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. BRCA1-associated breast cancers have well-described characteristics, so-called “BRCAness,” which include hormone receptor negativity, high grade, and basal phenotype,¹ 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 BRCA1-associated breast cancers display the basal-like molecular subtype.^2–5 This subtype, which comprises the majority of triple-negative breast cancers (ie, estrogen receptor–, progesterone receptor–, HER2-negative 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.^6,7

The therapeutic implications of BRCA1 dysfunction are at this time largely theoretical. However, in this issue of Journal of Clinical Oncology, Byrski et al⁸ 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,⁹ and an adjuvant regimen of docetaxel, carboplatin, and trastuzumab (TCH) is standard treatment for HER2-positive disease.¹⁰ 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.¹¹ 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.^12,13 Platinum agents bind directly to DNA, forming a platinum/DNA adduct that causes intra- or 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 high-fidelity 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 double-strand DNA breaks.¹⁴ 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.^15,16 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.¹⁴ 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 efficacy of PARP inhibitors in BRCA1- and BRCA2-deficient cancers,^17,18 which presumably rely more heavily on PARP-mediated repair because of compromised HR. These studies represent a first exploitation of aberrant DNA repair for breast cancer therapy. Cells with inadequate double-strand DNA break repair should also become particularly sensitive to double-strand break-inducing drugs, such as platinums. Clinical evidence for this is scant. Although some small, largely retrospective studies have suggested that BRCA1 and BRCA2 carriers have high response rates to largely anthracycline-based chemotherapy,^19,20 other studies have suggested more general chemosensitivity.²¹ Byrski et al²² previously examined this question in a small prospective trial of single-agent neoadjuvant cisplatin (75 mg/m² administered intravenously every 3 weeks for four cycles) administered to patients with BRCA1- and BRCA2-associated breast cancer and found a high pathologic complete response rate (9 of 10 patients; 90%). Although intriguing, this was a small study and could not address whether BRCA1- and BRCA2- associated breast cancer is generally more chemosensitive or whether the results represented sensitivity to a particular agent, as suggested by preclinical models.²³ In this issue of JCO, these investigators expand their earlier efforts by combining the data from their prospective study²² of neoadjuvant single-agent cisplatin (treatment now expanded to 12 patients with BRCA1-associated breast cancer) with retrospective data from 90 other neoadjuvantly treated nonplatinum regimens in patients with BRCA1-associated breast cancer derived from a Polish cohort study.⁸ They found an unremarkable 24% pathologic complete response (pCR) rate across all regimens in the 102 patients with BRCA1-positive breast cancer; however, the pCR rate was high in the cisplatin-treated cohort (10 of 12 patients; 83% [estimated 95% CI, 54% to 96%]) and was far lower in the other aggregated regimens (14 of 90 patients; 16% [estimated 95% CI, 9% to 25%). No nonplatinum regimen had a pCR rate higher than 22% (doxorubicin plus cyclophosphamide).

Although thought provoking, the study by Byrski et al⁸ has significant limitations. In addition to its small size and retrospective nature, study participants were clearly different between the platinum and nonplatinum cohorts. The cisplatin cohort had significantly smaller tumors, which were more likely node negative and hormone receptor negative, compared with the other cohorts; these are known confounding variables for pCR. Whereas 18 patients in the nonplatinum group had received prior chemotherapy, none of the patients in the platinum group had done so. The study included patients from a number of sites in Poland between 1996 and 2008. However, one single site contributed 11 of 12 patients in the cisplatin group, all of whom were treated in the most recent cohort (2005 to 2008). In a recent update²⁴ of their prospective cisplatin study, now including 25 patients with BRCA1-associated breast cancer who received this treatment, it was found that although the pCR rate was still impressive, it had fallen to 72%. Earlier studies by Chappuis et al²⁰ and Delaloge et al¹⁹ found pCR rates to anthracycline-based regimens in BRCA carriers of 44% and 53%, respectively, considerably higher than the rates in the current study⁸ and indicative of the difficulty in drawing conclusions from small uncontrolled trials. It should also be noted that all of the regimens in this study included at least one DNA-damaging agent. These caveats noted, studies like this one raise interesting questions about whether we can target chemotherapy agents to identifiable subtypes.

If augmented sensitivity to DNA-damaging agents exists, does this apply only to BRCA1 mutation carriers, or will this also be true in sporadic triple-negative breast cancers? As mentioned, there are significant overlaps in clinical and pathologic phenotypes between BRCA1-associated and sporadic basal-like breast cancer,²⁵ suggesting that they may share aberrant DNA damage–response pathways. Both BRCA1-associated and sporadic basal-like breast cancers demonstrate similar X-chromosome inactivation patterns²⁶ and more diffuse DNA copy number aberrations (both gains and losses) suggestive of genome-wide DNA instability.^27,28 Although these data support that both BRCA1-associated and sporadic basal-like breast cancers have similar phenotypes possibly reflective of BRCA1 functional loss, identification of the mechanism of BRCA1 dysfunction in sporadic tumors has been elusive. BRCA1 functions in DNA-damage repair as part of a multiprotein complex, so it is possible that disruption of other proteins involved in this pathway could result in impaired DNA-damage response. Clinical support for the concept of similar DNA-damage response alterations in triple-negative and BRCA1-associated cancers has come from a randomized phase II study²⁹ of gemcitabine plus carboplatin chemotherapy with or without the PARP inhibitor BSI-201, in which progression-free survival in the PARP inhibitor arm more than doubled. If validated in the registration phase III trial, this suggests that targeting DNA repair directly is useful in both BRCA1-associated and sporadic triple-negative breast cancers, but it does not directly address the question of whether conventional cytotoxic chemotherapy agents may have differential effects in these two groups. Arguing against the assumption of exquisite platinum sensitivity in sporadic basal-like breast cancer, Garber et al³⁰ found a pCR rate to single-agent neoadjuvant cisplatin of 21% in 28 patients with triple-negative breast cancers (two had BRCA1-associated disease, and both experienced pCR), which is similar to the expected rates of response to nonplatinum regimens. Whether the difference in pCR rates to single-agent platinum between the BRCA1 mutation carriers in the study by Byrski et al⁸ and the patients with triple-negative breast cancers in the study by Garber et al is real or represents a statistical artifact from a small sample is not yet known. The upcoming Cancer and Leukemia Group B 40603 (CDR0000636850, CALGB 40603) trial, a neoadjuvant cooperative group study in part examining the benefit of adding carboplatin to taxane therapy in clinical stage II to III triple-negative breast cancer, will allow us to more precisely test the benefit of platinum agents in this subtype. This study is particularly important because up-front biopsies for predictive biomarker determination are required and will shed light on the nature of platinum sensitivity and the BRCAness of triple-negative breast cancers. Similarly, an ongoing study from the Translational Breast Cancer Research Consortium (06-412, TBCRC 009) is a phase II examination of single-agent cisplatin or carboplatin in metastatic triple-negative disease focused on determining the biomarker basis for predicting platinum sensitivity in this subtype.

Do these data suggest that we should incorporate platinum agents into adjuvant or neoadjuvant therapy in BRCA1 carriers? No. On the basis of currently available evidence, we cannot say that there is definitive evidence of a platinum benefit in triple-negative or even BRCA1-associated breast cancer, nor can we say that there is adequate evidence to routinely incorporate platinum agents into adjuvant or neoadjuvant therapy for any identifiable subtype of breast cancer. What we can say is that this is a reasonable avenue to pursue in prospective trials, and we can feel reassured that the clinical evidence thus far fits with preclinical models. With the advent of rational approaches developed from BRCA1-associated models, which we hope will be successfully applied to sporadic basal-like breast cancer, we will finally alter the prognostic landscape for patients with this disease.

AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Lisa A. Carey, Bristol-Myers Squibb (U), AstraZeneca (U), BiPar Sciences (U), sanofi-aventis (U), Wyeth (U) Stock Ownership: None Honoraria: None Research Funding: Lisa A. Carey, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Roche, Boehringer Ingelheim, Eisai Expert Testimony: None Other Remuneration: None

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Lisa A. Carey
Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC