Efficacy of neoadjuvant cisplatin in triple-negative breast cancer

Daniel P. Silver, Andrea Richardson, Aron C. Eklund, Zhigang C. Wang, Zoltan Szallasi, Qiyuan Li, Nicolai Juul, Chee Onn Leong, Diana Calogrias, Ayodele Buraimoh, Aquila Fatima, Rebecca S. Gelman, Paula D. Ryan, Nadine M. Tung, Arcangela De Nicolo, Shridar Ganesan, Alexander Miron, Christian Colin, Dennis C. Sgroi, Leif W. EllisenEric P. Winer, Judy E. Garber

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1145-1153
Number of pages9
JournalJournal of Clinical Oncology
Volume28
Issue number7
DOIs
StatePublished - Mar 1 2010
Externally publishedYes

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Triple Negative Breast Neoplasms
Cisplatin
Breast Neoplasms
Biomarkers
Frameshift Mutation
Germ-Line Mutation
Nonsense Codon
Progesterone Receptors
Adjuvant Chemotherapy
Transcriptome
Estrogen Receptors
Methylation
Cluster Analysis
Neoplasms
Radiotherapy
Therapeutics
Physicians
Messenger RNA
DNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Silver, D. P., Richardson, A., Eklund, A. C., Wang, Z. C., Szallasi, Z., Li, Q., ... Garber, J. E. (2010). Efficacy of neoadjuvant cisplatin in triple-negative breast cancer. Journal of Clinical Oncology, 28(7), 1145-1153. https://doi.org/10.1200/JCO.2009.22.4725

Efficacy of neoadjuvant cisplatin in triple-negative breast cancer. / Silver, Daniel P.; Richardson, Andrea; Eklund, Aron C.; Wang, Zhigang C.; Szallasi, Zoltan; Li, Qiyuan; Juul, Nicolai; Leong, Chee Onn; Calogrias, Diana; Buraimoh, Ayodele; Fatima, Aquila; Gelman, Rebecca S.; Ryan, Paula D.; Tung, Nadine M.; De Nicolo, Arcangela; Ganesan, Shridar; Miron, Alexander; Colin, Christian; Sgroi, Dennis C.; Ellisen, Leif W.; Winer, Eric P.; Garber, Judy E.

In: Journal of Clinical Oncology, Vol. 28, No. 7, 01.03.2010, p. 1145-1153.

Research output: Contribution to journalArticle

Silver, DP, Richardson, A, Eklund, AC, Wang, ZC, Szallasi, Z, Li, Q, Juul, N, Leong, CO, Calogrias, D, Buraimoh, A, Fatima, A, Gelman, RS, Ryan, PD, Tung, NM, De Nicolo, A, Ganesan, S, Miron, A, Colin, C, Sgroi, DC, Ellisen, LW, Winer, EP & Garber, JE 2010, 'Efficacy of neoadjuvant cisplatin in triple-negative breast cancer', Journal of Clinical Oncology, vol. 28, no. 7, pp. 1145-1153. https://doi.org/10.1200/JCO.2009.22.4725
Silver, Daniel P. ; Richardson, Andrea ; Eklund, Aron C. ; Wang, Zhigang C. ; Szallasi, Zoltan ; Li, Qiyuan ; Juul, Nicolai ; Leong, Chee Onn ; Calogrias, Diana ; Buraimoh, Ayodele ; Fatima, Aquila ; Gelman, Rebecca S. ; Ryan, Paula D. ; Tung, Nadine M. ; De Nicolo, Arcangela ; Ganesan, Shridar ; Miron, Alexander ; Colin, Christian ; Sgroi, Dennis C. ; Ellisen, Leif W. ; Winer, Eric P. ; Garber, Judy E. / Efficacy of neoadjuvant cisplatin in triple-negative breast cancer. In: Journal of Clinical Oncology. 2010 ; Vol. 28, No. 7. pp. 1145-1153.
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T1 - Efficacy of neoadjuvant cisplatin in triple-negative breast cancer

AU - Silver, Daniel P.

AU - Richardson, Andrea

AU - Eklund, Aron C.

AU - Wang, Zhigang C.

AU - Szallasi, Zoltan

AU - Li, Qiyuan

AU - Juul, Nicolai

AU - Leong, Chee Onn

AU - Calogrias, Diana

AU - Buraimoh, Ayodele

AU - Fatima, Aquila

AU - Gelman, Rebecca S.

AU - Ryan, Paula D.

AU - Tung, Nadine M.

AU - De Nicolo, Arcangela

AU - Ganesan, Shridar

AU - Miron, Alexander

AU - Colin, Christian

AU - Sgroi, Dennis C.

AU - Ellisen, Leif W.

AU - Winer, Eric P.

AU - Garber, Judy E.

PY - 2010/3/1

Y1 - 2010/3/1

N2 - 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.

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