Impact of HER2 Heterogeneity on Treatment Response of Early-Stage HER2-Positive Breast Cancer: Phase II Neoadjuvant Clinical Trial of T-DM1 Combined with Pertuzumab

被引：159

作者：

Metzger Filho, Otto ^{[1
,2
]}

Viale, Giuseppe ^{[3
,4
]}

Stein, Shayna ^{[5
,6
]}

Trippa, Lorenzo ^{[5
]}

Yardley, Denise A. ^{[7
]}

Mayer, Ingrid A. ^{[8
]}

Abramson, Vandana G. ^{[8
]}

Arteaga, Carlos L. ^{[9
]}

Spring, Laura M. ^{[10
]}

Waks, Adrienne G. ^{[1
,2
]}

Wrabel, Eileen ^{[1
,2
]}

DeMeo, Michelle K. ^{[1
,2
]}

Bardia, Aditya ^{[10
]}

Dell'Orto, Patrizia ^{[3
]}

Russo, Leila ^{[3
]}

King, Tari A. ^{[2
,11
]}

Polyak, Kornelia ^{[1
,12
,13
]}

Michor, Franziska ^{[5
,6
,12
,13
,14
,15
]}

Winer, Eric P. ^{[1
,2
]}

Krop, Ian E. ^{[1
,2
]}

机构：

[1] Harvard Med Sch, Dana Farber Canc Inst, Med Oncol, Boston, MA 02115 USA

[2] Dana Farber Brigham & Womens Canc Ctr, Breast Oncol Program, Boston, MA 02215 USA

[3] IRCCS, European Inst Oncol, Div Pathol, Milan, Italy

[4] Univ Milan, Milan, Italy

[5] Dana Farber Canc Inst, Data Sci, Boston, MA 02115 USA

[6] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA

[7] Sarah Cannon Res Inst & Tennessee Oncol, Nashville, TN USA

[8] Vanderbilt Ingram Canc Ctr, Nashville, TN USA

[9] UT Southwestern Simmons Canc Ctr, Dallas, TX USA

[10] Massachusetts Gen Hosp, Boston, MA 02114 USA

[11] Brigham & Womens Hosp, Dept Surg, Div Breast Surg, 75 Francis St, Boston, MA 02115 USA

[12] Ludwig Ctr Harvard, Boston, MA 02215 USA

[13] Dana Farber Canc Inst, Ctr Canc Evolut, Boston, MA 02115 USA

[14] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA

[15] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

来源：

CANCER DISCOVERY | 2021年 / 11卷 / 10期

关键词：

IN-SITU HYBRIDIZATION; MONOCLONAL-ANTIBODY; PRIMARY THERAPY; AMPLIFICATION; GENE; RECOMMENDATIONS; CHEMOTHERAPY; EFFICACY; SAFETY; UK;

D O I：

10.1158/2159-8290.CD-20-1557

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Intratumor heterogeneity is postulated to cause therapeutic resistance. To prospectively assess the impact of HER2 (ERBB2) heterogeneity on response to HER2-targeted therapy, we treated 164 patients with centrally confirmed HER2-positive early-stage breast cancer with neoadjuvant trastuzumab emtansine plus pertuzumab. HER2 heterogeneity was assessed on pretreatment biopsies from two locations of each tumor. HER2 heterogeneity, defined as an area with ERBB2 amplification in >5% but <50% of tumor cells, or a HER2-negative area by FISH, was detected in 10% (16/157) of evaluable cases. The pathologic complete response rate was 55% in the nonheterogeneous subgroup and 0% in the heterogeneous group (P < 0.0001, adjusted for hormone receptor status). Single-cell ERBB2 FISH analysis of cellular heterogeneity identified the fraction of ERBB2 nonamplified cells as a driver of therapeutic resistance. These data suggest HER2 heterogeneity is associated with resistance to HER2-targeted therapy and should be considered in efforts to optimize treatment strategies. SIGNIFICANCE: HER2-targeted therapies improve cure rates in HER2-positive breast cancer, suggesting chemotherapy can be avoided in a subset of patients. We show that HER2 heterogeneity, particularly the fraction of ERBB2 nonamplified cancer cells, is a strong predictor of resistance to HER2 therapies and could potentially be used to optimize treatment selection.

引用

页码：2474 / 2487

页数：14

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