Surveillance for Breast Cancer After Childhood Cancer

Breast cancer is a recognized complication of chest irradiation for childhood cancer,^{1 - 2} and surveillance for breast cancer with regular clinical examination and annual screening mammography starting at age 25 years or 8 years after radiation is recommended.³ However, uptake of screening mammograms in this high-risk group is suboptimal, as shown in the report by Oeffinger and colleagues⁴ in this issue of JAMA. The authors examined breast cancer surveillance practices in a survey of 625 female survivors of pediatric cancer who were between 25 and 50 years and participants in the longitudinal Childhood Cancer Survivor Study (CCSS).⁵ These survivors were at a significantly increased risk of breast cancer as a result of treatment they received in the form of moderate- to high-dose (>20 Gy) irradiation to the chest for treatment of a childhood cancer (chest RT group). The women in the chest RT group were compared with 639 similarly aged CCSS participants who did not receive chest irradiation and with 712 siblings in the CCSS siblings cohort.

Oeffinger et al found that 55% of the women in the chest RT group reported having a screening mammogram within the previous 2 years. Rates of screening mammography varied by age at the time of the survey, with 23.3% of women aged 25 through 39 years and 53.6% of women aged 40 through 50 years reporting a screening mammogram in the previous year. Among women in the younger group, those who reported a physician recommendation for screening were 3 times as likely to have had screening in the previous 2 years when compared with those whose physician did not recommend that they have a mammogram.

In light of a recognized increased risk of breast cancer following radiation to the chest, chest irradiation is now used less frequently for the curative treatment of some pediatric cancers,⁶ which include different types of childhood cancer including Hodgkin disease, Wilms tumor, neuroblastoma, and non-Hodgkin lymphoma; however, there are an estimated 20 000 to 25 000 adult survivors of pediatric cancer older than 25 years in the United States who are in this risk category.^{7 - 8}

Current Childhood Oncology Group (COG) guidelines for breast cancer surveillance after pediatric cancer in the United States recommend yearly clinical breast examination from the age of puberty until age 25 years, and then every 6 months if the survivor was treated with irradiation of at least 20 Gy to mantle, minimantle, mediastinal, chest (thoracic), or axillary fields.³ In addition, it is recommended that these survivors have annual mammography and an adjunct breast magnetic resonance imaging (MRI) starting at age 25 years or 8 years after radiation, whichever is last. The effectiveness of the standard mammogram in detecting preinvasive and invasive breast cancer is known to be relatively poor in young women due to the density of breast tissue in this age group, increasing the importance of MRI in the detection and diagnosis of breast cancer in younger women with dense breast tissue.⁹

The estimated dose of radiation from a standard 2-view screening mammogram is approximately 3.85 mGy per mammogram.^{10 - 12} Although it is accepted that the additional dose is small compared with the higher therapeutic dose already received, it is not known to what extent repeated exposure to small doses of breast irradiation in women already at an increased risk of breast cancer may result in a significantly increased risk of second primary breast cancer. This is an important question that needs to be addressed in future studies.

The generally low uptake rate of screening mammogram in a high-risk population of pediatric cancer survivors has also been highlighted in a previous study of adult survivors.¹³ Some factors associated with the uptake of breast screening including age and race/ethnicity, physician recommendation, health beliefs, and personal understanding of breast cancer risk were explored by Oeffinger et al, but economic factors were not. Thus, whether the cost of annual breast cancer screening was a factor in this cohort is not known. In comparison, among a population of 461 Australian women at an increased risk of developing hereditary breast cancer, uptake of breast screening was 89% overall, although it decreased to 77% among those aged 30 through 39 years and to 56% among those younger than 30 years.¹⁴ It is possible that uptake was high because in this study the women younger than 40 years with a history of breast cancer were offered a screening mammogram through public hospitals at no extra cost or through private services with at least a 75% rebate through the government-funded Medicare system. All women older than 40 years were offered a free screening every 2 years. In contrast, there may be more pediatric cancer survivors in the United States without medical insurance and the cost of mammography may be a disincentive for undergoing annual mammography.

In the United Kingdom, a national recall of women who had been treated prior to age 35 years with supradiaphragmatic irradiation for Hodgkin lymphoma was initiated in 2003. A subsequent schedule for the surveillance of these women was published, which recommended annual MRI between the ages of 25 and 29 years and then annual 2-view mammography with or without MRI depending on the density of breast tissue until the age of 50 years when regular screening takes place within the National Health Service (NHS) Breast Screening Program.¹⁵ A survey of women invited to this recall showed that most women invited to screening reported that they were happy to participate and experienced relatively little distress and recognized the positive benefit from breast cancer screening.¹⁶ Because the breast screening program has been provided by the NHS, there has been no financial cost to the patient. The program has also involved tracking patients who may have relocated from their original area of treatment.

The strengths of the study by Oeffinger et al⁴ include the high-quality design of the questionnaire study, relatively high response rate, and the inherent strengths of the CCSS, which include surveillance practices in a high-risk population and extensive clinical experience of the investigators. Weaknesses include the relatively small sample of childhood cancer survivors who were invited to complete the mammography questionnaire, and inclusion of multiple institutions within the CCSS and multiple diagnoses of childhood cancer, which makes it more difficult to identify specific groups of survivors. Comparing the results of surveillance across a wide range of medical institutions could introduce some bias into the study design, which is also hospital-based and as such includes a higher risk of patients being lost to follow-up.

Although this study focuses on the specific issue of screening for breast cancer, survivors of childhood cancer may face many long-term health issues related to their treatment, including other effects of irradiation such as impaired bone growth, endocrine deficiencies, and potential long-term cardiac effects of anthracycline chemotherapy.⁶ As the number of adult survivors of childhood cancer increases, appropriate attention will need to be given to these “survivorship issues” and should include health education and the provision of dedicated long-term follow-up facilities. These follow-up programs need to be individualized and guided by the specific late effects associated with particular treatments used for different types of childhood cancer.

In conclusion, the report by Oeffinger et al highlights several important issues. These include the relatively low uptake of screening mammography in a high-risk population, the importance of clinician recommendation to improve the uptake of screening mammography, and the continuing need to educate clinicians and patients about the risks of breast cancer after chest irradiation in childhood through well-designed education programs. The risk of breast cancer after exposure to annual low-dose irradiation in the form of x-ray mammography should be explored in future studies as well as the role of MRI as a replacement for x-ray mammography rather than as an adjunctive examination in this group of young women. In addition, it is important to explore whether the rate of screening uptake could be improved if survivors were provided with screening at no extra cost.