title: Potential reduction of contralateral second breast-cancer risks by prophylactic mammary irradiation: validation in a breast-cancer-prone mouse model.
abstract: BACKGROUND
  Long-term breast-cancer survivors have a highly elevated risk (1 in 6 at 20 years) of contralateral second breast cancer. This high risk is associated with the presence of multiple pre-malignant cell clones in the contralateral breast at the time of primary breast cancer diagnosis. Mechanistic analyses suggest that a moderate dose of X-rays to the contralateral breast can kill these pre-malignant clones such that, at an appropriate Prophylactic Mammary Irradiation (PMI) dose, the long-term contralateral breast cancer risk in breast cancer survivors would be considerably decreased.
  
  
  OBJECTIVE
  To test the predicted relationship between PMI dose and cancer risk in mammary glands that have a high risk of developing malignancies.
  
  
  METHODS
  We tested the PMI concept using MMTV-PyVT mammary-tumor-prone mice. Mammary glands on one side of each mouse were irradiated with X-rays, while those on the other side were shielded from radiation. The unshielded mammary glands received doses of 0, 4, 8, 12 and 16 Gy in 4-Gy fractions.
  
  
  RESULTS
  In high-risk mammary glands exposed to radiation doses designed for PMI (12 and 16 Gy), tumor incidence rates were respectively decreased by a factor of 2.2 (95% CI, 1.1-5.0) at 12 Gy, and a factor of 3.1 (95% CI, 1.3-8.3) at 16 Gy, compared to those in the shielded glands that were exposed to very low radiation doses. The same pattern was seen for PMI-exposed mammary glands relative to zero-dose controls.
  
  
  CONCLUSIONS
  The pattern of cancer risk reduction by PMI was consistent with mechanistic predictions. Contralateral breast PMI may thus have promise as a spatially targeted breast-conserving option for reducing the current high risk of contralateral second breast cancers. For estrogen-receptor positive primary tumors, PMI might optimally be used concomitantly with systemically delivered chemopreventive drugs such as tamoxifen or aromatase inhibitors, while for estrogen-receptor negative tumors, PMI might be used alone.
authors.affiliation: Center for Radiological Research, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Igor
authors.initials: I
authors.lastname: Shuryak
authors.affiliation: Center for Radiological Research, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Lubomir B
authors.initials: LB
authors.lastname: Smilenov
authors.affiliation: Center for Radiological Research, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Norman J
authors.initials: NJ
authors.lastname: Kleiman
authors.affiliation: Center for Radiological Research, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Brenner
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000517:prevention & control* / Q000532:radiotherapy; D004307:Dose-Response Relationship, Radiation; D005260:Female; D051379:Mice; D008822:Mice, Transgenic; D016609:Neoplasms, Second Primary / Q000517:prevention & control* / Q000532:radiotherapy; D059351:Organ Sparing Treatments / Q000379:methods*; D011878:Radiotherapy / Q000379:methods*; D011879:Radiotherapy Dosage