1. Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets.
- Author
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Balko JM, Giltnane JM, Wang K, Schwarz LJ, Young CD, Cook RS, Owens P, Sanders ME, Kuba MG, Sánchez V, Kurupi R, Moore PD, Pinto JA, Doimi FD, Gómez H, Horiuchi D, Goga A, Lehmann BD, Bauer JA, Pietenpol JA, Ross JS, Palmer GA, Yelensky R, Cronin M, Miller VA, Stephens PJ, and Arteaga CL
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cell Line, Tumor, Cluster Analysis, DNA Copy Number Variations, Drug Resistance, Neoplasm genetics, Female, Gene Amplification, Genes, myc, Humans, Ki-67 Antigen genetics, Ki-67 Antigen metabolism, Myeloid Cell Leukemia Sequence 1 Protein genetics, Neoadjuvant Therapy, Neoplasm, Residual, Prognosis, Treatment Outcome, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms mortality, Gene Expression Profiling, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms pathology
- Abstract
Unlabelled: Neoadjuvant chemotherapy (NAC) induces a pathologic complete response (pCR) in approximately 30% of patients with triple-negative breast cancers (TNBC). In patients lacking a pCR, NAC selects a subpopulation of chemotherapy-resistant tumor cells. To understand the molecular underpinnings driving treatment-resistant TNBCs, we performed comprehensive molecular analyses on the residual disease of 74 clinically defined TNBCs after NAC, including next-generation sequencing (NGS) on 20 matched pretreatment biopsies. Combined NGS and digital RNA expression analysis identified diverse molecular lesions and pathway activation in drug-resistant tumor cells. Ninety percent of the tumors contained a genetic alteration potentially treatable with a currently available targeted therapy. Thus, profiling residual TNBCs after NAC identifies targetable molecular lesions in the chemotherapy-resistant component of the tumor, which may mirror micrometastases destined to recur clinically. These data can guide biomarker-driven adjuvant studies targeting these micrometastases to improve the outcome of patients with TNBC who do not respond completely to NAC., Significance: This study demonstrates the spectrum of genomic alterations present in residual TNBC after NAC. Because TNBCs that do not achieve a CR after NAC are likely to recur as metastatic disease at variable times after surgery, these alterations may guide the selection of targeted therapies immediately after mastectomy before these metastases become evident., (2013 AACR)
- Published
- 2014
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