Molecular Profiling of the Residual Disease of Triple-Negative Breast Cancers after Neoadjuvant Chemotherapy Identifies Actionable Therapeutic Targets

被引：393

作者：

Balko, Justin M. ^{[1
,5
]}

Giltnane, Jennifer M. ^{[2
,5
]}

Wang, Kai ^{[8
]}

Schwarz, Luis J. ^{[1
,9
,10
]}

Young, Christian D. ^{[1
]}

Cook, Rebecca S. ^{[3
,5
]}

Owens, Phillip ^{[3
]}

Sanders, Melinda E. ^{[2
,5
]}

Kuba, Maria G. ^{[2
]}

Sanchez, Violeta ^{[1
]}

Kurupi, Richard ^{[1
]}

Moore, Preston D. ^{[1
]}

Pinto, Joseph A. ^{[9
]}

Doimi, Franco D. ^{[9
]}

Gomez, Henry ^{[10
]}

Horiuchi, Dai ^{[6
,7
]}

Goga, Andrei ^{[6
,7
]}

Lehmann, Brian D. ^{[4
]}

Bauer, Joshua A. ^{[4
]}

Pietenpol, Jennifer A. ^{[4
,5
,8
]}

Ross, Jeffrey S. ^{[8
]}

Palmer, Gary A. ^{[8
]}

Yelensky, Roman ^{[8
]}

Cronin, Maureen ^{[8
]}

Miller, Vincent A. ^{[8
]}

Stephens, Phillip J. ^{[8
]}

Arteaga, Carlos L. ^{[1
,3
,5
]}

机构：

[1] Vanderbilt Univ, Dept Med, Vanderbilt Ingram Canc Ctr, Nashville, TN USA

[2] Vanderbilt Univ, Dept Pathol Microbiol & Immunol, Vanderbilt Ingram Canc Ctr, Nashville, TN USA

[3] Vanderbilt Univ, Dept Canc Biol, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA

[4] Vanderbilt Univ, Dept Biochem, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA

[5] Vanderbilt Univ, Breast Canc Res Program, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA

[6] Univ Calif San Francisco, Dept Cell & Tissue Biol, San Francisco, CA 94143 USA

[7] Univ Calif San Francisco, Dept Med, San Francisco, CA USA

[8] Fdn Med, Cambridge, MA USA

[9] Oncosalud, Lima, Peru

[10] Inst Nacl Enfermedades Neoplast, Lima, Peru

来源：

CANCER DISCOVERY | 2014年 / 4卷 / 02期

关键词：

BASAL-LIKE; DOWN-REGULATION; MYC; INHIBITION; TUMOR; ACTIVATION; EXPRESSION; RECURRENCE; MUTATIONS; PATHWAYS;

D O I：

10.1158/2159-8290.CD-13-0286

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：232 / 245

页数：14

共 49 条

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