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PLoS One. 2014 Jun 26;9(6):e99131. doi: 10.1371/journal.pone.0099131. eCollection 2014.

In situ quantitative measurement of HER2mRNA predicts benefit from trastuzumab-containing chemotherapy in a cohort of metastatic breast cancer patients.

Author information

1
Yale University, School of Medicine, Department of Pathology, New Haven, Connecticut, United States of America.
2
Yale University, School of Public Health, Department of Biostatistics, New Haven, Connecticut, United States of America.
3
Laboratory of Biostatistics, University of Athens School of Nursing, Athens, Greece.
4
Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
5
Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece.
6
Second Department of Medical Oncology, "Metropolitan" Hospital, Piraeus, Greece.
7
Oncology Section, Second Department of Internal Medicine, "Hippokration" Hospital, Athens, Greece.
8
Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece; Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
9
Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece; Department of Medical Oncology, "Papageorgiou" Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
10
Division of Oncology, Second Department of Internal Medicine, University of Athens School of Medicine, Attikon University Hospital, Athens, Greece.

Abstract

BACKGROUND:

We sought to determine the predictive value of in situ mRNA measurement compared to traditional methods on a cohort of trastuzumab-treated metastatic breast cancer patients.

METHODS:

A tissue microarray composed of 149, classified as HER2-positive, metastatic breast cancers treated with various trastuzumab-containing chemotherapy regimens was constructed. HER2 intracellular domain(ICD), HER2 extracellular domain(ECD) and HER2 mRNA were assessed using AQUA. For HER2 protein evaluation, CB11 was used to measure ICD and SP3 to measure ECD of the HER2 receptor. In addition, HER2 mRNA status was assessed using RNAscope assay ERRB2 probe. Kaplan - Meier estimates were used for depicting time-to-event endpoints. Multivariate Cox regression models with backward elimination were used to assess the performance of markers as predictors of TTP and OS, after adjusting for important covariates.

RESULTS:

HER2 mRNA was correlated with ICD HER2, as measured by CB11 HER2, with ECD HER2 as measured by SP3 (Pearson's Correlation Coefficient, r = 0.66 and 0.51 respectively) and with FISH HER2 (Spearman's Correlation Coefficient, r = 0.75). All markers, HER2 mRNA, ICD HER2 and ECD HER2, along with FISH HER2, were found prognostic for OS (Log-rank p = 0.007, 0.005, 0.009 and 0.043 respectively), and except for FISH HER2, they were also prognostic for TTP Log-rank p = 0.036, 0.068 and 0.066 respectively) in this trastuzumab- treated cohort. Multivariate analysis showed that in the presence of pre-specified set of prognostic factors, among all biomarkers only ECD HER2, as measured by SP3, is strong prognostic factor for both TTP (HR = 0.54, 95% CI: 0.31-0.93, p = 0.027) and OS (HR = 0.39, 95%CI: 0.22-0.70, p = 0.002).

CONCLUSIONS:

The expression of HER2 ICD and ECD as well as HER2 mRNA levels was significantly associated with TTP and OS in this trastuzumab-treated metastatic cohort. In situ assessment of HER2 mRNA has the potential to identify breast cancer patients who derive benefit from Trastuzumab treatment.

PMID:
24968015
PMCID:
PMC4072595
DOI:
10.1371/journal.pone.0099131
[Indexed for MEDLINE]
Free PMC Article

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