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Clin Cancer Res. 2017 Oct 1;23(19):5687-5695. doi: 10.1158/1078-0432.CCR-17-0900. Epub 2017 Jul 5.

Neratinib Efficacy and Circulating Tumor DNA Detection of HER2 Mutations in HER2 Nonamplified Metastatic Breast Cancer.

Author information

1
Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri. cynthiaxma@wustl.edu rbose@wustl.edu mjellis@bcm.edu.
2
Division of Public Health Science, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
3
Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
4
Department of Medicine, Stanford University School of Medicine, Stanford, California.
5
Department of Medicine, Duke Cancer Institute, Durham, North Carolina.
6
Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
7
Medical Oncology, Mayo Clinic, Rochester, Minnesota.
8
Medical Oncology, University of Southern California, Los Angeles, California.
9
Medical Oncology, Rush University Medical Center, Chicago, Illinois.
10
Department of Medicine, University of Alabama Birmingham, Birmingham, Alabama.
11
Department of Oncology-Hematology, St. Luke's Cancer Institute, Kansas City, Missouri.
12
Department of Medicine, University of North Carolina, Chapel Hill, North Carolina.
13
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
14
Guardant Health Inc., Redwood City, California.
15
Puma Biotechnology, Los Angeles, California.
16
Genomic and Pathology Service, Washington University School of Medicine, St. Louis, Missouri.
17
Department of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan.
18
Department of Medicine, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
19
Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
20
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. cynthiaxma@wustl.edu rbose@wustl.edu mjellis@bcm.edu.

Abstract

Purpose: Based on promising preclinical data, we conducted a single-arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined as complete/partial response (CR/PR) or stable disease (SD) ≥24 weeks, in HER2mut nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2mut detection.Experimental Design: Tumor tissue positive for HER2mut was required for eligibility. Neratinib was administered 240 mg daily with prophylactic loperamide. ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor HER2mut).Results: Nine of 381 tumors (2.4%) sequenced centrally harbored HER2mut (lobular 7.8% vs. ductal 1.6%; P = 0.026). Thirteen additional HER2mut cases were identified locally. Twenty-one of these 22 HER2mut cases were estrogen receptor positive. Sixteen patients [median age 58 (31-74) years and three (2-10) prior metastatic regimens] received neratinib. The CBR was 31% [90% confidence interval (CI), 13%-55%], including one CR, one PR, and three SD ≥24 weeks. Median PFS was 16 (90% CI, 8-31) weeks. Diarrhea (grade 2, 44%; grade 3, 25%) was the most common adverse event. Baseline ctDNA sequencing identified the same HER2mut in 11 of 14 tumor-positive cases (sensitivity, 79%; 90% CI, 53%-94%) and correctly assigned 32 of 32 informative negative cases (specificity, 100%; 90% CI, 91%-100%). In addition, ctDNA HER2mut variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression.Conclusions: Neratinib is active in HER2mut, nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with HER2mut cancers for clinical trial participation. Clin Cancer Res; 23(19); 5687-95. ©2017 AACR.

PMID:
28679771
DOI:
10.1158/1078-0432.CCR-17-0900
[Indexed for MEDLINE]

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