STUDY DESCRIPTION: This is a single-arm study to assess the feasibility, toxicity and cosmetic outcome of partial radiotherapy of the chest wall in breast cancer patients at increased risk of local relapse submitted to nipple-areola complex (NAC) sparing mastectomy and immediate implant-based reconstruction Inclusion criteria

Histologically confirmed diagnosis of in situ ductal carcinoma (pTis) or invasive breast carcinoma (pT1 and pT2), submitted to NAC sparing mastectomy with prosthetic-based breast reconstruction (expander or prosthesis) and:

Group A)

Negative sentinel node dissection or axillary clearance (pN0) and all the following risk factors:

Close (less than 1 mm) or positive (ink on tumor margin) surgical margin in a single breast quadrant Tumor diameter >2 cm Age ≤50 years Group B)

Positive sentinel dissection (pN1a) followed by axillary clearance (or primary axillary clearance) with only 1 positive node and any of the following risk factors:

Close (less than 1 mm) or positive (ink on tumor margin) surgical margin in a single breast quadrant Age ≤50 years Tumor diameter >2 cm Grade 3 histology Lymphovascular invasion HER-2 overexpression/amplification Triple negativity Treatment - Radioterapy The tumor bed is defined by the area at risk (skin and the pectoralis muscles) delineated by surgical clips and 3D-MRI reconstruction for a precise localization of the tumor excised. The clinical target volume (CTV) is defined as the tumor bed with a 1.5 cm margin limited by skin contour.

A dose of 40 Gy is delivered in 16 fractions (2.5 Gy per fraction). For conventional post-mastectomy radiotherapy this moderately hypofractionated schedule is considered feasible and safe (31). Even more so, this schedule should be feasible and safe for a smaller irradiated volume as in the current protocol. Regional nodal irradiation is not considered at our Institution for patients fulfilling the entry criteria of the protocol.

OUTCOME MEASURES Primary To assess feasibility of PCWRT via VMAT-IGRT linac-based or helical Tomotherapy To assess the safety of PCWRT via VMAT-IGRT linac-based or helical Tomotherapy To assess the surgical complication of implant-based breast reconstruction after PCWRT Secondary To assess the cosmetic outcome of implant-based breast reconstruction after PCWRT To assess patients' satisfaction of implant-based breast reconstruction after PCWRT

There is uncertainty on the indications to chest wall irradiation in patients submitted to mastectomy plus immediate implant-based reconstruction with: A) negative axillary nodes and additional risk factors; B) 1-3 positive axillary nodes and no additional risk factors.

The reduction of locoregional recurrences is valuable from a clinical and psychological standpoint and may also translate into a survival advantage. Nevertheless, whole chest wall radiotherapy can be associated with significant toxicity due to irradiation of non-target organs and does significant worsen the cosmetic result of prosthetic-based breast reconstruction (capsular contracture, implant displacement, infection).

Most Institution have adopted NAC sparing mastectomy as standard treatment for non-locally advanced breast cancer patients not amenable to breast conserving surgery. Available literature data, including our own data, suggest that in these patients local recurrence in the NAC area is exceedingly rare, while most local recurrences occur where the original tumor was located.

It is now accepted that, in selected breast cancer patient submitted to breast conserving surgery, accelerated partial breast radiotherapy is associated with similar recurrence rates as compared to whole breast radiotherapy and favorable cosmetic outcomes. Therefore, we hypothesize that partial chest wall radiotherapy of the quadrant where the original tumor was located after NAC sparing mastectomy may be associated with the same reduction of local recurrences while significantly reducing the complications of prosthetic-based breast reconstruction.

STUDY DESCRIPTION:

This is a single-arm prospective study to assess the feasibility, toxicity and cosmetic outcome of partial radiotherapy of the chest wall in breast cancer patients at increased risk of local relapse submitted to skin/nipple-areola complex (NAC) sparing mastectomy and immediate implant-based reconstruction

STUDY TYPE Interventional

STUDY DESIGN Endpoint Classification: Feasibility/Safety Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment

INCLUSION CRITERIA AND EXCLUSION CRITERIA (see below)

RADIOLOGY All patients will be submitted to preoperative full radiological work up including mammography, ultrasound scan and breast MRI in order to define precise tumor localization and extension (e.g. area covered by multiple tumor foci and/or extension of in situ associated to invasive tumor).

Immediately before surgery, non-permanent marks will be placed to delineate the skin covering the breast area involved by the tumor and two projection photographs will be taken and stored.

SURGERY NAC sparing or skin-sparing (in case of preoperative/intraoperative diagnosis of tumor involvement of the nipple ducts) mastectomy will be performed by raising thin skin flaps at the level of the superficial and deep fascia. The specimen will be oriented in the three dimensions by placement of stitches and sent for definitive pathology . The area of the pectoralis major muscle localized under the tumor will be delineated by placing 4 titanium radiopaque clips at cardinal points.

Nodal staging will be performed either by sentinel node biopsy, intraoperative evaluation and immediate/delayed full axillary dissection in case of macrometastatic sentinel node, or immediate full axillary dissection in case of preoperative citological diagnosis of metastatic axillary node.

RADIOTHERAPY The tumor bed is defined by the area at risk (skin and the pectoralis muscles) delineated by indelible skin marks (placed under the guidance of preoperative non-permanent skin marks) and surgical clips and 3D-MRI reconstruction for a precise localization of the tumor excised. The clinical target volume (CTV) is defined as the tumor bed with a 1.5 cm margin limited by skin contour.

The planning tumor volume (PTV) is defined using 4D-CT imaging and includes CTV plus 0.3/0.5 mm for setup error contribution. Internal target volume (ITV) accounts for motion of CTV in the patient.

Contouring of the target and organs at risk (OARs) is performed using both 3D-CT and 4D-CT imaging. All patients are scanned on a Aquilion Big Bore CT scanner (Toshiba). For generating 4D-CT datasets, a respiratory sensor box, integrated with the CT scanner reconstruction, is placed on the patient's chest. After the scan, the source data and the respiratory signal are used to retrospectively reconstruct the images. A maximum intensity projection (MIP) reconstruction over all respiratory phase is used to delineate target volumes. The contouring of OARs is performed using 3D-CT images.

Treatment plan is performed using Eclipse Treatment Planning System (TPS) or Tomotherapy TPS. Patients are treated with Volumetric Modulated Arc Therapy (VMAT) technique (1/2 half arcs) or helical Tomotherapy using 6 MV photon beams. Treatment plans is optimized for coverage and homogeneity. Clinically significant maximum target dose up to 112% is considered acceptable. A comparison plan using standard tangential fields is performed for each patient.

A dose of 40 Gy is delivered in 16 fractions (2.5 Gy per fraction). For conventional post-mastectomy radiotherapy this moderately hypofractionated schedule is considered feasible and safe (31). Even more so, this schedule should be feasible and safe for a smaller irradiated volume as in the current protocol. Regional nodal irradiation is not considered at our Institution for patients fulfilling the entry criteria of the protocol.

For patient setup verification, a cone-beam kVCT or a MVCT scan are performed before each treatment fraction and compared to the planning CT. Automatic registration between the reference and verification images is realised; patient position is corrected using a 6-degrees of freedom robotic couch top (linac) or a 4-degrees of freedom robotic couch top (Tomotherapy). Patients are immobilized using an arm shuttle device.

OUTCOME MEASURES PRIMARY

1. To assess the feasibility of PCWRT via VMAT-IGRT linac-based or helical Tomotherapy

   Surgical clips and permanent skin marks must allow proper identification of tumor bed both at CT imaging and on board imaging (CBCT-MVCT). The dose distribution must respect the standard dose constraints utilized in conventional CWRT. The following parameters will be evaluated:

   1.1. Patient set-up reproducibility 1.2. Plan reproducibility through in vivo dosimetry 1.3. Dosimetrical reduction of PCWRT vs. conventional CWRT

2. To assess the safety of PCWRT via VMAT-IGRT linac-based or helical Tomotherapy

   With hypofractionated CWRT the most frequent toxicity is acute skin toxicity (G2 skin toxicity in 10% of the cases). All toxicities are expected to be lower with PCWRT as compared to conventional CWRT since the radiation field is smaller. The following parameters will be evaluated:

   2.1. Acute and late cutaneous toxicity 2.2. Late subcutaneous fibrosis 2.3. Radiation pneumonitis

3. To assess the surgical complications of implant-based breast reconstruction after PCWRT

Reconstruction failures (RF), defined as the removal of the tissue expander/prosthesis, of conventional CWRT are reported in 20% of the cases. As for toxicities, also surgical complication rates are expected to be lower with PCWRT as compared to conventional CWRT since the radiation field of is smaller. The following parameters will be evaluated:

3.1. Infections, Skin/NAC necrosis, major revisions, early capsular contracture 3.2. Complication rates leading to implant removal.

SECONDARY

1. To assess the cosmetic outcome of implant-based breast reconstruction after PCWRT 1.1 An acceptable cosmetic result (excellent or good, on a scale of excellent-good-fair-poor) is defined as a stable reconstruction with good symmetry and contour relative to the contralateral breast.

   1.2 Outcome will be measured by means of photographic analysis using five views (frontal, right and left lateral, and right and left quarter views) and independent assessment of the results by a plastic surgeon who has not treated the patient.

   1.3 The modified Baker classification will be used to score the extent of contracture seen in the photographs

2. To assess patients' satisfaction of implant-based breast reconstruction after PCWRT 2.1 The BREAST-Q Reconstruction Module Patient Satisfaction with Breasts survey will be administered before and after treatment at predetermined time intervals

SAMPLE SIZE AND STATISTICAL CONSIDERATIONS No sample size calculation is appropriate because the main purpose of the proposed study is to assess the feasibility of PCWRT in order explore this intervention further in a large clinical trial.

Based on the clinical activity of the past 3 years at the Institute, 20 potential candidates per year are expected. If a 70% enrolment rate is hypothesized, a target accrual of 28 patients could be completed in two years. This target should allow to assess primary endpoint 1. appropriately and provide estimates of endpoints 2. and 3. that be used to design a subsequent larger clinical trial.

Inclusion Criteria:

• Histologically confirmed diagnosis of in situ ductal carcinoma (pTis) or invasive breast carcinoma (pT1 and pT2), submitted to NAC sparing mastectomy with prosthetic-based breast reconstruction (expander or prosthesis) and:
• Group A)

Negative sentinel node dissection or axillary clearance (pN0) and all the following risk factors:

• Close (less than 1 mm) or positive (ink on tumor margin) surgical margin in a single breast quadrant

• Tumor diameter >2 cm

• Age ≤50 years

• Grade 3 histology

  • Group B)

Positive sentinel dissection (pN1a) followed by axillary clearance (or primary axillary clearance) with only 1 positive node and any of the following risk factors:

• Close (less than 1 mm) or positive (ink on tumor margin) surgical margins in a single breast quadrant

• Age ≤50 years

• Tumor diameter >2 cm

• Grade 3 histology

• Lymphovascular invasion

• HER-2 overexpression/amplification

• Triple negativity

  • Patients must be older than 18 and less than 81 years of age
  • WHO (ECOG) Performance Status of 0-2
  • Patients must consent to return for scheduled treatments and follow up
  • Written informed consent document signed

Exclusion Criteria:

• Stages IIIB, IIIC and IV (any T4, any N3 or M1)
• Pathological metastasis in ≥2 axillary lymph nodes, clinically apparent metastasis in internal mammary and/or supraclavicular lymph nodes
• Close (less than 1 mm) or positive (ink on tumor margin) surgical margin in multiple breast quadrants
• Patients submitted to neoadjuvant chemotherapy
• Recurrence of breast cancer following mastectomy and/or adjuvant chemotherapy.
• Concomitant primary cancer in the contralateral breast
• History of other malignancy except carcinoma in situ of the cervix or non-melanoma skin cancer
• Pregnant or breast-feeding
• Other severe concomitant disease that could impact upon the ability to deliver treatment or increase the risk of toxicity (such as uncompensated congestive heart failure, unstable coronary heart disease, uncompensated chronic obstructive pulmonary disease, collagen vascular diseases including systemic lupus erythematosus, systemic sclerosis, dermatomyositis, and ataxia telangiectasia)
• Contraindications to radiation therapy (such as previous irradiation of the breast or chest wall)
• Severe psychiatric disorder that may interfere with the process of informed consent and/or treatment or follow-up compliance