Multicentre Trial Principal Investigators Claudio Andreoli e Alberto Costa Salvatore Maugeri Foundation I.R.C.C.S. Breast conservative surgery with and without RT in women aged with early breast cancer R Studio

Study Background  Breast conservative surgery (CS) followed by irradiaton of the remaining breast tissue (CS+RT) is generally accepted as the treatment of choice for the vast majority of patients with early stage breast cancer  It results in advantages of improved cosmesis and quality of life as compared to mastectomy without exposing patients to a higher risk of breast cancer deaths R Studio

PartecipatingCentres N° pts Pavia176 Ortona110 Bergamo109 Reggio Emilia 80 Alba65 Bologna56 Ciriè35 San Giovanni Rotondo 31 Torino26 Udine21 Roma20 TOTAL749 Total randomized pts at the Start : January 2001 End : December R Studio

Aims of the study Primary Aim Cumulative incidence of local recurrences after CS+RT vs CS alone Secondary Aims Disease-free survival Distant disease-free survival Overall survival Ancillary studies Long-term sequelae, costs to the NHS R Studio

Quadrantectomy R R RT of the breast No RT Axillary dissection / SNB Adjuvant treatment according to Center policy and related to axillary nodal status and biological tumor parameters Histology R Studio Study design

RATIONAL RATIONAL The rational of the study is to define a reliable RISK FACTOR PROFILE to determine a group of patients at “ LOW RISK “ for local recurrence in whom radiation therapy could be avoided. The rational of the study is to define a reliable RISK FACTOR PROFILE to determine a group of patients at “ LOW RISK “ for local recurrence in whom radiation therapy could be avoided R Studio

INCLUSION CRITERIA INCLUSION CRITERIA Age : > 55 < 75 yrs Maximum tumor size 2.5 cm. Unifocal infiltrating Ca of any grading and hormone receptor status Axillary nodes status pN0-pN1bi No extensive intraductal component No extensive peritumoral vascular invasion Age : > 55 < 75 yrs Maximum tumor size 2.5 cm. Unifocal infiltrating Ca of any grading and hormone receptor status Axillary nodes status pN0-pN1bi No extensive intraductal component No extensive peritumoral vascular invasion R Studio

INCLUSION CRITERIA INCLUSION CRITERIA No distant disease No any clinical condition that can interfere with radiation treatment and standard follow-up No previous history of malignant diseases except for skin basocellular carcinoma, in situ ca of the cervix No previous oncological treatment No distant disease No any clinical condition that can interfere with radiation treatment and standard follow-up No previous history of malignant diseases except for skin basocellular carcinoma, in situ ca of the cervix No previous oncological treatment R Studio

SURGERY SURGERY TUMOUR DIAMETER > 1,5 CM. Patients underwent the classical Veronesi quadrantectomy wich includes the removal of the tumor with a large rim of healthy tissue, the skin above the tumor and the underlying muscolar fascia. TUMOUR DIAMETER < 1,5 CM A limited resection was performed. Respect the Holland histo-pathological criteria and remove the skin above the tumor and the underlying muscolar fascia R Studio

RADIOTHERAPY RADIOTHERAPY Photon beam of 4 -6 MV (Linear acc.) 50 Gy. Breast 10 Gy di Boost tumour bed Opposed tangential fields 2 Gy / day ( 5 days a week ) Energy Dosage Technique Fraction R Studio

Patient population and follow-up examinations A total of 749 patients were enrolled in 11 participating centers from January 2001 and December 2005 Treatment allocation was centralized and stratified per site Follow-up included physical examination every 6 mos for the first 5 years and annually thereafter and radiological examinations once a year to include bilateral breast US and mammography R Studio

STATISTICAL ANALYSIS AND DATA CENTRE Pinuccia VALAGUSSA National Cancer Institute, MILAN

Analysis of Primary and Secondary Aims Cut-off date for present analysis was November 2007 Median follow-up was 53 months (lead 83 mos) Analyses were conducted according to the Intent-To-Treat (ITT) principle Total number of events local recurrence 10; regional recurrence 5; distant relapse 20; contralateral breast 4; other primary cancer ( no breast )12; death in the absence of cancer R Studio

Main Patient Characteristics in % CS alone (376 patients) CS+RT (373 patients) Age > 65 years5046 pT2 lesions1412 Ductal ca.7375 Lobular ca.1514 pN positive1614 ER negative8.510 PgR negative R Studio

#% 95% CI #% Total Age < 66 yr > 65 yr > 65 yr (0-3.0) pT1pT pN-pN ER positive ER negative Actuarial Risk of Local Recurrence CS (376 patients)CS+RT (373 patients) R Studio

5-yr Cumulative Incidence of Local Recurrence (ITT analysis) Years % 2.5% CS 2.5% CS+RT 0.7% P = R Studio

Distant Disease-Free Survival Probability Years CS 96.5% CS+RT 96% R Studio

Overall Survival Probability Years CS 96% CS+RT 95% R Studio

QUART : incidenza cumulativa recidive locali (2.333 casi INT – 1972 – 1984) anni probabilità %

Conclusions Present data indicate that breast irradiation Present data indicate that breast irradiation after conservative surgery might be avoided after conservative surgery might be avoided in selected patients with early breast cancer aged years in selected patients with early breast cancer aged years without exposing them to an increased risk without exposing them to an increased risk of local and distant disease recurrence. of local and distant disease recurrence. Longer follow-up is needed to consolidate this preliminary results. Longer follow-up is needed to consolidate this preliminary results R Studio

If RT could be omitted …. 1) broader use of breast conserving treatment 1) broader use of breast conserving treatment 2) no complications and risks of RT 2) no complications and risks of RT 3) better cosmetic result 3) better cosmetic result 4) easier diagnosis of local recurrence 4) easier diagnosis of local recurrence 5) easier reconstruction after MX in case of LR 5) easier reconstruction after MX in case of LR 6) cost reduction for the NHS 6) cost reduction for the NHS 7) reduction of waiting list 7) reduction of waiting list 8) better QoL for the patient 8) better QoL for the patient 9) avoidance of indirect costs for the patient 9) avoidance of indirect costs for the patient 10) earlier return to work or active life

Acknowledgements and to the study investigators Claudio Amanti (Roma), Nicoletta Biglia (Torino), Marina Bissolotti (Pavia), Ettore Cianchetti (Ortona), Giuliana Gentile (Udine), Privato Fenaroli (Bergamo), Vinicio Fosser (Vicenza), Mirella Merson (Bergamo), Roberto Murgo (S.G.Rotondo), Maria Carmela Orlandi (Cirié), Claudio Pedrazzoli (Reggio Emilia), Gianpaolo Sacchetto (Alba), Piero Sismondi (Torino), Carlo Tondini (Bergamo), Mario Taffurelli (Bologna) and to the study investigators Claudio Amanti (Roma), Nicoletta Biglia (Torino), Marina Bissolotti (Pavia), Ettore Cianchetti (Ortona), Giuliana Gentile (Udine), Privato Fenaroli (Bergamo), Vinicio Fosser (Vicenza), Mirella Merson (Bergamo), Roberto Murgo (S.G.Rotondo), Maria Carmela Orlandi (Cirié), Claudio Pedrazzoli (Reggio Emilia), Gianpaolo Sacchetto (Alba), Piero Sismondi (Torino), Carlo Tondini (Bergamo), Mario Taffurelli (Bologna) To the 749 women participating in the study R Studio