Breast Cancer After Radiation for Hodgkin's: Is it Genetic?
FGFR2 Genotype and Risk of Radiation-Associated Breast Cancer in Hodgkin LymphomaMa YP, van Leeuwen FE, Cooke R, et al
SummaryIn 2 independent case-control studies, investigators in the United Kingdom and The Netherlands examined the potential relationship between 14 individual single nucleotide polymorphisms (SNPs) that had previously been shown to influence the development of breast cancer and the risk of a woman developing a secondary breast cancer following the use of radiation to the chest wall in the management of Hodgkin lymphoma. The patients in the UK series had been treated for lymphoma between 1963 and 2003, while the patients in The Netherlands were managed between 1965 and 1997. A total of 693 Hodgkin lymphoma patients were included in the analysis; 232 had developed a secondary breast cancer and 461 had not.
The presence of one particular SNP, rs12119648, which is related to the FGFR2 gene, was found to be highly statistically significantly associated with risk for a secondary breast cancer (overall hazard ratio 1.59, 95% confidence interval 1.26-2.02; P = .000111). Of note, although the FGFR2 gene is overexpressed in estrogen-receptor positive breast cancer and has been shown to have oncogenic effects, the impact of FGFR2 on the development of a secondary breast cancer in this population was greater than the impact of FGFR2 on breast cancer in the general population.
ViewpointPrior experience with the provocative relationship between specific genetic factors and radiation sensitivity led to the speculation that there may be a clinically relevant relationship between chest wall radiation for Hodgkin lymphoma and the risk for subsequent development of breast cancer as a complication of this therapeutic modality. The issue of secondary breast cancer in women receiving chest wall radiation for Hodgkin lymphoma is a major concern, with reports noting a cumulative risk as high as 25% after several decades of follow-up.
In this study, researchers examined the presence of prospectively defined SNPs that had been noted in other settings to be associated with the risk of developing breast cancer. The presence or absence of these SNPs in patients who developed or did not develop breast cancer after receiving chest radiation for Hodgkin lymphoma revealed what can appropriately be described as a potentially highly clinically relevant association between the rs1219648 SNP and the risk for this serious complication of curative therapy.
This finding is of particular interest considering a somewhat controversial recent report of long-term survival in patients with limited-stage Hodgkin lymphoma who received combination chemotherapy alone vs subtotal nodal radiation with or without chemotherapy. In that study, after a median follow-up of 11.3 years, a similar impact of the treatment strategies was seen on the course of the primary malignancy, but a greater risk for death from multiple causes was associated with radiation treatment. Although the extent of radiation therapy in this trial might have contributed to some of the excess toxicity, the higher mortality in the radiation group was still disproportionately associated with causes other than disease progression.
In view of the equivalent cancer-related outcome, it is reasonable to speculate that the presence of the rs1219648 polymorphism might be contributing to the severity of the radiotoxic effects in patients with Hodgkin lymphoma, and its detection could serve as justification for avoiding radiation therapy in favor of chemotherapy alone.