Radiation Therapy and the Risk of Second Primary Breast Cancers in Women with BRCA Deleterious Variants
Radiation has been shown to be advantageous, particularly in women undergoing breast-conserving surgery as well as many having mastectomy with more advanced disease. In addition, it reduces the risk of invasive and noninvasive recurrent DCIS.
Radiation utilizes ionizing radiation GNO which causes varying degrees of DNA damage as it detaches electrons from atoms within the cell. It generally causes breaks of both DNA stands (double-strand breaks…DSB)). These common DSBs are for the most part easily repaired by a process called homologous recombination in which genetic information is exchanged between sister chromatids. This type of repair is usually error-free, a process in which the BRCA genes play an important role. When women inherit a germline mutation in one of these genes, it forces the DNA repair mechanism into a more error-prone pathway. Breast tissue in young premenopausal women is generally more dense and more proliferative than older women Breast tissue is also less differentiated than the breasts of younger women. These factors may increase the vulnerability of the breasts to external DNA-damaging agents such as ionizing radiation.
Prior studies on this topic tended to be smaller in number and or have less follow-up. This current study by Mark van Barele et. al. (Journal of the National Cancer Institute) is a multinational, multi-institutional trial that attempted to answer a single question. Does radiation therapy delivered after breast cancer surgery increase the risk of contralateral breast cancer (CBC) compared to those not receiving radiation? This information can be utilized in clinical decision-making, and preventive measures such as screening, preventative surgery, or lifestyle changes.
The authors selected 3602 eligible post-breast cancer treatment patients of whom 2297 (64%) receive radiotherapy. Tumor and treatment characteristics for the various groups were similar overall. The only significant difference noted was that 15% of patients in the radiation group were diagnosed with stage III as opposed to 3% in the non-radiation group. Also noted was a 10% increase in the number of patients in the radiation group receiving chemotherapy. Contralateral breast cancer occurred in 252 patients in the radiation group (180 being invasive) and 98 patients in the non-radiation group (70 being invasive). Death occurred in 235 patients in the radiation group and 95 patients and the non-radiotherapy group.
The risk of invasive and in situ contralateral breast cancer was increased for patients receiving radiotherapy (hazard ratio equals 1.44). The risk of developing contralateral breast cancer associated with radiotherapy compared to those patients without radiotherapy was proportional over time we appear to peak 5-6 years after the diagnosis of breast cancer. In patients carrying the pathogenic variant in the BRCA2 gene, the risk of contralateral breast cancer was higher than for those counting a mutation in the BRCA1 gene (HR = 1.77 versus 1.29). The increased risk of contralateral breast cancer after radiation is also true for patients younger than 40 years of age at diagnosis where the HR=1.38. The effects of radiation associated with only invasive contralateral breast cancer were in line with the prior analysis. Interestingly, no statistically significant interactions of chemotherapy, endocrine therapy, or specific BRCA mutation were observed.
The authors concluded that there was an association with an increased risk of contralateral breast cancer among BRCA carriers who received radiation compared to those who did not. They also noted that the risk was comparable for different age groups and noted that BRCA2 pathogenic areas showed the highest risk of post-radiation contralateral breast cancer.
Dr. Alan Stolier, MD, FACS, clinical breast oncologist, shares his expert medical perspective with a series of educational and scientific articles.