title: Concurrent or sequential letrozole with adjuvant breast radiotherapy: final results of the CO-HO-RT phase II randomized trial.
abstract: BACKGROUND
  We present here final clinical results of the COHORT trial and both translational sub-studies aiming at identifying patients at risk of radiation-induced subcutaneous fibrosis (RISF): (i) radiation-induced lymphocyte apoptosis (RILA) and (ii) candidates of certain single-nucleotide polymorphisms (SNPs).
  
  
  METHODS
  Post-menopausal patients with stage I-II breast cancer (n = 150) were enrolled and assigned to either concurrent (arm A) or sequential radiotherapy (RT)-letrozole (arm B). Among them, 121 were eligible for RILA and SNP assays. Grade ≥2 RISF were the primary end point. Secondary end points were lung and heart events and carcinologic outcome. RILA was performed to predict differences in RISF between individuals. A genome-wide association study was performed to identify SNPs associated with RILA and RISF. Analyses were done by intention to treat.
  
  
  RESULTS
  After a median follow-up of 74 months, 5 patients developed a grade ≥2 RISF. No significant difference was observed between arms A and B. Neither grade ≥2 lung nor symptomatic cardiac toxicity was observed. Median RILA value of the five patients who had grade ≥2 RISF was significantly lower compared with those who developed grade ≤1 RISF (6.9% versus 13%, P = 0.02). Two SNPs were identified as being significantly associated with RILA: rs1182531 (P = 4.2 × 10(-9)) and rs1182532 (P = 3.6 × 10(-8)); both located within the PHACTR3 gene on chromosome 20q13.33.
  
  
  CONCLUSIONS
  With long-term follow-up, letrozole can safely be delivered concomitantly with adjuvant breast RT. Translational sub-studies showed that high RILA values were correlated with patients who did not develop RISF.
  
  
  BACKGROUND
  NCT00208273.
authors.affiliation: Inserm, U1194, Institut de Recherche en Cancérologie de Montpellier (IRCM), Cancer Institute ICM-Val d'Aurelle, Montpellier Department of Radiation Oncology, Montpellier Cancer Institute ICM-Val d'Aurelle, Montpellier, France.
authors.forename: C
authors.initials: C
authors.lastname: Bourgier
authors.affiliation: University of Rochester Medical Centre, Rochester Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kerns
authors.affiliation: Biostatistics Unit, Cancer Institute ICM-Val d'Aurelle, Montpellier, France.
authors.forename: S
authors.initials: S
authors.lastname: Gourgou
authors.affiliation: Department of Radiation Oncology, Montpellier Cancer Institute ICM-Val d'Aurelle, Montpellier, France.
authors.forename: C
authors.initials: C
authors.lastname: Lemanski
authors.affiliation: Department of Surgery, Cancer Institute ICM-Val d'Aurelle, Montpellier, France.
authors.forename: M
authors.initials: M
authors.lastname: Gutowski
authors.affiliation: Department of Radiation Oncology, Montpellier Cancer Institute ICM-Val d'Aurelle, Montpellier, France.
authors.forename: P
authors.initials: P
authors.lastname: Fenoglietto
authors.affiliation: Department of Medical Oncology, Cancer Institute ICM-Val d'Aurelle, Montpellier, France.
authors.forename: G
authors.initials: G
authors.lastname: Romieu
authors.affiliation: Laboratory of Non-invasive Imaging and Radiation Biology, Van Andel Research Institute, Grand Rapids, USA.
authors.forename: N
authors.initials: N
authors.lastname: Crompton
authors.affiliation: Inserm, U1194, Institut de Recherche en Cancérologie de Montpellier (IRCM), Cancer Institute ICM-Val d'Aurelle, Montpellier.
authors.forename: J
authors.initials: J
authors.lastname: Lacombe
authors.affiliation: Inserm, U1194, Institut de Recherche en Cancérologie de Montpellier (IRCM), Cancer Institute ICM-Val d'Aurelle, Montpellier.
authors.forename: A
authors.initials: A
authors.lastname: Pèlegrin
authors.affiliation: Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Ozsahin
authors.affiliation: Mount Sinai School of Medicine and NYU School of Medicine, New York, USA.
authors.forename: B
authors.initials: B
authors.lastname: Rosenstein
authors.affiliation: Inserm, U1194, Institut de Recherche en Cancérologie de Montpellier (IRCM), Cancer Institute ICM-Val d'Aurelle, Montpellier Department of Radiation Oncology, Montpellier Cancer Institute ICM-Val d'Aurelle, Montpellier, France david.azria@icm.unicancer.fr.
authors.forename: D
authors.initials: D
authors.lastname: Azria
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D003131:Combined Modality Therapy / Q000009:adverse effects*; D005260:Female; D005355:Fibrosis / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D000077289:Letrozole; D008875:Middle Aged; D009570:Nitriles / Q000627:therapeutic use*; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018714:Radiotherapy, Adjuvant / Q000009:adverse effects*; D014230:Triazoles / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D009570:Nitriles; D009687:Nuclear Proteins; C479826:PHACTR3 protein, human; D014230:Triazoles; D000077289:Letrozole
keywords: breast cancer; radiation-induced late effects; radio-hormonotherapy