Curative therapy, including chest RT for Hodgkin lymphoma, is associated with a definitively increased risk of breast cancer, most often manifesting approximately 20 years after treatment. These breast cancers tend to be more aggressive, with greater frequency of hormone receptor negativity and potential HER2 positivity.
When Hodgkin's disease, now referred to as Hodgkin lymphoma, was first described in 1853, it was a deadly disease. Patients usually died within months of diagnosis, and treatment was focused on improving patient comfort. In 1954, an era where only 5% of patients with Hodgkin lymphoma survived, Drs. Henry Kaplan and Edward Ginzton invented the first medical linear accelerator in the Western Hemisphere to deliver therapeutic radiotherapy (RT) with improved accuracy and potency, leading to curative outcomes in a group of patients with Hodgkin lymphoma. Around this time, DeVita et al demonstrated the first curative combination chemotherapy in cancer, the MOPP (nitrogen mustard, vincristine, procarbazine, and prednisone) regimen for patients with Hodgkin lymphoma. The concept of combined-modality treatment was advanced by Dr. Kaplan and Dr. Saul Rosenberg, who demonstrated that extended-field RT and combination chemotherapy could be curative for Hodgkin lymphoma patients.[3,4] Despite these advances, the late toxicities of chemotherapy and increased risk of secondary malignancies with RT have threatened the survival rates and quality of life of Hodgkin lymphoma patients. What is the cost of curing Hodgkin lymphoma, particularly in our young population?
In this issue of ONCOLOGY, Overholser and colleagues review a woman’s risk of developing breast cancer after receiving RT to the chest, and identify strategies to reduce this risk. Although the authors cite data suggesting no significant differences between RT-induced breast cancers compared with sporadic breast cancers-except for an increased risk of bilateral breast cancer-our clinical experience, along with more recent studies, suggests otherwise. Broeks et al analyzed gene expression profile data to query whether differences in molecular subtype exist between sporadic breast cancers and breast cancers associated 1with RT exposure. Breast cancers after Hodgkin lymphoma were enriched for the basal and human epidermal growth factor receptor 2 (HER2)-enriched tumor subtypes (50% overall) and were found to have significantly higher expression of the Ki-67 proliferation marker compared with controls, as well as a profile of chromosomal instability. Using data from the Stanford Hodgkin’s Disease Database from 1966 to 1999, Horst et al retrospectively reviewed 147 patients with a history of Hodgkin lymphoma and chest RT who subsequently developed breast cancer. At our center, among patients with invasive breast cancer and complete pathologic information (n = 51), breast cancers after Hodgkin lymphoma were almost three times more likely to be triple-negative compared with age-matched controls (39% vs 14%). In this cohort, 49% had estrogen receptor (ER)-negative and progesterone receptor (PR)-negative disease, and only 14% were HER2-positive. Meattini et al also showed elevated rates of hormone receptor–negative cancers (28%) compared with sporadic cases (13%) in a series of 39 patients. Taken together, these data suggest RT-associated breast cancers have a more aggressive biology compared with sporadic cases.
These results challenge whether women at risk for secondary breast cancer after chest RT for Hodgkin lymphoma should be universal candidates for chemopreventive agents, such as selective estrogen receptor modulators or aromatase inhibitors, which are only effective in preventing ER-positive tumors. Overholser and colleagues discuss the role of endocrine therapy to reduce risk for breast cancer, and cite interesting data from patients who developed premature ovarian failure due to ovarian irradiation or alkylating chemotherapeutic agents, which demonstrates that these patients were at decreased risk for developing subsequent breast cancer. Data from large studies of chemoprevention in breast cancer reveal that this strategy is less effective in patients at risk for developing hormone receptor–negative tumors. Thus, if the breast cancers occurring in women post RT have elevated rates of ER and PR negativity, then women could be unnecessarily exposed to agents such as tamoxifen and could be potentially put at elevated risk for post–Hodgkin lymphoma treatment–related toxicity. Most importantly, patients who received chest RT are at greater risk of cardiac complications, including coronary artery disease, valvular heart disease, congestive heart failure, and pericardial disease. Heidenreich et al evaluated women who received prior RT doses > 35 Gy to the mediastinum for the presence of occult coronary artery disease and discovered elevated rates of stress-induced perfusion defects or wall motion abnormalities on echocardiogram. Moreover, patients had a significantly elevated relative risk of mortality from myocardial infarction, ranging between 7.3 and 8.1, depending on the length of time since radiation exposure. Given potential risks of thrombosis with drugs like tamoxifen, caution must be taken when evaluating patients’ eligibility for this type of chemoprevention strategy.
Although increased hormone receptor negativity in RT-associated breast cancer could appear to limit therapeutic options, the unique mutational profile of RT-associated breast cancers could also potentially confer susceptibility to certain therapies. Radiation is known to damage DNA and cause chromosomal instability. As previously noted, Broeks et al demonstrated that RT-associated breast cancers have a profile of chromosomal instability, and in other contexts, this has been found to be associated with increased host antitumor immunity.[6,11] Looking ahead, the DNA damage and potentially increased mutation rate in RT-associated breast cancer may be linked with responsiveness to immunotherapies, such as immune checkpoint inhibitors. In melanoma, an increase in overall mutational and neoantigen load-novel tumor-specific antigens that can be recognized by the immune system-was associated with clinical benefit from checkpoint blockade. Cancers that respond the most favorably to checkpoint inhibitors include non–small-cell lung cancer, largely caused by chronic exposure to carcinogens in cigarette smoke, and melanoma, largely caused by exposure to ultraviolet light. In breast cancer, preliminary studies show that inhibition of programmed death 1 (PD-1) and PD ligand 1 (PD-L1) has been associated with clinical activity in metastatic triple-negative breast cancer,[14,15] with multiple trials ongoing in this space. An exploration of the role of immunotherapy in RT-induced breast cancers and other RT-associated malignancies is an interesting topic and worthy of further investigation.
In summary, curative therapy, including chest RT for Hodgkin lymphoma, is associated with a definitively increased risk of breast cancer, most often manifesting approximately 20 years after treatment. These breast cancers tend to be more aggressive, with greater frequency of hormone receptor negativity and potential HER2 positivity. This breast cancer phenotype has implications for chemopreventive strategies in at-risk Hodgkin lymphoma survivors, and a careful risk:benefit analysis should be discussed with patients considering this approach. Overholser and colleagues nicely summarize the current state of knowledge in this important area. As RT delivery methods continue to improve and RT use for this disease decreases, it is our hope that the incidence of RT-associated breast cancer following curative treatment for Hodgkin lymphoma will decline.
Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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