title: 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/m(2) 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.
authors.affiliation: Dana-Farber Cancer Institute, Department of Medical Oncology, Smith 209, 1 Jimmy Fund Way, Boston, MA 02115, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Silver
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
authors.forename: Aron C
authors.initials: AC
authors.lastname: Eklund
authors.forename: Zhigang C
authors.initials: ZC
authors.lastname: Wang
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Szallasi
authors.forename: Qiyuan
authors.initials: Q
authors.lastname: Li
authors.forename: Nicolai
authors.initials: N
authors.lastname: Juul
authors.forename: Chee-Onn
authors.initials: CO
authors.lastname: Leong
authors.forename: Diana
authors.initials: D
authors.lastname: Calogrias
authors.forename: Ayodele
authors.initials: A
authors.lastname: Buraimoh
authors.forename: Aquila
authors.initials: A
authors.lastname: Fatima
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Gelman
authors.forename: Paula D
authors.initials: PD
authors.lastname: Ryan
authors.forename: Nadine M
authors.initials: NM
authors.lastname: Tung
authors.forename: Arcangela
authors.initials: A
authors.lastname: De Nicolo
authors.forename: Shridar
authors.initials: S
authors.lastname: Ganesan
authors.forename: Alexander
authors.initials: A
authors.lastname: Miron
authors.forename: Christian
authors.initials: C
authors.lastname: Colin
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Sgroi
authors.forename: Leif W
authors.initials: LW
authors.lastname: Ellisen
authors.forename: Eric P
authors.initials: EP
authors.lastname: Winer
authors.forename: Judy E
authors.initials: JE
authors.lastname: Garber
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics; D002945:Cisplatin / Q000009:adverse effects / Q000627:therapeutic use*; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000032:analysis; D005260:Female; D019398:Genes, BRCA1; D016158:Genes, p53; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D020360:Neoadjuvant Therapy; D009687:Nuclear Proteins / Q000032:analysis; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D011960:Receptors, Estrogen / Q000032:analysis*; D011980:Receptors, Progesterone / Q000032:analysis*; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000032:analysis
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C508053:ERBB2 protein, human