title: Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Departments of 1Medicine, 2Pathology, Microbiology & Immunology, 3Cancer Biology, and 4Biochemistry; 5Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee; Departments of 6Cell & Tissue Biology and 7Medicine, University of California, San Francisco, San Francisco, California; 8Foundation Medicine, Cambridge, Massachusetts; 9Oncosalud; and 10Instituto Nacional de Enfermedades Neoplásicas (INEN), Lima, Perú
authors.forename: Justin M
authors.initials: JM
authors.lastname: Balko
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Giltnane
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Schwarz
authors.forename: Christian D
authors.initials: CD
authors.lastname: Young
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Cook
authors.forename: Phillip
authors.initials: P
authors.lastname: Owens
authors.forename: Melinda E
authors.initials: ME
authors.lastname: Sanders
authors.forename: Maria G
authors.initials: MG
authors.lastname: Kuba
authors.forename: Violeta
authors.initials: V
authors.lastname: Sánchez
authors.forename: Richard
authors.initials: R
authors.lastname: Kurupi
authors.forename: Preston D
authors.initials: PD
authors.lastname: Moore
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Pinto
authors.forename: Franco D
authors.initials: FD
authors.lastname: Doimi
authors.forename: Henry
authors.initials: H
authors.lastname: Gómez
authors.forename: Dai
authors.initials: D
authors.lastname: Horiuchi
authors.forename: Andrei
authors.initials: A
authors.lastname: Goga
authors.forename: Brian D
authors.initials: BD
authors.lastname: Lehmann
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Bauer
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Pietenpol
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.forename: Gary A
authors.initials: GA
authors.lastname: Palmer
authors.forename: Roman
authors.initials: R
authors.lastname: Yelensky
authors.forename: Maureen
authors.initials: M
authors.lastname: Cronin
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Stephens
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D056915:DNA Copy Number Variations; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling; D016259:Genes, myc; D006801:Humans; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics; D020360:Neoadjuvant Therapy; D018365:Neoplasm, Residual; D011379:Prognosis; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*
chemical_list: D019394:Ki-67 Antigen; D064549:Myeloid Cell Leukemia Sequence 1 Protein