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Relapsed and De Novo Metastatic HER2-positive Breast Cancer Treated With Trastuzumab: Tumor Genotypes and Clinical Measures Associated With Patient Outcome.

Abstract：

BACKGROUND:We examined tumor genotype characteristics of human epidermal growth factor receptor 2 (HER2)-positive relapsed (R-) and de novo (dn-) metastatic breast cancer (MBC) in trastuzumab-treated patients who were previously not exposed to this agent. MATERIALS AND METHODS:We analyzed genotypes obtained upon deep sequencing from 113 HER2-positive primary tumors from 69 patients with R-MBC and 44 patients with dn-MBC. RESULTS:Mutations were observed in 90 (79.6%) tumors, 56 R-MBC and 34 dn-MBC (median number per tumor: 2; mean: 11.2; range: 0-150). The top mutated gene was TP53 (63.7%) followed by PIK3CA (24.8%) and others that were mostly co-mutated with TP53 (eg, 22 of 28 PIK3CA mutated tumors were co-mutated in TP53, 17 of these were R-MBC [P = .041]). dn-MBC had higher CEN17 average copies (P = .048). Tumor mutational burden inversely correlated with average HER2 copies (rho -0.32; P < .001). In all patients, PIK3CA mutations and higher proliferation rate were independent unfavorable prognosticators. In R-MBC, longer disease-free interval between initial diagnosis and relapse conferred lower risk for time-to-progression (P < .001) and death (P = .009); PIK3CA mutations conferred higher risk for death (P = .035). In dn-MBC, surgical removal of the primary tumor before any other therapy was favorable for time-to-progression (P = .002); higher tumor mutational burden was unfavorable for survival (P = .026). CONCLUSIONS:Except for the overall unfavorable prognostic effect of PIK3CA mutations in trastuzumab-treated MBC, our exploratory findings indicate that the outcome of patients with R-MBC is related to patient benefit from the preceding adjuvant chemotherapy and provide initial evidence that tumor mutational burden may be related to prognosis in dn-MBC, which is of potential clinical relevance and merits further investigation.

journal_name

Clin Breast Cancer

journal_title

Clinical breast cancer

authors

Kotoula V,Tsakiri K,Koliou GA,Lazaridis G,Papadopoulou K,Giannoulatou E,Tikas I,Christodoulou C,Chatzopoulos K,Bobos M,Pentheroudakis G,Tsolaki E,Batistatou A,Kotsakis A,Koutras A,Linardou H,Razis E,Res E,Pectasides D

doi

10.1016/j.clbc.2018.10.014

subject

Has Abstract

pub_date

2019-04-01 00:00:00

pages

113-125.e4

issue

eissn

1526-8209

issn

1938-0666

pii

S1526-8209(18)30424-5

journal_volume

pub_type

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Relapsed and De Novo Metastatic HER2-positive Breast Cancer Treated With Trastuzumab: Tumor Genotypes and Clinical Measures Associated With Patient Outcome.