Radiotherapy in Preoperative Setting With CyberKnife for Breast Cancer

Study Overview
=================
Brief Summary
-----------------
The aim of this study is to prospectively evaluate, in patients affected by early breast cancer, safety and feasibility of single fraction radiotherapy with Cyberknife R in preoperative setting, and to identify factors predictive for outcome based on biologic and clinical parameters.

Detailed Description
-----------------
Monocentric, open-label, single-arm phase II study evaluating safety and efficacy of neoadjuvant radiotherapy in early breast cancer patients. Patients eligible are women aged 50 or more years old, affected by histologically proven invasive breast cancer, with positive hormonal receptors, grading 1 or 2, HER-2 negative, without lymphovascular invasion, and tumour size up to 2 cm (measured on mammography, ultrasound or magnetic resonance), negative clinical nodal status, eligible for BCS.

Official Title
-----------------
Radiotherapy in Preoperative Setting With CyberKnife as Treatment in Early Breast Cancer: an Explorative Study

Conditions
-----------------
Early Breast Cancer

Intervention / Treatment
-----------------
* Radiation: Neoadjuvant radiotherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed informed consent Women ≥ 50 years old Histological diagnosis of invasive breast cancer ER positive (≥ 10% of tumoral cells present ER) and/or PR positive (≥ 10% of tumoral cells present PR) Grading 1 or 2 Her2 negative (IHC 0-1+; in patients with IHC 2+, absence of amplification at FISH No lymphovascular invasion evidence at biopsy Early breast cancer (T1 N0 M0) clinically and radiologically defined (ultrasound study/ magnetic resonance) Patients eligible for BCS. Exclusion Criteria: Extension of breast disease within 5 mm from the skin surface 2. Tumor size &gt; 2 cm 3. Patients affected by collagenopathies 4. Patients with BRCA1/2 mutations 5. Previous irradiation to homolateral breast 6. Previous irradiation to homolateral thoracic wall 7. DCIS and/or Paget's disease 8. Psychiatric disorders preventing informed consent signature. -

Ages Eligible for Study
-----------------
Minimum Age: 50 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neoadjuvant radiotherapy arm<br>Early breast cancer patients eligible for breast conservative surgery will undergo neoadjuvant radiotherapy with Cyberknife robotic system | Radiation: Neoadjuvant radiotherapy<br>* single 21 Gy fraction of Radiotherapy before surgery<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of acute skin toxicity events, measured according to RTOG/EORTC scale | Acute skin toxicity (from the end of radiotherapy to surgery) according to Radiation Therapy Oncology Group (RTOG)/ European Organization for research and treatment of cancer (EORTC) scale. Measuring acute skin toxicity from a minimum of 0 (no change over baseline) to a maximum of 4 (Ulceration, Hemorrage, necrosis) | 15 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with pathologic complete response (pCR) after surgery,according to Chevalier score | Rate of pCR according to Chevalier score | 30 days | 
| Number of patients with complete resection after surgical excision | Rate of complete resection R0 with margin<1cm (except for deep margin) | 30 days | 
| Number of patients free from locoregional progression at 36 months | locoregional progression free survival measured at 36 months | 36 months | 
| Number of patients free from metastatic progression at 36 months | Metastasis progression free survival measured at 36 months | 36 months | 
| Number of patients dying for breast cancer at 36 months | cause-specific free survival measured at 36 months | 36 months | 
| Number of patients dying for any cause at 36 months | global survival measured at 36 months | 36 months | 
| Rate of chronic skin toxicity events, measured according to CTCAE | Incidence of chronic skin toxicity (over 90 days since the end of radiotherapy; fibrosis, telangiectasia, tardive oedema) according to Common terminology criteria for adverse events (CTCAE) v 4.03. From a minimum of 1 (Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated to a maximum of 4 (Life-threatening consequences; urgent intervention indicated | 90 days | 
| Rate of chronic extra-cutaneous toxicity, measured according to CTCAE | Incidence of chronic extra-skin toxicity (over 90 days from the end of radiotherapy; lung fibrosis, pericarditis, myocardial ischemia, valvulopathy, thoracic wall pain, fracture) according to according to Common terminology criteria for adverse events (CTCAE) v 4.03. From a minimum of 1 (Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated to a maximum of 4 (Life-threatening consequences; urgent intervention indicated | 90 days | 
| Correlation of differential genetic expression, immunologic and histopathologic features of tumor sample and biomarkers in blood and urine samples with toxicity and rate of response to radiotheraèy | Radiogenomic: confirm of differential genetic expression of genes already validated in previous literature (30-Radiation- induced gene signature; AOI 16-gene breast signature; IRDS gene signature) with Next Generation Sequencing (NGS, RNA-seq) or Real Time PCR on frozen biopsy tissue. Immunologic: quantitative analysis of infiltrating leucocytes (MS and M1 macrophages, CD8+ and CD4+ lymphocytes) with immunohistochemistry on fresh biopsy tissue Histopathologic: qualitative analyses (pericytes) and quantitative pattern of vascularization in immunohistochemistry. Biochemical: analysis of oxidative stress markers on peripheral blood and urines: a) 1 hour before SBRT; b) 1 hour after SBRT; c) 1 week after SBRT; d) during 24 hours before BCS; e) during 2-4 weeks after BCS. | 60 days |