title: Integration of a Radiosensitivity Molecular Signature Into the Assessment of Local Recurrence Risk in Breast Cancer.
abstract: OBJECTIVE
  Recently, we developed radiosensitivity (RSI), a clinically validated molecular signature that estimates tumor radiosensitivity. In the present study, we tested whether integrating RSI with the molecular subtype refines the classification of local recurrence (LR) risk in breast cancer.
  
  
  METHODS
  RSI and molecular subtype were evaluated in 343 patients treated with breast-conserving therapy that included whole-breast radiation therapy with or without a tumor bed boost (dose range 45-72 Gy). The follow-up period for patients without recurrence was 10 years. The clinical endpoint was LR-free survival.
  
  
  RESULTS
  Although RSI did not uniformly predict for LR across the entire cohort, combining RSI and the molecular subtype identified a subpopulation with an increased risk of LR: triple negative (TN) and radioresistant (reference TN-radioresistant, hazard ratio [HR] 0.37, 95% confidence interval [CI] 0.15-0.92, P=.02). TN patients who were RSI-sensitive/intermediate had LR rates similar to those of luminal (LUM) patients (HR 0.86, 95% CI 0.47-1.57, P=.63). On multivariate analysis, combined RSI and molecular subtype (P=.004) and age (P=.001) were the most significant predictors of LR. In contrast, integrating RSI into the LUM subtype did not identify additional risk groups. We hypothesized that radiation dose escalation was affecting radioresistance in the LUM subtype and serving as a confounder. An increased radiation dose decreased LR only in the luminal-resistant (LUM-R) subset (HR 0.23, 95% CI 0.05-0.98, P=.03). On multivariate analysis, the radiation dose was an independent variable only in the LUMA/B-RR subset (HR 0.025, 95% CI 0.001-0.946, P=.046), along with age (P=.008), T stage (P=.004), and chemotherapy (P=.008).
  
  
  CONCLUSIONS
  The combined molecular subtype-RSI identified a novel molecular subpopulation (TN and radioresistant) with an increased risk of LR after breast-conserving therapy. We propose that the combination of RSI and molecular subtype could be useful in guiding radiation therapy-based decisions in breast cancer.
authors.affiliation: Department of Radiation Oncology, Moffitt Cancer Center, Tampa, Florida; Department of Chemical Biology and Molecular Medicine, Moffitt Cancer Center, Tampa, Florida. Electronic address: javier.torresroca@moffitt.org.
authors.forename: Javier F
authors.initials: JF
authors.lastname: Torres-Roca
authors.affiliation: Department of Bioinformatics, Moffitt Cancer Center, Tampa, Florida; Department of Biostatistics, Moffitt Cancer Center, Tampa, Florida.
authors.forename: William J
authors.initials: WJ
authors.lastname: Fulp
authors.affiliation: Department of Radiation Oncology, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Jimmy J
authors.initials: JJ
authors.lastname: Caudell
authors.affiliation: Institut Curie, INSERM U900, Paris, France; Mines ParisTech, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Servant
authors.affiliation: Institut Curie, INSERM U900, Paris, France.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Bollet
authors.affiliation: Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Marc
authors.initials: M
authors.lastname: van de Vijver
authors.affiliation: Department of Radiation Oncology, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Arash O
authors.initials: AO
authors.lastname: Naghavi
authors.affiliation: East Carolina University, Greensborough, North Carolina.
authors.forename: Eleanor E
authors.initials: EE
authors.lastname: Harris
authors.affiliation: Department of Bioinformatics, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Eschrich
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy* / Q000628:therapy; D016001:Confidence Intervals; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression; D006801:Humans; D015412:Mastectomy, Segmental / Q000379:methods; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local; D016609:Neoplasms, Second Primary; D011379:Prognosis; D011836:Radiation Tolerance / Q000235:genetics*; D011879:Radiotherapy Dosage; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D018570:Risk Assessment; D013997:Time Factors; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone