Reducing second breast cancers: a potential role for prophylactic mammary irradiation.

Breast-conserving surgery followed by radiotherapy is the standard of care for most women with early-stage breast cancer, resulting in excellent long-term survival. Post-treatment, however, the rate of second breast cancers is significant; for example, the average ipsilateral second-cancer rate from four long-term studies is 13% after 15 years, and increases with still longer follow-up times. Rates in the contralateral breast are typically only slightly lower. We focus here on the rate of second cancers, which are genetically independent of the primary (ie, not recurrences); this rate is much higher than could be explained from the natural background rate of breast cancer in the general population, for both breasts. After conservative surgery, the ipsilateral breast is typically administered a fractionated whole-breast radiotherapeutic dose of at least 45 Gy, followed by a local boost to the tumor site. There is now considerable evidence that such large radiation doses to the breast result in significantly increased breast cancer risks. For example, recent long-term studies of Hodgkin’s disease patients who underwent radiotherapy show large radiation-induced breast cancer risks at sites exposed to doses 40 Gy, with excess relative risks in the range of 10 to 30. That tissues exposed to fractionated radiation doses as high as 40 to 50 Gy are at significant risk for radiation-induced cancer has only recently become apparent. Early models of radiation-induced cancer had predicted that virtually all radiation-mutated cells would be killed by such large doses, and thus the risk of radiationinduced cancer would be minimal. However, the epidemiologic data showing high risks of radiation-induced cancer at high radiation doses have made it apparent that simple models of radiation carcinogenesis involving radiation-induction of premalignant cells, modulated solely by cell killing, are not adequate at high radiation doses. Consequently, more recent models take into account repopulation of normal and of premalignant cells by proliferation, occurring during and after fractionated radiotherapy, whereby some repopulating cells carry and pass on radiationinduced premalignant damage. Including repopulation in models of radiation-induced cancer results in predictions of substantial cancer risks at high radiation doses, consistent with epidemiologic data. Thus, recent epidemiologic data and theory both lead to the expectation that women who receive a whole breast dose of 45 to 50 Gy will be at significant long-term risk for radiation-induced breast cancer, for all relevant ages. Here we estimate the cancer risks associated with adjuvant whole-breast irradiation after lumpectomy, both in the ipsilateral and contralateral breasts, and compare the predictions with the measured long-term risks of genetically independent second cancers in each breast. This allows an assessment for each breast of the relative importance of tumor recurrence, background risk, and radiation risk. The resulting insights in turn suggest potential strategies for reducing these risks.