared to previous population-based analyses showing between 30.3% and 40.5% of patients with N1 disease (1-3 positive lymph nodes) receiving PMRT by 2012 [5, 6], in our study, 64.7% of such patients were recommended for PMRT. This confirms the trend of an increasing number of patients with N1 disease being considered for PMRT and it is in keeping with national clinical guidelines [7–9]. Furthermore, the number of patients in our study with non-invasive cancer receiving post-mastectomy radiotherapy appears relatively high compared to an earlier UK study [33], although our study was not restricted to the breast screening population, and the receipt of radiotherapy following mastectomy y for DCIS may be related to margin status, grade, and presence of micro-invasion.

Subdividing the data by UK regions, we found in our study that patients in Northern Ireland/Ireland, Scotland, the North of England and the West Midlands were significantly less likely to be recommended for PMRT. This highlights some interesting geographical variation, which merits further investigation. A similar US-based study found that density of radiation oncology practices was associated with receipt of PMRT in patients with N1 stage breast cancer [5]. Results of the Selective Use of Post Mastectomy Radiotherapy (SUPREMO) trial are awaited and are likely to reduce the variation in practice of PMRT use in intermediate-risk breast cancer (defined as pT1–2N1; pT3N0; or pT2N0 if also grade III or with lympho-vascular invasion) [14].

There is accumulating evidence that individual patient and tumour molecular profiles will be able to predict the response to adjuvant treatment. Several phase III trials are currently underway [34] or have already reported on the effectiveness of the 70- or 21-gene recurrence scores in selecting patients for adjuvant chemotherapy [35, 36]. Genomic-adjusted radiation dose (GARD) therapy may allow personalisation of radiotherapy on the basis of the biological effect of a given physical dose of radiation, calculated using individual tumour genomics, and has been shown to predict time to recurrence and overall survival [37]. In terms of complications from IBR, predictive risk models have been externally validated with receipt of PMRT (or not) as a predictor [38, 39]. Other risk prediction models for individual radiotherapy side-effects in the breast have been validated [40, 41], though none in the setting of IBR. In the future, personalised medicine approaches including the patient germline and tumour genomic profile may aid decision-making around IBR and PMRT.

Strengths and Limitations

To our knowledge, this is the largest prospective cohort study to date in the UK and Ireland investigating patterns of PMRT in patients undergoing mastectomy with and without IBR, but there are several limitations. Due to its observational design, the study is at risk of bias. Patients were recruited consecutively from participating centres but there were baseline differences between the treatment groups. Although we adjusted for known confounders such as cancer stage, patient age, BMI, smoking status, and ASA grade, we acknowledge that it is not possible to adjust for all potential confounders. Our study included patients from 71 centres in the UK and Ireland as well five centres in Italy in Egypt. It is possible that participating units differed from those not taking part. However, approximately half of all UK breast units were represented in the study.

Due to the short follow-up period (up to initiation of first adjuvant treatment), we were only able to analyse treatment recommendations and were unable to ascertain successful receipt or completion of PMRT in all patients. It was not possible to follow patients up to completion of adjuvant therapy with this surgical trainee collaborative design, but collaborations with oncology trainees should allow us to address this issue in the future. Moreover, a data-linkage study is planned in future to explore oncological outcomes in terms of local recurrence, disease-free and overall survival. While it is not possible to establish causation with this observational study design, the design and conduct of randomized controlled trials in the setting of IBR are perceived as difficult due to patient and surgeon’s preference for type and timing of breast reconstruction [25].

The present study provides evidence that approximately one third of patients undergoing IBR were recommended for PMRT. About two thirds of patients with T1-2 N1 disease were recommended for PMRT, which reflects current clinical treatment guidelines for this patient group. Within the UK and Ireland, the study also highlighted regional variation in PMRT practice which merits further investigation. Although IBR was more likely to be performed for lower stage cancers and in younger patients with fewer co-morbidities, patients undergoing IBR were no less likely to be recommended for radiotherapy, irrespective of reconstruction technique. Further work is required to establish the impact of PMRT on the long-term outcomes of different types of IBR to help women and surgeons make more informed decisions about breast reconstruction options.

Competing interests

TR is currently a National Institute of Health Research (NIHR) Clinical Lecturer (CL-2017-11-02) and was previously funded by a NIHR Doctoral Research Fellowship (DRF-2014-07-079). AT is funded by a Sir Henry Wellcome Fellowship. SP is an NIHR Clinician Scientist (CS-2016-16-019). This work was undertaken with the support of the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care.

The other authors have no competing interests to declare.

Data availability statement

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Authors’ contributions

SP and TR conceived the study design (subgroup analysis); TR contributed to the design, conduct, analysis of the data, interpretation of the results and wrote the first draft of the paper. AT performed the analysis, contributed to data interpretation, and drafted the manuscript. RLOC, TR, RVD, SP contributed to the study design for iBRA-2; MDG and JS contributed to study design and interpretation of the data. All authors read and approved the final manuscript.

Members of the iBRA-2 steering group are (in alphabetical order) Nicola LP Barnes, Jane Blazeby, Elizabeth Conroy, Rajiv V Dave, Matthew D Gardiner, Adrian Harnett, Chris Holcombe, Ciara O’Brien, Rachel O’Connell, Shelley Potter, Tim Rattay, and Joanna Skillman.

Local iBRA-2 investigators (alphabetically by centre) and members of the Breast Reconstruction Research Collaborative are PUBMED citable collaborators in this study and were: Aberdeen Royal Infirmary, NHS Grampian; Alain Curnier, Amir Tadros, Ivan Depasquale, Yazan A Masannat Elizabeth Smyth, Mairi Fuller, Roger Bourne, Steven Heys, Ishrak Hamo. Addenbrookes Hospital, Cambridge Universities NHS Foundation Trust; Fatima Aloraifi, Laura Fopp, Radhika Bali, Sarah Bache, Sarah L Benyon, Michael S Irwin, Amit Agrawal, Charles M Malata. Airedale NHS Foundation Trust; Claire Murphy. Basildon and Thurrock Hospitals NHS Foundation Trust; Adam Misky, Dennis Wayne Chicken. Beaumont Hospital and the RCSI; Nassreen Abdullah, Arnold D K Hill. Belfast City Hospital, Belfast Health and Social Care Trust; Carolyn Cullinane, Gareth Irwin, Stuart A McIntosh, Sigi Refsum, Samantha Sloan, Peter Mallon. Betsi Cadwaladr University Health Board; Chiara Sirianni, Ilyas Khattak, Chiara Sirianni. Blackpool Teaching Hospitals NHS Foundation Trust; Geerthan Nagachandra, Pasupathy Kiruparan, Debasish Debanth. Breast Care Centre, North Bristol NHS Trust, Southmead Hospital, Bristol; Simon Davey, Terry-Ann Curran, Matilda Svenning, Sasirekha Govindarajulu, Zenon Rayter, Rachel Ainsworth, Simon Cawthorn, Ajay Sahu, Sherif Wilson, Elena Prousskaia. Breast Unit Department. University of Naples “Federico II”, Naples, Italy; Antonello Accurso, Nicola Rocco, Rosa Di Micco, Antonello Accurso, Gennaro Limite. Breast Unit Department S. Maria delle Grazie ASL Na 2 Pozzuoli; Raffaele Ceccarino, Raffaele Liccardo, Guido Coco. Broomfield Hospital, Mid Essex Hospital Services NHS Trust; Metin Nizamoglu, Mary Morgan, Venkat Ramakrishnan. Cannizzaro Hospital, Catania; Giuseppe Catanuto. Castle Hill Hospital, Hull and East Yorkshire Hospitals NHS Trust; Alex Wilkins, Penelope McManus, Peter Kneeshaw, Kartikae Grover, Tapan Mahapatra, Brendan Wooler, Bilal Elahi, Naila Ihsan. Charing Cross Hospital, Imperial College Healthcare NHS Trust; Alexandra Bucknor, Dimitris Reissis, Judith Hunter, Simon Wood, Navid Jallali, Francis P Henry, Liaquat S Verjee, Jason Lee. Chesterfield Royal Hospital NHS Foundation Trust; Shazia M Khan, Iman Azmy, Julia Massey, Ciaran Hollywood, Michael Oluwajana. Countess of Chester Hospital NHS Foundation Trust; Sonia Bathla, Joanna Seward, Claudia Harding-MacKean. Darent Valley Hospital, Dartford and Gravesham NHS Trust; Risha Lane, Kothandaraman Murali, Bashishta Biswas, Pawel Trapszo, Seema Seetharam. Dorset County Hospital NHS Foundation Trust; Katy Kennedy, Louise Alder, Tomasz Graja. East Cheshire NHS Trust; Khalid Amin, Jalal Kokan, Chandeena Roshanlall. Edinburgh Breast Unit, Western General Hospital, NHS Lothian; Emma Gill, Dhananjay Kulkarni, JM Dixon, Oliver Young, Talha Saleem. Glasgow Royal Infirmary, NHS Greater Glasgow and Clyde; M Biddle, Marie Kearns, Eva Weiler-Mithoff, Ben Chew, Andy Malyon, John Scott, David McGill, Iain Mackay. Glenfield Hospital, University Hospitals of Leicester; Salena Bains, Sara Barrows, Tim Rattay, Simon Pilgrim, Sheila Shokuhi, Kelly Lambert, Frances Kenny, Kalliope Valassiadou, Monika Kaushik, Jaroslaw Krupa, Dimitris Dragoumis. Good Hope Hospital, Heart of England NHS Foundation Trust; Quratul ain, Pavlos Lampropoulos, Sarah Moss, Haitham Khalil, Anwar Haq, Balapathiran Balasubramanian. Guy's and St Thomas' NHS Foundation Trust; Petros Charalampoudis, Hisham Hamed, Ashutosh Kothari, Tibor Kovacs, Michael Douek. Harrogate and District NHS Foundation Trust; Iftikhar Mehmood, Biswajit Ray, Matthew Adelekan. Homerton University Hospital NHS Foundation Trust; Laura Humphreys, Salim Tayeh, Christina Choy, Laila Parvanta. Istituto Oncologico Veneto, Padova, Italy; Silvia Michieletto, Tania Saibene. James Paget University Hospitals NHS Foundation Trust; James O'Brien, Sue Down, Sarah Downey, Jerome Pereira. Lincoln County Hospital, United Lincolnshire Hospitals NHS Trust; A S Sami, Anzors Gvaramadze, Jibril A Jibril, Dinesh Thekkinkattil. Llanelli Peony Breast Unit; S Udayasankar, Saira Khawaja, Yousef Shariaha, Simon Holt. Luton and Dunstable University Hospital; Ruth James, Hirah Rizki, Katharine Kirkpatrick, Duraisamy Ravichandran, Deepak Shrestha. Maidstone and Tunbridge Wells NHS Trust; Ellora Barua, Deepika Akolekar. Mid Cheshire Hospitals NHS Foundation Trust; Ahmed Hamad, Eleftheria Kleidi, Susan Hignett, Vanessa Pope, Salma Naseem. Milton Keynes University Hospital NHS Foundation Trust; Jennifer Isherwood, Rachel Soulsby, Amanda Taylor, Kian Chin. Morriston Hospital, Abertawe Bro Morgannwg University Health Board; Dai Nguyen. Musgrove Park Hospital, Taunton and Somerset NHS Foundation Trust; Francesca Guest, Amanda Thorne. Nevill Hall Hospital, Aneurin Bevan University Health Board; Valentina Lefemine. Norfolk and Norwich University Hospitals NHS Foundation Trust; Chris Kirchhoff, Declan C Murphy, Michelle Lo, Ruth Harcourt, Simon J Pain, Maged I Hussien, Katalin Zechmeister, E.M. Sassoon, Andrea Figus, Richard M Haywood, Rozina Ali, Susanna Alexander, Adrian Harnett, Konstantinos Geropantas, Daniel Epurescu. North Middlesex University Hospital; Rebecca Lewis, Oladapo Fafemi, Jasdeep Gahir, Tasha Gandamihardja. Nottingham Breast Institute, Nottingham University Hospitals NHS Trust; Jennett Kelsall, Nazli Muhibullah, Charlene Otieno, Fayyaz Mazari, Marta Dauria, Lisa Whisker, Douglas Macmillan, Eleanor Gutteridge, Tuabin Rasheed, Hazem Khout, Kristjan Asgeirsson, Stephen McCulley. Ospedale Santa Chiara, University of Pisa, Italy; Maria Donatella Mariniello, Manuela Roncella, Matteo Ghilli, Livio Colizzi, Elena Rossetti, Lo Russo Marzia, Loredana Fustaino, Alessandro Quattrini Li. Oxford University Hospitals NHS Foundation Trust; Kate L Harvey, Rebecca Windle, Dionysios Dennis Remoundos, Pankaj Roy, Gael MacLean, Asha Adwani. Peterborough City Hospital, North West Anglia NHS Foundation Trust; Elena Popa, Steven Goh, Geeta Shetty. Poole Hospital NHS Foundation Trust; Sarah Clark. Portsmouth Hospitals NHS Trust; Lorenzo Bernaudo, Avi Agrawal, Lucy Mansfield. Princess Alexandra Hospital NHS Trust; Sally Tebbal, Ashraf Patel, Veronica Grassi. Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust; Ojas Pujji, Kathryn Hamnett, Naren Basu. Royal Bolton Hospital, Bolton NHS Foundation Trust; Emily Granger, Michael Durbar, Panagiotis Pikoulas, Clare Garnsey, Philip Walker, Angela J Vollermere, Ioannis Michalakis. Royal Devon and Exeter NHS Foundation Trust; Robin Jones, Mina Youssef, Charlotte Ives, Mohammad Masood, Julie Dunn, Sisse Olsen, Douglas Ferguson, Rachel Tillett. Royal Free London NHS Foundation Trust; Anna Allan, Alex Woollard, Rebecca Canny, Alexander Woollard, Afshin Mosahebi, Stephen Hamilton, Shadi Ghali,Daniel Marsh, Jagdeep Chana, Nilesh Sojitra, Ibby Younis. Royal Hampshire County Hospital, Hampshire Hospitals NHS Foundation Trust; Dick Rainsbury, Natalie Chand, Vasileios Kalles, Anne Stebbing, Kevin Harris, Siobhan Laws. Royal Liverpool and Broadgreen University Hospitals NHS Trust; Chris Holcombe, Anne Tansley, Geraldine Mitchell, Emma de Sousa, Julia Henderson, Mysore Chandrashekar. Royal Marsden NHS Foundation Trust; Bernadette Pereira, Chloe Constantinou, Dalia Elfadl, Foivos Irakleidis, Izaro Hernan, Miriam Byrne, Natalie To, Rachel O'Connell, Jennifer Rusby, Peter Barry, Katerine Krupa, William Allum, Fiona MacNeill, Nicola Roche, Gerald Gui, Kelvin Ramsey, Paul Harris, Stuart James, Kieran Power. Royal United Hospitals Bath NHS Foundation Trust; Shelley Potter, Richard Sutton, Jamie McIntosh, Nicola Laurence. Royal Victoria Infirmary, Newcastle Upon Tyne Hospitals NHS Foundation Trust; Louise MacLennan, Robert Milligan, Henry Cain, Adam Critchley, Joe O'Donoghue, Loraine Kalra, Nick Collis. Salisbury NHS Foundation Trust; Gina Weston-Petrides, Roanne Fiddes, Victoria Brown, Anna Aertssen, Diana Slade-Sharman, Mansoor Khan, Caroline McGuiness. Sant'Andrea Hospital of Rome; Vittoria Amorosi, Santanelli di Pompeo Fabio. St Bartholomew's Hospital, Barts Health NHS Trust; Georgios Exarchos, Natasha Jiwa, Jennifer Hu, Serena Ledwidge, Laura Johnson, Anthony Peel, Naseem Dhooma. St Vincent's University Hospital, Dublin; Eric Farrell, Liam Devane, Ruth Tevlin, Enda McDermott, Ruth Prichard, Denis Evoy, Jane Rothwell, James Geraghty, Colin Morrison, Catriona Lawlor. St. James University Hospital, The Leeds Teaching Hospitals NHS Trust; Fiona Langlands, Lauren Taylor, Philip Turton, Raj Achuthan, Kieran Horgan, Shireen Mckenzie, Brian Hogan, Mark Lansdown, Channegowda Navin. The Ipswich Hospital NHS Trust; Liz Sherwin, Caroline Mortimer, Neeraj Garg. The Mid Yorkshire Hospitals NHS Trust; Rahma Adam, Tahera Arif, Zbigniew Kryjak, Deedar Ali, Ravi Sowdi. The Royal Wolverhampton NHS Trust; Elena Fage, Senthurun Mylvaganam, Pilar Matey, Raghavan Vidya, Tapan Sircar. University Hospital of North Tees; Oubida Asaad, Pud Bhaskar, Matei Dordea. University Hospital of South Manchester; Ada Chrysafi, Damian McCartan, Rajiv Dave, Rachel Foster, Rebecca Wilson, Sylvia Okwemba, Yousef Majeed, Ciara O'Brien, Vinod Mathen, John Murphy, Nicola Barnes, Ashu Gandhi, James Harvey, Cliona C Kirwan, Richard Johnson. University Hospitals Coventry & Warwickshire; Krupali Patel, Maria Dalmau Ribas, Natali Vigneswaran, Tom Challoner, Joanna Skillman, Alan Park, Maged Rizkalla, Abigail Tomlins, Kat McEvoy. University Hospitals of North Midlands NHS Trust; Sadaf Jafferbhoy, Soni Soumian, Sankaran Narayanan, Robert Kirby. West Hertfordshire Hospitals NHS Trust; Sladana Bajrusevic, Joseph Maalo, Michalis Charalambous, Lee Min Lai, Kelvin Chong , Simon Thomson, Sherif Monib. Whiston Hospital, St Helens and Knowsley Teaching Hospitals NHS Trust; Leena Chagla, Riccardo Audisio, Rieka Taghizadeh, Azhar Iqbal. Wirral University Teaching Hospital NHS Foundation Trust; Karen James, Maria Callaghan, Shabbir Poonawala, Jonathan Lund, Raman Vinayagam. Worcestershire Acute Hospitals NHS Trust; Sadaf Jafferbhoy, Steven Thrush, Rachel Bright Thomas, Michelle Mullan, Jevan Taylor. York Teaching Hospital NHS Foundation Trust; Ryo Yoshimura, Tom Mathew, Ben Mancey Jones, Kailas Munot, Rana Nasr, Jenny Piper, Deena El-Sharief. Zagazig University Hospital, Egypt; Mohammed Mustafa.

^§Members of the iBRA-2 Steering Group, the Breast Reconstruction Research Collaborative and Mammary Fold Academic and Research Collaborative are PUBMED citable collaborators and are listed at the end of this manuscript.

TR is an NIHR Clinical Lecturer and SP is an NIHR Clinician Scientist.

Corresponding author: Dr Tim Rattay, Leicester Cancer Research Centre, University of Leicester, Clinical Sciences Building, Leicester LE2 2LX, UK, [email protected].

Previous communications: Earlier versions of this analysis were presented at the British Association of Surgical Oncology (BASO) Annual Scientific Meeting on 4^th November 2018, and at the UK Association of Breast Surgery Conference on 13^th May 2019, abstract published in Eur J Surg Oncol (2019) 45 (5): 878. https://doi.org/10.1016/j.ejso.2019.01.190.

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iBRA2RadiotherapySupplTables.xlsx
Supplementary Tables

Patterns of Post-Mastectomy Radiotherapy in Immediate Breast Reconstruction – Results from the iBRA-2 Cohort Study

Status:

Version 1

Abstract

Figures

Introduction

Methods

Study definitions and endpoints

Statistical analysis

Results

PMRT recommendation by tumour and nodal stage

Impact of PMRT use on IBR

Regional variation in PMRT

Discussion

Strengths and Limitations

Conclusions

Declarations

Competing interests

Data availability statement

Authors’ contributions

References

Supplementary Files

Status:

Version 1