In summary, there is consistent observational evidence showing that women treated for a pediatric or young adult cancer with moderate- to high-dose therapeutic chest radiation (≥20 Gy) have a substantially elevated risk of breast cancer at a young age and that this excess risk does not appear to plateau with aging. Available limited evidence suggests that the characteristics of the breast cancers in these women and the outcomes following diagnosis are similar to those in the general population; and that there appears to be a benefit associated with early detection given that women diagnosed with early stage breast cancer following chest radiation have a high likelihood for a favorable outcome. However, many of these women may have fewer treatment options for their breast cancer (eg, additional radiation, doxorubicin chemotherapy) because of treatment exposures used to cure their first cancer (35
Mammography appears to detect the majority of cancers in these women. However, more than half of mammograms in women who had previous chest radiation have moderate to very dense breast tissue, thus limiting the sensitivity of mammography in detecting early cancers in this population. A systematic review of 11 prospective studies reported that screening with both MRI and mammography among women with a hereditary risk of breast cancer appears to rule out cancerous lesions better than mammography alone (53
). While all 11 studies reported a higher sensitivity for MRI than mammography for invasive cancer, mammography was more sensitive than MRI for ductal carcinoma-in-situ. It is not known whether combining mammography with MRI is superior to either test alone for detecting early cancers among women who have been treated with chest radiation. However, given the similar incidence rates among young women between these two high risk populations, the increased likelihood of dense breast tissue, and the similar response to curative therapy for early diagnosed breast cancer, it is seems reasonable to speculate that the data from the hereditary risk-focused studies apply to women treated with chest radiation. Given the relatively limited size of both populations, an adequately powered randomized clinical trial to determine if surveillance with mammography and/or MRI (versus no surveillance) is associated with a reduction in mortality is unlikely to be feasible or ethical (53
). However, ongoing prospective and high quality retrospective studies that further assess the screening metrics of different imaging approaches for women who have been treated with chest radiation might still provide useful information.
It should be recognized that while women in this risk group may benefit from breast cancer surveillance at a younger age, there is still too little understood regarding the potential harms. For example, women initiating surveillance at 25 years of age would have at least 15 additional mammograms (prior to initiating screening at the usual age of 40) and thus an increased likelihood of experiencing false positive tests with the associated economic and emotional costs of additional testing and/or biopsies. Adding an MRI may further add to the false positive rate among these women and would substantially increase the economic cost of surveillance. Of note, the combination of mammography and MRI appears to be more cost-effective in screening young women with a hereditable risk of breast cancer than mammography alone (57
Another potential harm with mammography is the additional radiation exposure and the potential for radiation-induced breast cancer. Among women in the general population (61
) and those with a hereditary risk of breast cancer (68
), much effort has been devoted to estimating the number of breast cancers induced by mammography. Because there are no studies that directly measure risk of breast cancer caused by radiation exposure with mammography, estimates have been based upon low-dose radiation exposure from other sources, such as atomic bomb radiation, chest fluoroscopy, and thymic irradiation (71
). Combining this information with the number of breast cancers detected provides an indicator of the benefit/risk balance (63
). The estimated mean breast dose with a contemporary standard 2-view screening mammogram is about 3.85 – 4.5 mGy (68
). Thus, in a woman treated with 20 Gy chest radiation, fifteen additional surveillance mammograms from age 25 to 39 would increase the total radiation exposure to 20.05775 Gy or by about 0.3%. Faulkner and Law estimate that among women in the general population between the ages of 30–34, radiation exposure from a 2-view mammogram induces about 82 cancers per million women screened and detects about 630 cancers, giving a detected/induced ratio of almost 8 (74
). For women ages 35–39, the detected/induced ratio is about 19. Based upon the lifetime risks of women treated with moderate to high-dose chest radiation at a young age, they estimate that detection/induction ratios will be at least 3–4 times higher than the general population (74
). In addition, they emphasize that the induction rates from mammography used in the general population are likely not applicable to this population of women treated with high doses of therapeutic radiation (74
In addition to better understanding the potential harms and benefits of specialized surveillance in this population, we need to better understand the multiple factors that may modify breast cancer risk of women who have received low or moderate dose chest radiation, especially given recent modifications in therapy including reduction in the radiation dose and reduction in the volume of developing breast tissue exposed (75
). While it is anticipated that the incidence of breast cancer may decrease in women treated with contemporary therapy, it is not known what the long-term effect of these lower radiation doses will be on overall risk. Potentially, lower exposure may still be highly carcinogenic but associated with a longer latency period to induction of breast cancer.
Many women treated with chest radiation are unaware of their risks, are not followed at a cancer center, and are seen by clinicians who may be unfamiliar with their long-term health risks. In a recent survey of women in North America treated for a pediatric cancer with chest radiation, only 49% were aware that chest radiation increased the risk of breast cancer. Among women ages 25–39, nearly half had never had a mammogram (or other imaging study) and less than 20% were in a regular pattern of BC surveillance (76
). While most women in this high risk group who were 40–50 years of age reported some level of breast cancer surveillance, only 53% had at least two mammograms in the previous four years. Thus, interventions aimed at informing women and their clinicians regarding these risks and options for breast cancer surveillance are needed.
Finally, a continuing theme of research that aims to reduce the very serious long-term morbidity and premature mortality faced by pediatric and young adult cancer survivors (1
) is that there is consistent evidence linking the exposure to the late effect (i.e., chest radiation and breast cancer), but limited evidence that specialized surveillance will benefit this high risk population. In balancing the potential life-saving benefits of a young and productive population of women with the potential harms of specialized breast cancer surveillance, various national and international groups, based upon consensus, recommend initiating surveillance at a young age (55
) (). Current recommendations are based upon rather arbitrary radiation levels to the chest, which will need to be continually re-evaluated as research provides better estimates of dose-specific risks (24
). Presently, for women treated for a pediatric or young adult cancer with chest radiation ≥20 Gy, the COG recommends annual surveillance mammography and MRI, starting at age 25 or eight years after completion of radiation therapy, whichever occurs last. These recommendations can be viewed in the Long-Term Follow-Up Guidelines
document (pages 128–129) posted at www.survivorshipguidelines.org
Summary of consensus-based recommendations for breast imaging surveillance from different national and international organizations.
In summary, we identified consistent evidence that women treated for a pediatric or young adult cancer with moderate- to high-dose therapeutic chest radiation (≥20 Gy) have a substantially elevated risk of breast cancer at a young age and that this excess risk does not appear to plateau with aging. Available limited evidence suggests that the characteristics of the breast cancers in these women and the outcomes following diagnosis are similar to those in the general population; and that there appears to be a benefit associated with early detection given that women diagnosed with early stage breast cancer following chest radiation have a high likelihood for a favorable outcome. Further research is required to better define the harms and benefits of lifelong surveillance, and how estimates of risk and outcome might change given lower radiation doses use in contemporary treatment.