Use of Neoadjuvant Platinum—The Ongoing Conundrum

After years of being neglected as treatment for breast cancer, the platinum agents cisplatin and carboplatin have rebounded in popularity. Interest in platinum salts grew following laboratory studies that suggested an association between triple-negative breast cancers (TNBCs) and cancers developing in patients with germline mutations in BRCA1. Given that BRCA-associated cancers are thought to arise from the inability to repair damaged DNA, investigators sought to capitalize on that defect by administering chemotherapy that directly damages DNA. Indeed, 2 studies drove further enthusiasm. A neoadjuvant trial in Poland demonstrated a pathologic complete response (pCR) rate of 61% after just 4 doses of cisplatin in women with breast cancer and pathogenic mutations in BRCA1. In the advanced-disease setting, a trial evaluating single-agent cisplatin or carboplatin as first-line or second-line therapy for 86 patients with metastatic TNBC demonstrated an overall response rate of 25.6%, which increased to 54.5% in 11 patients with germline BRCA mutations. With the hypothesis that acquired inability to repair DNA, or "BRCA-ness," in sporadic TNBC could be a marker for sensitivity to DNA-damaging agents such as platinum, Isakoff et al reported that a BRCA-like genomic instability signature, including homologous recombination deficiency (HRD), loss of heterozygosity, and large-scale state transitions, in 32 of 66 patients (48%) with sporadic TNBC was able to discriminate responders from nonresponders.

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