As noted above, there is a growing indication that women with BRCA1/BRCA2 mutations who are treated conservatively have an increased, not decreased, rate of ipsilateral breast cancer, occurring usually after 5 years of follow-up.
The second concern stems from the emerging understanding of the role of the BRCA genes in DNA repair activities within the cell, and the implication of the loss of these functions for radiation hypersensitivity. Both BRCA1 and BRCA2 are involved in DNA double-strand break repair, and loss of function in these genes could potentially accelerate the rate of cell kill caused by ionizing radiation. Another potentially relevant mechanism is the defect in the G2-M phase checkpoint displayed by BRCA1-deficient cells, which also alters radiation sensitivity. Furthermore, murine models of Brca1- and Brca2-deficient mice have demonstrated evidence of hypersensitivity to ionizing radiation.[21,266] Clinical manifestations of these findings could include the following:
- An increased response to adjuvant radiation therapy with a decrease of in-breast recurrence rates.
- An increase in ipsilateral and contralateral breast cancers secondary to genetic instability.
- An increase in radiation-related toxicity.
In one study, the rate of local recurrence among women with strong family histories who were treated with lumpectomy was highest when radiation was omitted, suggesting that these tumors are radiosensitive. Rates of contralateral disease are consistently elevated in this population, but are equal for women treated with conservative therapy and for those who chose mastectomy without radiation, indicating that the increased risk is due to the mutation, not the exposure to radiation. And finally, studies have failed to find an increase in either early acute radiation tissue reactions or late radiation reactions to the skin, underlying tissue or bone.[267,268,269]
These data are consistent with a model in which hereditary BRCA1/BRCA2 cancers are sterilized by radiation therapy equally well, but due to the underlying genetic predisposition, the increased risk of second primaries in the treated breast remains. The findings of a significantly increased risk of contralateral breast cancer in this population is consistent across studies, and increasingly women with BRCA1/BRCA2 mutations are considering bilateral mastectomy at the time of first diagnosis of breast cancer, regardless of stage. Finally, there is no evidence for an increase in radiation toxicity among BRCA1/BRCA2 mutation carriers.
Level of evidence: 3di
Contralateral breast cancer in BRCA mutation carriers
As early as 1995, the Breast Cancer Linkage Consortium estimated the risk of contralateral breast cancer (CBC) in BRCA1 mutation carriers to be as high as 60% by age 60 years. This report has been followed by several retrospective studies of various cohorts of women with hereditary patterns of breast cancer in both the United States and Europe. One retrospective cohort study reviewed the records of 91 AJ women diagnosed with breast cancer before the age of 42 years, 30 of whom had a deleterious BRCA1 or BRCA2 mutation. At a median follow-up of 63 months, the rate of CBC was 40% in the mutation carriers compared with 8.2% among noncarriers. Carriers had a shorter median interval between cancers than noncarriers (36 months vs. 63.9 months). The same group reported 5-, 10-, and 15-year probabilities of CBC of 11.9%, 37.6% and 53.2%, respectively, among 87 mutation carriers. Rates of CBC in this clinical cohort did not differ by mutation type (BRCA1 vs. BRCA2) or by age at first diagnosis. A case-control study from the Netherlands compared rates of CBC between 49 women with BRCA1-related breast cancer and 196 breast cancer cases not known to have a BRCA1/BRCA2 mutation (sporadic controls). At 5 years of follow-up, rates of CBC were 20.4% among mutation carriers versus 5.6% among the controls. In an expanded cohort of BRCA1-related breast cancer patients, the risk of CBC was inversely correlated with age at first diagnosis, with the majority of cases of CBC occurring among women whose first breast cancer was diagnosed at or before age 50 years. A similar analysis matching 28 BRCA2 mutation-positive cases with 112 sporadic controls found a five-fold increase in CBC among cases (25% vs. 4.5%). A larger study of members of BRCA1/BRCA2 families in the Netherlands reported similar 10-year risks of CBC for women from BRCA1 and BRCA2 families (34.2% and 29.2%). In another study, 127 patients with early-onset breast cancer (aged ?42 years) who had been treated with breast-conserving therapy, were genotyped for mutations in BRCA1 and BRCA2. At a median follow-up of 12 years, the rate of contralateral breast cancer among the 22 mutation-positive patients was 42% compared with 9% in the noncarriers. A similar analysis from the Institut Curie in Paris reported a rate of CBC of 37% among mutation carriers compared with 7.3% in noncarriers at a median follow-up of 8.75 years.