Contralateral breast cancer risk with radiation therapy in BRCA mutation carriers: what do we tell patients?

BRCA1/2 pathogenic variants are found in approximately 3% to 12% of all women with breast cancer and 20% to 25% of women with a family history of breast or ovarian cancer (1,2). Among other functions, BRCA1 and BRCA2 proteins are involved in the repair of double-stranded DNA breaks by homologous recombination. BRCA1/2 genes are tumor suppressor genes, with loss or mutation of the wild-type allele seen within tumors (3). BRCA pathogenic variant carriers have a increased lifetime risk of contralateral breast cancer after an index diagnosis, reaching 40% in BRCA1 carriers and 26% in BRCA2 carriers (4). The optimal multidisciplinary management of an index breast cancer in women with a pathogenic variant is a balance between oncologic outcomes for the primary cancer and the risk of a second event.

Certain factors modify contralateral breast cancer risk in BRCA pathogenic variant carriers, and recognition of these factors can inform counseling on how treatment may modify this risk. Family history influences contralateral breast cancer risk, with a BRCA1 pathogenic variant conferring a 40% increase in risk with each first-degree relative affected with breast cancer before 50 years of age (5). Age at first breast cancer also modifies second cancer risk, with women diagnosed younger than 40 years of age having a higher contralateral breast cancer risk than those older than 50 years of age (6). A protective factor for contralateral breast cancer in younger women is oophorectomy, while tamoxifen for risk reduction has shown mixed results (7). Whether adjuvant radiation therapy (RT) following surgical management of the index breast cancer elevates contralateral breast cancer risk is uncertain. In a Women’s Environment, Cancer, and Radiation Epidemiology study report, a population-based, nested case-control study of cases with contralateral breast cancer and controls without who were matched on age, race, year of diagnosis, and cancer registry, BRCA carriers had an elevated risk of contralateral breast cancer, as did noncarrier women who underwent RT. Among pathogenic variant carriers, however, the interaction between RT and contralateral breast cancer was not statistically significant (8). In contrast, a systematic review found limited evidence that BRCA pathogenic variants may modify risk after exposure to ionizing radiation, although these results were not consistent across studies (9).

In this issue of the Journal, van Barele and colleagues (10) found that BRCA1/2 pathogenic variant carriers with a primary breast cancer who underwent RT had an increased contralateral breast cancer risk compared with patients who did not undergo RT. Using a large cohort of 3603 BRCA1/2 carriers with a primary breast cancer from a prospective database, the authors investigated the association between RT and contralateral breast cancer risk. In total, 2297 (64%) received RT, and the median follow-up was 9.6 years. The group that received RT had an increased contralateral breast cancer risk (hazard ratio = 1.44), with the peak risk coming approximately 5 to 6 years after diagnosis. When analyzed separately, statistical significance was seen in BRCA2 carriers but not in BRCA1 carriers. This study is the largest to evaluate this question. Similar studies examining the effect of RT include far fewer patients and would likely be underpowered to observe a difference between RT and no therapy for lower-frequency events such as contralateral breast cancer.

It remains uncertain whether BRCA1/2 heterozygosity confers a haploinsufficient DNA damage-repair phenotype that could facilitate tumor initiation in response to low-dose radiation scatter. Reports have shown that histologically normal breast tissue in BRCA1/2 carriers has an increased proliferative background (11) and multiple low copy number aberrations at a statistically significantly increased frequency compared with normal control tissue (12). Normal cells from BRCA1 carriers may have an abnormal response to replication stress (13). Noncancerous tissue of BRCA2 mutation carriers may also exhibit DNA damage together with attenuated replication checkpoint and apoptotic responses as well as an age-associated expansion of the luminal progenitor compartment (14). Although these data suggest a BRCA1/2 haploinsufficient phenotype in normal epithelium, these studies are small, and the link to carcinogenesis has not been established.

There is limited evidence suggesting that the BRCA heterozygous state is associated with radiosensitivity. Most studies have not shown an impaired DNA damage response in heterozygous cells. In a study of immortalized lymphoblastoid cell lines from BRCA mutation carriers, heterozygous BRCA cells showed enhanced radiosensitivity, with an impaired proliferative ability after irradiation (15). Another study of peripheral blood lymphocytes from BRCA2 carriers showed increased radiosensitivity after radiation exposure compared with noncarrier relatives (16). In a separate study with a vertebrate B-cell line, BRCA2 heterozygous cells demonstrated reduced RAD51 focus formation after irradiation. This limited evidence that some non-malignant cells in BRCA carriers may respond differently to ionizing radiation from noncarriers could theoretically be linked to a greater risk of radiation carcinogenesis. These studies were not carried out in breast epithelial cells, however, and are limited by the small number of samples and interindividual variation.

An important observation in this study was that the peak risk for contralateral breast cancer occurred 5 to 6 years after the index cancer. Other studies assessing risk of contralateral breast cancer after RT in noncarriers have demonstrated a statistically significantly longer latency (17), which is consistent with the general pattern of breast cancer development after radiation exposure. In a study of bilateral breast cancers in BRCA carriers, both with and without RT, the mean interval between first and second tumor was 5.1 years (18). In an era before magnetic resonance imaging screening, when occult contralateral primaries may exist even before the treatment of the index cancer, this brings into question whether the observed association between receipt of RT and contralateral risk is causal. Interestingly, more than 90% of the BRCA1/2 carriers in the RT group were tested after diagnosis, which raises the possibility that the development of the second cancer may have more often been the indication for testing in the RT group, which could confound the interpretation of the results.

In terms of immediate clinical application, the authors appropriately observe that additional studies are needed to confirm these findings. Numerous studies in unselected women have shown that breast-conserving surgery and mastectomy have equivalent oncologic outcomes, but the implication of an increased risk of contralateral breast cancer following RT for BRCA carriers could have a dramatic effect on patient counseling and preference. Contralateral prophylactic mastectomy has been shown to reduce the risk of contralateral breast cancer in BRCA carriers by 91%, independent of the effect of bilateral prophylactic oophorectomy (19). Compared to mastectomy, however, breast-conserving surgery has been shown to have improved psychosocial and satisfaction outcomes as well as quicker return to work and function (20). The impact of contralateral prophylactic mastectomy on survival remains unclear.

Although many BRCA carriers will, in conjunction with their surgeon, choose bilateral mastectomy for the treatment of their index cancer (21), breast-conserving surgery has been shown to have equivalent long-term outcomes. In a study of 395 mutation carriers, 99 cancers underwent breast conservation, and 325 cancers underwent mastectomy. With a median follow-up of 7.9 years, there was no difference in locoregional recurrence, distant recurrence, or breast cancer–specific survival between breast conservation and mastectomy (22). In a meta-analysis, breast-conserving surgery was found to have an increased rate of local recurrence, but there was no difference in disease-free survival, metastasis-free survival, breast cancer–specific survival, or overall survival compared with mastectomy (23). These studies suggest that breast-conserving surgery is a safe alternative to mastectomy in BRCA carriers who are willing to continue high-risk surveillance of the remaining breast tissue.

In the era of personalized medicine, it is important to understand individual risk and benefit related to the multidisciplinary management of breast cancer. Understanding how underlying germline genetic mutations affect treatment response has led to important advances in therapy, most clearly demonstrated by the development of poly-ADP ribose polymerase inhibitor therapy (24). Given that germline mutations are rare, studies involving large cohorts provide valuable data; van Barele and colleagues (10) should be applauded for their study showing an association between RT and an increased contralateral breast cancer risk in BRCA mutation carriers, although the study does not establish a direct causal link or speak to whether the relative risk is any higher in carriers than in noncarriers. Further validation studies are needed, and, in our opinion, breast-conserving surgery remains an appropriate option for carriers after careful counseling regarding the substantial risk of contralateral breast cancer, with or without RT.

Data availability

No new data were generated or analyzed for this editorial.

Author contributions

Minna Lee, MD (Writing—original draft; Writing—review & editing), Mark Robson, MD (Writing—original draft; Writing—review & editing).

Funding

The work was supported in part by National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748 to Memorial Sloan Kettering Cancer Center. M.R. is supported by the Breast Cancer Research Foundation.

Conflicts of interest

M.L. has no disclosures. M.R. reports personal fees from Research to Practice, Intellisphere, myMedEd, Change Healthcare, and Physician’s Education Resources; consulting for Artios Pharma (uncompensated), AstraZeneca (uncompensated), Daiichi-Sankyo (uncompensated), Epic Sciences (uncompensated), Merck (uncompensated), Pfizer (uncompensated), Tempus Labs (uncompensated), and Zenith Pharma (uncompensated); grants from AstraZeneca (institution, clinical trials), Merck (institution, clinical trial), Pfizer (institution, clinical trial); and other support from AstraZeneca (editorial services) and Pfizer (editorial services), all outside the submitted work.

M.R., who is a JNCI associate editor and co-author on this paper, was not involved in the editorial review or decision to publish the manuscript.