Efficacy of Neoadjuvant Cisplatin in Triple-Negative Breast Cancer

Abstract

Purpose Cisplatin is a chemotherapeutic agent not used routinely for breast cancer treatment. As a DNA cross-linking agent, cisplatin may be effective treatment for hereditary BRCA1-mutated breast cancers. Because sporadic triple-negative breast cancer (TNBC) and BRCA1-associated breast cancer share features suggesting common pathogenesis, we conducted a neoadjuvant trial of cisplatin in TNBC and explored specific biomarkers to identify predictors of response. Patients and Methods Twenty-eight women with stage II or III breast cancers lacking estrogen and progesterone receptors and HER2/Neu (TNBC) were enrolled and treated with four cycles of cisplatin at 75 mg/m2 every 21 days. After definitive surgery, patients received standard adjuvant chemotherapy and radiation therapy per their treating physicians. Clinical and pathologic treatment response were assessed, and pretreatment tumor samples were evaluated for selected biomarkers. Results Six (22%) of 28 patients achieved pathologic complete responses, including both patients with BRCA1 germline mutations;18 (64%) patients had a clinical complete or partial response. Fourteen (50%) patients showed good pathologic responses (Miller-Payne score of 3, 4, or 5), 10 had minor responses (Miller-Payne score of 1 or 2), and four (14%) progressed. All TNBCs clustered with reference basal-like tumors by hierarchical clustering. Factors associated with good cisplatin response include young age (P = .001), low BRCA1 mRNA expression (P = .03), BRCA1 promoter methylation (P = .04), p53 nonsense or frameshift mutations (P = .01), and a gene expression signature of E2F3 activation (P = .03). Conclusion Single-agent cisplatin induced response in a subset of patients with TNBC. Decreased BRCA1 expression may identify subsets of TNBCs that are cisplatin sensitive. Other biomarkers show promise in predicting cisplatin response.

A phase II study of capecitabine plus cisplatin in metastatic triple-negative breast cancer patients pretreated with anthracyclines and taxanes

“…20,21 Nevertheless, based on the potential molecular similarities shared between BRCA1 tumors and TNBC and preclinical results mentioned previously, 5-7 the role of platinums was reconsidered in TNBC. After the remarkable pCR in neoadjuvant setting was obtained by Silver and colleagues, 8 Sirohi et al 22 demonstrated that platinum-based regimens were associated with higher chemosensitivity in TNBC than in other subtypes both in neoadjuvant and metastatic settings, and even showed an advantage in PFS. Although there are several studies indicating contrary results, the outcomes of major phase III clinical trials in the future would be able to further clarify the role of platinum-based regimens in TNBC.…”

“…[5][6][7] Thus, efficacy of platinum-based chemotherapy in TNBC is currently under investigation by many authors. 4 In a phase II trial, Silver et al 8 have demonstrated a pathological complete response rate of 21% with neoadjuvant cisplatin monotherapy. Furthermore, there are certain randomized phase II studies 9,10 which have clarified that platinum-based regimens were associated with increased response rate and/or prolonged progression-free survival (PFS) in TNBC compared with non-platinum-based regimens.…”

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

“…218,219 Studies evaluating pre-surgical chemotherapy for primary breast cancers reported a higher complete response rate to anthracycline- [220][221][222] and to platinum-containing 223,224 regimens for triple-negative as compared with other breast cancers. Although about 10% of all basal-like breast cancers have been diagnosed in BRCA1 germline mutation carriers, 225 currently we have limited knowledge whether other components of the Fanconi system are disturbed in triple-negative/basal-like breast cancer.…”

FZD7 has a critical role in cell proliferation in triple negative breast cancer

“…Although TNBC constitutes B15% of all breast cancers, its death rate is disproportionately higher than any other subtype of breast cancer, especially among young African-American, Asian and Hispanic patients (Anders and Carey, 2009;Kassam et al, 2009;Rahman et al, 2009). Although, anti-HER2 antibodies, Herceptin, estrogen receptor antagonists and aromatase inhibitors have improved treatment of many breast cancer subtypes, the treatment of TNBC remains a great challenge (Gluz et al, 2009;Amir et al, 2010;Silver et al, 2010). Therefore, it is imperative to identify new potential therapeutic targets for TNBC.…”