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Ref Type Journal Article
PMID (28679771)
Authors Ma CX, Bose R, Gao F, Freedman RA, Telli ML, Kimmick G, Winer E, Naughton M, Goetz MP, Russell C, Tripathy D, Cobleigh M, Forero A, Pluard TJ, Anders C, Niravath PA, Thomas S, Anderson J, Bumb C, Banks KC, Lanman RB, Bryce R, Lalani AS, Pfeifer J, Hayes DF, Pegram M, Blackwell K, Bedard PL, Al-Kateb H, Ellis MJC
Title Neratinib Efficacy and Circulating Tumor DNA Detection of HER2 Mutations in HER2 Nonamplified Metastatic Breast Cancer.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 23
Issue 19
Date 2017 Oct 01
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
ERBB2 V697L missense unknown ERBB2 (HER2) V697L lies within the juxtamembrane domain of the Erbb2 (Her2) protein (PMID: 30449325). V697L has been identified in the scientific literature (PMID: 29247016, PMID: 28679771), but has not been biochemically characterized and therefore, its effect on Erbb2 (Her2) protein function is unknown (PubMed, Apr 2020).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB2 L869R breast cancer sensitive Neratinib Case Reports/Case Series Actionable In a Phase II trial, Nerlynx (neratinib) treatment resulted in a clinical benefit rate of 31% (5/16) in metastatic breast cancer patients harboring ERBB2 (HER2) mutations, with 1 patient harboring ERBB2 (HER2) L869R achievd stable disease for 24 weeks or more (PMID: 28679771; NCT01670877). 28679771
ERBB2 G778_P780dup breast cancer sensitive Neratinib Case Reports/Case Series Actionable In a Phase II trial, Nerlynx (neratinib) treatment resulted in a clinical benefit rate of 31% (5/16) in metastatic breast cancer patients harboring ERBB2 (HER2) mutations, with 1 complete response (referred to as V777_G778insGSP) and 1 stable disease for more than 24 weeks (referred to as P780_Y781insGSP) in 3 patients harboring ERBB2 G778_P780dup (PMID: 28679771; NCT01670877). 28679771
ERBB2 L755S breast cancer conflicting Neratinib Case Reports/Case Series Actionable In a Phase II trial, Nerlynx (neratinib) treatment resulted in a clinical benefit rate of 31% (5/16) in metastatic breast cancer patients harboring ERBB2 (HER2) mutations, with 1 partial response and 1 stable disease in 6 patients harboring ERBB2 (HER2) L755S (PMID: 28679771; NCT01670877). 28679771
ERBB2 mutant breast cancer predicted - sensitive Neratinib Phase II Actionable In a Phase II trial, Nerlynx (neratinib) demonstrated activity in metastatic breast cancer patients harboring ERBB2 (HER2) mutations, with treatment resulting in a clinical benefit rate of 31% (5/16; 1 complete response, 1 partial response, and 3 patients achieving stable disease for 24 weeks or more) and a median progression-free survival of 16 weeks (PMID: 28679771). 28679771
ERBB2 S310F ERBB2 V842I breast cancer predicted - sensitive Neratinib Case Reports/Case Series Actionable In a Phase II trial, Nerlynx (neratinib) treatment resulted in a clinical benefit rate of 31% (5/16) in metastatic breast cancer patients harboring ERBB2 (HER2) mutations, with 1 patient harboring ERBB2 (HER2) S310F and V842R achieved stable disease over 6 months (PMID: 28679771; NCT01670877). 28679771