Potential Reduction of Contralateral Second Breast-Cancer Risks by Prophylactic Mammary Irradiation: Validation in a Breast-Cancer-Prone Mouse Model

Abstract

BackgroundLong-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.AimsTo test the predicted relationship between PMI dose and cancer risk in mammary glands that have a high risk of developing malignancies. MethodsWe 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 16Gy in 4-Gy fractions. ResultsIn 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.ConclusionsThe 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.

Recombinant human endostatin enhances the radioresponse in esophageal squamous cell carcinoma by normalizing tumor vasculature and reducing hypoxia

“…Tumors were irradiated with X-rays (8 Gy dose, 2 Gy/min) on D16, using an RS-2000 biological irradiator. The selection of a single dose of 8-Gy of X-rays was made on the basis of previous studies using single doses of 2–20 Gy 21 22 . Tumor growth was measured every day until D25, and the tumor volume was calculated according to the formula: Tumor volume = (length [L] × width [W]) 2 /2.…”

“…Second, a single large-dose of IR was employed to exclude the potential confounding effects of conventional fractionated IR. However, the use of a single 8-Gy dose, selected on the basis of previous studies 21 22 , differs from regimens that are used clinically. Therefore, the optimal combination of rh-Endo with conventional IR warrants further investigation.…”

Effects of Radiation Therapy on Breast Epithelial Cells in BRCA1/2 Mutation Carriers

“… 28 As a proof of principle, a recent study demonstrates that prophylactic mammary irradiation significantly reduces tumor incidence in a mammary tumor-prone animal model. 29 …”

Prophylactic breast irradiation reduces background parenchymal enhancement (BPE) on MRI: A secondary analysis

“…Potential reduction of breast cancer by prophylactic mammary irradiation was previously proposed [ 11 ] and subsequently supported by an experimental mouse model [ 12 ]. In mammary-cancer-prone mice, irradiation of the mammary glands on one side decreased the tumor incidence rate compared with the mammary glands on the contralateral shielded side [ 12 ].…”