Preoperative Radiation Therapy and Immediate Breast Reconstruction

The PRADAIIBE study is a multicentric phase 3 clinical trial, investigating the effects of radiotherapy timing on breast reconstruction results, in breast cancer patients.

This study will be recruiting Belgian breast cancer patients. They can participate if there is an indication for both surgical removal of the complete breast tissue, in the form of a skin or nipple sparing mastectomy (SSM/NSM) and postoperative radiotherapy treatment, as well as a wish for breast reconstruction.

During the screening visit the eligibility criteria are checked, demographic information is collected, a baseline assessment is performed and the participant will be randomly assigned to either the control of intervention group.

Those assigned to the control group will follow the standard of care treatment in the classic sequence of oncological surgery followed by radiotherapy. The breast reconstruction surgery will take place either at the same time (mostly tissue expander implantation) as the oncological surgery, or at a delayed moment.

Patients assigned to the intervention group will receive the same standard of care treatments, with the difference that the radiotherapy is administered before the oncological surgery. In this arm of the study, the breast reconstruction is performed at the same time as the oncological surgery (Immediate reconstruction).

After the treatment is finished the patients will return for follow up visits at 3 months, 1 year, 2 years, 5 years and 10 years after finishing the treatment. An additional visit is provided at 3 months after the last session of radiotherapy for patients undergoing delayed reconstruction.

During these baseline and follow-up visits, 2 questionnaires (BREAST-Q v2; EQ5D5L)will be completed, photographs of the breasts will be taken, adverse events will be recorded and oncological recurrence will be evaluated.

The key result (primary outcome) is breast satisfaction (BREAST-Q v2, BQ-score) at 1 year follow-up. Secondary outcomes evaluate BREAST-Q-scores, EQ5D5L-scores, photograph evaluation, adverse events, treatment pathway duration, and pathological complete response rates. These are assessed per follow-up visit. The tertiary outcome follows oncological recurrence.

With the results from this study the goal is to improve patient satisfaction, QoL and aesthetic results of breast reconstruction after breast cancer treatment, as well as reduce postoperative complications and treatment duration.

The PRADAIIBE study is a multicentric phase 3 clinical trial, investigating the effects of radiotherapy timing on breast reconstruction results, in breast cancer patients.

This study will be recruiting Belgian breast cancer patients. They can participate if there is an indication for both surgical removal of the complete breast tissue, in the form of a skin or nipple sparing mastectomy (SSM/NSM) and postoperative radiotherapy treatment, as well as a wish for breast reconstruction.

After informed consent is signed, patients will be screened. If they meet the study inclusion criteria and do not meet the exclusion criteria, they will be included in the study as a participant. If they are not found to be eligible, they will be registered as a 'screen failure'.

After study inclusion, baseline assessments will be taken, this includes two questionnaires, the first one is focussed on satisfaction with the patient's own breasts (BREAST-Q v2, BQ-score) and the second one on their perception of their quality of life (EQ5D5L, VAS-score, Index-score). Next, 4 photographs of the exposed breast area will be taken. These photographs will be assessed by an expert panel (Aesthetic Item Scale (AIS), TAS-score) and computer software.

Next, the eligible participant will be randomized using the central eCRF randomization tool (Caster EDC). At randomization, participants will be stratified based on study site. They will be randomly assigned to one of the following treatment arms:

* Standard treatment arm: SSM/NSM, immediate or delayed breast reconstruction, and postoperative radiation therapy (postop-RT).
* Experimental treatment arm: preoperative radiotherapy (preop-RT) followed by SSM/NSM combined with an immediate breast reconstruction.

Those assigned to the control group will follow the standard of care treatment in the classic sequence of oncological surgery followed by radiotherapy. The breast reconstruction surgery will take place either at the same time (mostly tissue expander implantation) as the oncological surgery, or at a delayed moment.

Patients assigned to the intervention group will receive the same standard of care treatments, with the difference that the radiotherapy is administered before the oncological surgery. This allows the breast reconstruction is performed at the same time as the oncological surgery (Immediate reconstruction). In the treatment arm breast reconstruction will always be performed immediately (during oncological surgery).

In the unexpected event of tumour downstaging due to preoperative treatment, changing the indication from SSM/NSM to breast conserving surgery/treatment (BCS/BCT), while the patient has already been included and randomized in this trial, a separate pathway is foreseen.

In this case the patient should receive the treatment and surgery which is most indicated, being BCS/BCT. The same follow up will be provided, using a BREAST-Q questionnaire tailored to BCT follow up. They will be analysed following the 'Intention To Treat' (ITT) principle, but will be filtered out in the 'Per Protocol Analysis' (PPA).

Systemic treatment (Chemotherapy, endocrine therapy, etc.) will be administered per standard of care, according to the discretion of the treating physician(s). It will be registered in the study, but it is not considered as part of the study treatments.

After the treatment period is finished (last radiotherapy treatment or surgery), the patients will be followed-up at 3 months, 1 year, 2 years, 5 years and 10 years after finishing the treatment. An additional visit is provided at 3 months after conclusion of radiotherapy (intermediate follow up visit) for patients/participants undergoing delayed reconstruction, as these patients typically have to wait 6-12 months before reconstructive surgery is performed.

During these follow-up visits the BREAST-Q and EQ5D5L questionnaires, photographic assessment (expert panel using AIS), adverse events, pathologic response, treatment period duration and oncological recurrence (from the +1 year visit onwards) will be recorded. During the intermediate follow up visit, just the EQ5D5L questionnaire and adverse events will be assessed.

The research question of the PRADAIIBE trial is to investigate whether preop-RT followed by SSM/NSM combined with an immediate breast reconstruction (implant based or autologous) improves patient satisfaction with the breast reconstruction and overall quality of life, when compared to standard of care treatment i.e.: post-mastectomy radiation therapy (PMRT) and delayed breast reconstruction.

The primary objective is to determine if there is improvement in patient satisfaction with breasts at 1 year after last locoregional treatment (as measured using the pre-operative and post-operative satisfaction with Breasts scale from the BREAST-Q Reconstruction Module Version 2 questionnaire). This is operationalised through determining the median/mean BREAST-Q score at 1 year after last locoregional treatment, as well as the mean/median difference in the BREAST-Q score between baseline and at 1 year after last locoregional treatment.

For the secondary outcomes, the BREAST-Q, EQ5D5L, AIS, AE, treatment duration, and pathological response will be assessed during all follow-up visits.

For the tertiary outcomes, the tumour recurrence will be monitored (local, regional, metastatic and death). This data will be shared and aggregated with similar international studies, as coordinate by the PRADA-Consortium.

Eligibility Criteria:
Screening assessments, including review of all study eligibility criteria must be completed before enrollment and randomization.

Inclusion criteria:

In order to be eligible to participate in this study, a subject must meet all of the following criteria:

1. Women ≥18 years with histopathologically confirmed breast cancer who:

   1. require SSM for any reason (e.g. extensive disease)
   2. require adjuvant radiation therapy of at least the chest wall
   3. have a wish for a breast reconstruction
2. An Eastern Cooperative Oncology Group (ECOG) Performance Status grade ≤2
3. Subject is not pregnant or breastfeeding
4. Subject is able and willing to provide written informed consent, which includes compliance with and ability to undergo all study procedures and attend the scheduled follow-up visit(s) per protocol.

Exclusion criteria:

A potential subject who meets any of the following criteria will be excluded from participation in this study:

1. A previous history of breast cancer or another malignancy for which radiation therapy of the breast or axilla was performed.
2. Collagen synthesis disease
3. Contraindications for an MRI (as defined by the local Radiology Department)
4. Smoking at time of surgery (previous smoking is allowed but needs to be registered in the eCRF)
5. BMI \> 35 kg/m2
6. cT4d tumor or any reason making SSM not possible

NOTE: If neoadjuvant chemotherapy is given, and if the indication for adjuvant systemic treatment is dependent on the presence or absence of a pathological complete tumor response pCR (such as in patients with a triple negative or Her2 positive tumor), centers can choose

* to exclude these patients,
* only to include these patients when a non-pCR is proven via a biopsy prior to the start of the RT.
* to include these patients after the end of neoadjuvant chemotherapy.