title: Radiation-induced CD8 T-lymphocyte Apoptosis as a Predictor of Breast Fibrosis After Radiotherapy: Results of the Prospective Multicenter French Trial.
abstract: BACKGROUND
  Monocentric cohorts suggested that radiation-induced CD8 T-lymphocyte apoptosis (RILA) can predict late toxicity after curative intent radiotherapy (RT). We assessed the role of RILA as a predictor of breast fibrosis (bf +) after adjuvant breast RT in a prospective multicenter trial.
  
  
  METHODS
  A total of 502 breast-cancer patients (pts) treated by conservative surgery and adjuvant RT were recruited at ten centers. RILA was assessed before RT by flow cytometry. Impact of RILA on bf + (primary endpoint) or relapse was assessed using a competing risk method. Receiver-operator characteristic (ROC) curve analyses were also performed in intention to treat. This study is registered with ClinicalTrials.gov, number NCT00893035 and final analyses are presented here.
  
  
  RESULTS
  Four hundred and fifty-six pts (90.8%) were included in the final analysis. One hundred and eight pts (23.7%) received whole breast and node irradiation. A boost dose of 10-16 Gy was delivered in 449 pts (98.5%). Adjuvant hormonotherapy was administered to 349 pts (76.5%). With a median follow-up of 38.6 months, grade ≥ 2 bf + was observed in 64 pts (14%). A decreased incidence of grade ≥ 2 bf + was observed for increasing values of RILA (p = 0.012). No grade 3 bf + was observed for patients with RILA ≥ 12%. The area under the ROC curve was 0.62. For cut-off values of RILA ≥ 20% and < 12%, sensitivity and specificity were 80% and 34%, 56% and 67%, respectively. Negative predictive value for grade ≥ 2 bf + was equal to 91% for RILA ≥ 20% and positive predictive value was equal to 22% for RILA < 12% where the overall prevalence of grade ≥ 2 bf + was estimated at 14%. A significant decrease in the risk of grade ≥ 2 bf + was found if patients had no adjuvant hormonotherapy (sHR = 0.31, p = 0.007) and presented a RILA ≥ 12% (sHR = 0.45, p = 0.002).
  
  
  CONCLUSIONS
  RILA significantly predicts the risk of breast fibrosis. This study validates the use of RILA as a rapid screening test before RT delivery and will change definitely our daily clinical practice in radiation oncology.
  
  
  BACKGROUND
  The French National Cancer Institute (INCa) through the "Program Hospitalier de Recherche Clinique (PHRC)".
authors: Montpellier Cancer Institute (ICM), Montpellier Cancer Research Institute (IRCM), University of Montpellier, Montpellier, France.
authors: David
authors: D
authors: Azria
authors: Montpellier Cancer Institute (ICM), Montpellier Cancer Research Institute (IRCM), University of Montpellier, Montpellier, France.
authors: Olivier
authors: O
authors: Riou
authors: Montpellier Cancer Institute (ICM), Montpellier Cancer Research Institute (IRCM), University of Montpellier, Montpellier, France.
authors: Florence
authors: F
authors: Castan
authors: Institut Jean Godinot, Reims, France.
authors: Tan Dat
authors: TD
authors: Nguyen
authors: Centre GF Leclerc, Dijon, France.
authors: Karine
authors: K
authors: Peignaux
authors: Montpellier Cancer Institute (ICM), Montpellier Cancer Research Institute (IRCM), University of Montpellier, Montpellier, France.
authors: Claire
authors: C
authors: Lemanski
authors: AP-HP Henri Mondor, Créteil, France.
authors: Jean-Léon
authors: JL
authors: Lagrange
authors: Institut Curie, Paris, France.
authors: Youlia
authors: Y
authors: Kirova
authors: Centre Oscar Lambret, Lille, France.
authors: Eric
authors: E
authors: Lartigau
authors: AP-HP Henri Mondor, Créteil, France.
authors: Yazid
authors: Y
authors: Belkacemi
authors: Montpellier Cancer Institute (ICM), Montpellier Cancer Research Institute (IRCM), University of Montpellier, Montpellier, France.
authors: Céline
authors: C
authors: Bourgier
authors: Gustave Roussy, Villejuif, France.
authors: Sofia
authors: S
authors: Rivera
authors: Centre Paul Strauss, Strasbourg, France.
authors: Georges
authors: G
authors: Noël
authors: Centre Marie Curie, Valence, France.
authors: Sébastien
authors: S
authors: Clippe
authors: Centre Hospitalier Lyon Sud, Pierre Bénite, France.
authors: Françoise
authors: F
authors: Mornex
authors: AP-HP Saint-Louis, Paris, France.
authors: Christophe
authors: C
authors: Hennequin
authors: Centre Oscar Lambret, Lille, France.
authors: Andrew
authors: A
authors: Kramar
authors: Montpellier Cancer Institute (ICM), Montpellier Cancer Research Institute (IRCM), University of Montpellier, Montpellier, France.
authors: Sophie
authors: S
authors: Gourgou
authors: Montpellier Cancer Institute (ICM), Montpellier Cancer Research Institute (IRCM), University of Montpellier, Montpellier, France.
authors: André
authors: A
authors: Pèlegrin
authors: Montpellier Cancer Institute (ICM), Montpellier Cancer Research Institute (IRCM), University of Montpellier, Montpellier, France.
authors: Pascal
authors: P
authors: Fenoglietto
authors: Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors: Esat Mahmut
authors: EM
authors: Ozsahin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000528:radiation effects*; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000150:complications* / Q000175:diagnosis / Q000401:mortality / Q000532:radiotherapy; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D005348:Fibrocystic Breast Disease / Q000175:diagnosis* / Q000453:epidemiology / Q000209:etiology*; D005355:Fibrosis; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D018714:Radiotherapy, Adjuvant / Q000009:adverse effects*; D012008:Recurrence; D012307:Risk Factors
chemical_list: D014408:Biomarkers, Tumor
keywords: Apoptosis; Breast fibrosis; Lymphocyte; Prediction; Radiotherapy