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.
Highlights
Breast cancer is one of the most common types of cancer in the US, and as many as one in eight women may develop breast cancer during their lifetime [1]
We investigated the effects of various doses of mammary irradiation on tumor development in these mice, and show that the expected breast cancer risk pattern with increased dose (Figure 1) was apparent: a small increase in cancer risk at low radiation doses, followed by a decrease in cancer risk at Prophylactic Mammary Irradiation (PMI)-relevant doses, with the mammary tumor incidence rate reduced by a factor of about three
We focus here on comparisons between tumor incidence rates in the PMI-irradiated mammary glands and in the corresponding shielded mammary glands; as described above, this is designed to model a comparison of cancer rates in a human contralateral breast exposed to PMI vs. cancer rates in the same breast receiving a typical scatter dose after standard radiotherapy to the ipsilateral breast
Summary
Breast cancer is one of the most common types of cancer in the US, and as many as one in eight women may develop breast cancer during their lifetime [1]. For estrogen-receptor positive tumors, adjuvant tamoxifen reduces contralateral breast cancer risks by as much as 40% [10] - which for long-term survivors represents a risk reduction from about 16% to 10%, still a disturbingly high risk. 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. 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
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