Breast Cancer

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Radiation to the breast tissue may induce secondary breast cancers. Although the risk is not isolated to those with HD, SMNs are recognized as a leading cause of death in long-term survivors of HD, with breast cancer representing the most frequent solid tumor among such women [4, 57,60]. Radiation exposure to the breast between the ages of 10-30 years imparts the greatest risk of developing secondary breast cancer. During puberty, the breast undergoes rapid growth and differentiation secondary to a surge in pituitary hormones and the resultant increase in estrogen. Hormonal stimulation of proliferating tissue may potentiate the risk of developing subsequent breast cancer. The role of genetic predisposition is less clear. It has been speculated that genetic predisposition could accelerate the tumorigenic process by providing the initiating event, as is known to occur for renal cancer in rats that carry the tuberous sclerosis 2 gene [22].

Breast cancer was the most frequent SMN in the CCSS cohort of 13,581 long-term survivors of pediatric cancer (N=60), and 65% of the SMNs occurred in female survivors of Hodgkin's disease [42]. In another report of SMNs following treatment for Hodgkin's disease between 1955 and 1986,breast cancer was the most common of the 212 SMNs, with a standardized incidence ration (SIR) of 56.7 [5]. This report updated the results of an earlier study of 1,380 patients who were less than 16 years of age when diagnosed with HD. By extending the latent period from 11.4 years to 17 years, the number of SMNs increased from 109 to 212 in 173 individuals. Breast cancer was the most common SMN, with 42 incidences occurring in 30 women in a median time of 18 years (4.3 - 28). This represented a 57-fold risk, compared with the general population. The cumulative probability of developing breast cancer by age 40 was 14%, and the probability by age 45 was 20% [5].

Another international study of 3,817 women diagnosed with HD before age 30 reported that 105 developed breast cancer at a mean of 18 years after diagnosis and at a mean age of 40.7 years [57]. Increased risk of breast cancer was observed in patients who had received more than 40Gy to the chest, and there was a dose-response relationship. Overall, women who became menopausal before age 40, either as a result of radiation or alkylating agent chemotherapy, experienced significant reductions in risk, compared with women who retained ovarian function. Among those patients who did not become menopausal, the number of alkylating agent cycles received was inversely related to the risk of breast cancer, also implying decreased risk when ovarian function is lost. Regarding the possible role of genetic susceptibility in survivors of HD, Nichols et al. found that TP53, BRCA1 or BRCA2 were not frequently mutated in a cohort who had developed SMNs [44].

Many reports have documented that the risk of breast cancer following chest irradiation persists for more than 25 years afterward; however, more than 40% of females who were treated for Hodgkin's disease prior to the age of 30 were not aware of their increased risk [10]. This underscores the continued need for ongoing patient education and public awareness. Although there are limitations of mammogra-phy in young women, including hyper-density and radiosensitivity of a young breast, it has been shown to be technically possible and may be successful in detecting breast cancer following radiation exposure. Therefore, it is recommended that females who have received previous chest irradiation begin yearly mammograms beginning 8 years post-radiation, or at age 25 [28]. In addition, they should be instructed to perform monthly breast self-examinations and have an annual clinical breast exam starting at puberty. Lastly, because hormone replacement therapy has been shown to influence the risk of breast cancer, surveillance is especially critical when recommending HRT [28].

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