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Targeted chemotherapy? Platinum in BRCA1-dysfunctional breast cancer.

Although BRCA1-associated breast cancer is rare, comprising only 5% of breast cancers or fewer than 10,000 cases per year in the United States, academic interest outstrips its clinical impact; there have been more than 5,000 articles on this topic in the peer-reviewed literature in the past decade. This disproportionate attention is the result not of a powerful BRCA1 lobby influencing editorial offices but rather of the role of BRCA1 and BRCA2 in cellular behavior and the potential clinical implications of BRCA dysfunction. BRCA1associated breast cancers have well-described characteristics, so-called “BRCAness,” which include hormone receptor negativity, high grade, and basal phenotype, to which can be added human epidermal growth factor receptor 2 (HER2) negativity; these characteristics can also be seen in sporadic breast cancers. Eighty percent of BRCA1associated breast cancers display the basal-like molecular subtype. This subtype, which comprises the majority of triple-negative breast cancers (ie, estrogen receptor–, progesterone receptor–, HER2negative breast cancers), has distinct biology and is the subject of great therapeutic interest. This association of BRCA1 and basal-like breast cancer has led many to surmise that sporadic basal-like breast cancer may involve BRCA1 pathway dysfunction through nonmutational means, and BRCA1-directed therapeutic approaches may be effective in sporadic triple-negative breast cancer. The therapeutic implications of BRCA1 dysfunction are at this time largely theoretical. However, in this issue of Journal of Clinical Oncology, Byrski et al add retrospective but intriguing support to preclinical data that BRCA1-associated breast cancer may be particularly sensitive to certain classes of DNA-damaging drugs, such as platinum agents. Platinum salts (cisplatin, carboplatin, oxaliplatin) are moderately effective agents in breast cancer, and an adjuvant regimen of docetaxel, carboplatin, and trastuzumab (TCH) is standard treatment for HER2-positive disease. These drugs have predictable toxicity and can have the long-term adverse effects of nausea, neuropathy, hearing loss (cisplatin), renal damage (especially cisplatin), thrombocytopenia (especially carboplatin), and leukemogenesis. On the basis of this therapeutic index, TCH is used as adjuvant therapy in HER2-positive disease; otherwise, platinums are typically reserved until late in the metastatic lines of therapy. That approach may change as we gain greater understanding of the biology of breast cancer and the pharmacology of cytotoxic chemotherapy. In particular, the role of DNA repair in effect and toxicity of chemotherapy has gained recent attention. Platinum agents bind directly to DNA, forming a platinum/DNA adduct that causes intraor interstrand DNA crosslinks, resulting in double-strand DNA breaks. Such breaks trigger growth arrest and augment DNA repair mechanisms, but they may also induce cell death. Which outcome predominates (ie, whether the damaged cell lives or dies) is partly dependent on the efficiency of repair pathways. DNA repair mechanisms are numerous and highly complex. Moreover, the consequences of DNA damage may be beneficial or not. For example, the pathway responsible for therapeutic effect may not be the same as that responsible for toxicity, and triggering a particular pathway may drive the cell to repair (therapeutic resistance) or may result in DNA damage–sensing induction of cell death (therapeutic sensitivity). We are just beginning to understand these relationships. The most important and well-described DNA repair pathways include nucleotide excision repair, mismatch repair, base excision repair, homologous recombination (HR), and nonhomologous end joining (NHEJ). Nucleotide excision repair, mismatch repair, and base excision repair rely on an undamaged opposite strand of DNA to serve as a template for repair of a damaged strand of DNA. Double-strand break repair occurs through two main mechanisms: HR, a highfidelity process that uses the homologous sequence to resynthesize DNA, and NHEJ, a process in which broken ends of DNA are religated. NHEJ does not require a template and therefore can be used in circumstances in which no template for repair is available, but it is also more prone to error. BRCA1 plays a crucial role in DNA interstrand crosslink repair through several mechanisms and is integral in HR, the less error-prone mechanism of repairing doublestrand DNA breaks. When cells lose all BRCA1 function, they become hypersensitive to DNA damage and develop gross chromosomal aberrations when challenged with DNA-damaging drugs or agents. A woman with one inherited BRCA1 mutation still has BRCA1 function from the other allele; however, there is usually somatic loss of the functional allele in her breast cancer, leading to complete tumoral inactivation of BRCA1 function and resultant hypersensitivity to DNA damage. Where does this lead us therapeutically? Synergistic cell death resulting from the concomitant targeting of molecular pathways that are dispensable when inactivated in isolation is a concept known in genetics as synthetic lethality. In BRCA1 deficiency, other DNA repair pathways may become more important. Several DNA repair pathways, including NHEJ, are dependent in part on a molecule called poly (ADP-ribose) polymerase type 1 (PARP-1). Exciting clinical proof of principle has come from studies demonstrating the clinical JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 28 NUMBER 3 JANUARY 2