Cancer susceptibility genes and their potential implication regarding systemic therapy for early‐stage breast cancer

The development of leukemias after chemotherapy and/or radiotherapy for breast cancer has been recognized for 4 decades. Some of these leukemias may not be secondary to cytotoxic therapy (therapy-related leukemias [TRLs]) but rather, at least in some cases, may arise independently from a common genetic background. In this context, it is intriguing that diverse epidemiologic studies have observed a familial link between breast cancer and acute myelogenous leukemia (AML), substantiating the theory that the 2 diseases may share specific inherited mutations in 1 cancer susceptibility genes that are integral to their pathogenesis. Moreover, the risk of TRL is increased in women with a positive family history of breast and/or ovarian cancers. In this issue of Cancer, Churpek et al conducted a retrospective tumor registry study that brings long-awaited genetic detail to these clinical and epidemiological observations. The authors used 42-gene BROCA targeted genomic capture and next-generation sequencing technologies to analyze the genomes of hematopoietic cells (either leukemia or postleukemia treatment remission samples) and germline epithelial cells (buccal mucosa or skin fibroblasts) obtained from women with leukemia who had received cytotoxic therapy for a previous diagnosis of early-stage breast cancer (ESBC). The investigators found deleterious germline mutations in breast cancer susceptibility genes in approximately 20% of these individuals. The aberrations occurred in genes involved in pivotal DNA damage response and repair pathways, namely BRCA1, BRCA2, p53, CHEK2, and PALB2 (partner and localizer of BRCA2). These data confirm and expand data from previous smaller studies regarding the link between breast cancer germline gene mutations and the development of TRL. It is interesting to note that BRCA2 and PALB2 are integral components of the Fanconi pathway and the breast cancer that occurs in individuals who carry the PALB2 mutation may overlap with that of BRCA2 carriers. In particular, defects in both alleles of BRCA2 (identical to FANCD2) and PALB2 (identical to FANCN) result in Fanconi anemia (FA), an inherited chromosomal instability disorder characterized by bone marrow failure, cellular hypersensitivity to DNA cross-linking agents, and a striking 800-fold increased risk of developing myelodysplastic syndrome (MDS) and AML. To our knowledge, there are currently 18 complementation groups that have been defined, and all FA proteins cooperate in a pathway that leads to the recognition and repair of DNA damage. Moreover, FA proteins coordinate other proteins to determine the net response to DNA damage, including ATM, ATR, Bloom syndrome, and CHK1. Thus, it appears to be plausible to speculate that inherited mutations or acquired defects such as epigenetic silencing of 1 FA genes could play a formative role in both breast cancer and AML pathogenesis. It is interesting to note that although the vast majority of the leukemias in the study by Churpek et al were AMLs, 8% were acute lymphoblastic leukemias (ALLs), a finding that recapitulates a recent observation made by our group. These ALLs appear to be linked selectively to germline mutations in p53 and, as detected in the large study by Stengel et al, are accompanied by complex karyotypes. Churpek et al raise the issue of what is a “true TRL” and what is potentially an independent leukemia, using as an example a patient who developed t(3;21)-associated AML at 18 years after chemotherapy for breast cancer. In fact, in our recent analysis of bone marrow malignancies arising after adjuvant therapy for ESBC, we found that the risk of developing a bone marrow neoplasm did not plateau at 5 years but instead remained steady well into years 6 through 10. In addition, t(3;21) often occurs within the setting of environmental exposures (eg, benzene) and is associated with MDS/AML, which