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Intratumor lactate levels reflect HER2 addiction status in HER2-positive breast cancer.

ABSTRACT: Despite different molecular tumor profiles indicate that human epidermal growth factor receptor 2 (HER2) messenger RNA (mRNA) levels mirror HER2 addiction and trastuzumab benefit in HER2-positive breast cancer (BC), the identification of noninvasive clinical predictors of trastuzumab sensitivity remains an unmet clinical need. In the current study, we investigated whether intratumor lactate levels reflect HER2 addiction and, in turn, trastuzumab susceptibility. Accordingly, the gene expression profiles of transgenic murine BC cell lines expressing the human d16HER2 variant (HER2-addicted) or human full-length HER2 (WTHER2; HER2-nonaddicted) revealed a significant enrichment of glycolysis-related gene pathways in HER2-addicted cells. We studied the metabolic content of 22 human HER2-positive BC by quantitative nuclear magnetic resonance spectroscopy and found that those cases with higher lactate levels were characterized by higher HER2 transcript levels. Moreover, gene expression analyses of HER2-positive BC samples from a TCGA data set revealed a significant enrichment in glycolysis-related pathways in high/HER2-addicted tumors. These data were confirmed by metabolic analyses of human HER2-positive BC cell lines with high or low HER2 transcript levels, which revealed significantly more active glycolytic metabolism in high HER2 transcript than in low HER2 transcript cells. Overall, our results provide evidence for noninvasive intratumor lactate detection as a potential metabolic biomarker of HER2 addiction and trastuzumab response suggesting the possibility to use in vivo imaging to assess lactate levels and, in turn, select HER2-positive BC patients who are more likely to benefit from anti-HER2 treatments.

SUBMITTER: Castagnoli L

PROVIDER: S-EPMC6282573 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Intratumor lactate levels reflect HER2 addiction status in HER2-positive breast cancer.

Castagnoli Lorenzo L Iorio Egidio E Dugo Matteo M Koschorke Ada A Faraci Simona S Canese Rossella R Casalini Patrizia P Nanni Patrizia P Vernieri Claudio C Di Nicola Massimo M Morelli Daniele D Tagliabue Elda E Pupa Serenella M SM

Journal of cellular physiology 20180821 2

Despite different molecular tumor profiles indicate that human epidermal growth factor receptor 2 (HER2) messenger RNA (mRNA) levels mirror HER2 addiction and trastuzumab benefit in HER2-positive breast cancer (BC), the identification of noninvasive clinical predictors of trastuzumab sensitivity remains an unmet clinical need. In the current study, we investigated whether intratumor lactate levels reflect HER2 addiction and, in turn, trastuzumab susceptibility. Accordingly, the gene expression p ...[more]

PMID: 30132876

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Project description:BackgroundOverexpression of human epidermal growth factor receptor 2 (HER2) caused by HER2 gene amplification is a driver in breast cancer tumorigenesis. We aimed to investigate the prognostic significance of manual scoring and digital image analysis (DIA) algorithm assessment of HER2 copy numbers and HER2/CEP17 ratios, along with ERBB2 mRNA levels among early-stage HER2-positive breast cancer patients treated with trastuzumab.MethodsThis retrospective study comprised 371 early HER2-positive breast cancer patients treated with adjuvant trastuzumab, with HER2 re-testing performed on whole tumor sections. Digitized tumor tissue slides were manually scored and assessed with uPath HER2 Dual ISH image analysis, breast algorithm. Targeted ERBB2 mRNA levels were assessed by the Xpert® Breast Cancer STRAT4 Assay. HER2 copy number and HER2/CEP17 ratio from in situ hybridization assessment, along with ERBB2 mRNA levels, were explored in relation to recurrence-free survival (RFS).ResultsThe analysis showed that patients with tumors with the highest and lowest manually counted HER2 copy number levels had worse RFS than those with intermediate levels (HR = 2.7, CI 1.4-5.3, p = 0.003 and HR = 2.1, CI 1.1-3.9, p = 0.03, respectively). A similar trend was observed for HER2/CEP17 ratio, and the DIA algorithm confirmed the results. Moreover, patients with tumors with the highest and the lowest values of ERBB2 mRNA had a significantly worse prognosis (HR = 2.7, CI 1.4-5.1, p = 0.003 and HR = 2.8, CI 1.4-5.5, p = 0.004, respectively) compared to those with intermediate levels.ConclusionsOur findings suggest that the association between any of the three HER2 biomarkers and RFS was nonlinear. Patients with tumors with the highest levels of HER2 gene amplification or ERBB2 mRNA were associated with a worse prognosis than those with intermediate levels, which is of importance to investigate in future clinical trials studying HER2-targeted therapy.

Project description:Single estrogen receptor (ER)+ and progesterone receptor (PR)+ tumors account for about10% of all breast cancers. However, the prognosis of these single hormone receptor-positive (HR+) tumor remains unclear. We aimed to investigate the characteristics of single HR+ breast tumors according to HER2 status in order to improve the treatment of patients with single HR+. Patients from the SEER program (2010-2016) were divided into ER+PR-, ER-PR+, ER+PR+ and ER-PR- molecular subtypes stratified by HER2 status. Overall survival (OS) and breast cancer-specific survival (BCSS) were compared by Kaplan-Meier curves after propensity score matching (PSM). A total of 203,406 patients were enrolled. Single ER+ and PR+ tumors account for 11.9% of the total population. For HER2- subtype, patients with ER+PR- (n = 16906 pairs) and ER-PR+ (n = 1395 pairs) had worse prognoses than those with ER+PR+ with hazard ratio (HR) and 95% confidence interval (CI) of 1.52 (1.41-1.64) and 2.25 (1.76-2.88) for OS; and 1.94 (1.76-2.14) and 2.57 (1.94-3.40) for BCSS, respectively; ER+PR- showed a better prognosis than ER-PR+ (n = 1394 pairs) and ER-PR- (n = 9626 pairs) with HR (95% CI) of 1.32 (1.06-1.65) and 1.44 (1.33-1.55) for OS, and 1.32 (1.03-1.69) and 1.46 (1.34-1.60) for BCSS, respectively; ER-PR+ had a similar prognosis relative to ER-PR- (n = 1395 pairs) after PSM. For HER2+ subtype, patients with ER-PR+, ER+PR-, and ER-PR- had similar OS and BCSS; ER+PR+ showed a similar prognosis compare with ER-PR+ (n = 535 pairs), but had better OS and BCSS than ER+PR- (n = 5376 pairs) and ER-PR- (n = 8143 pairs) after PSM. In addition, ER+PR+HER2+ showed similar OS and better BCSS compared with ER+PR+HER2- after PSM. In conclusion, single PR+ patients experienced poorer prognoses than single ER+ patients, and may be treated as ER-PR- patients in HER2- subtype. In HER2+ patients, both single ER+ and single PR+ cases showed similar prognoses compared with ER-PR- cases, and may be treated as ER-PR- patients.

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Dataset Information

Intratumor lactate levels reflect HER2 addiction status in HER2-positive breast cancer.

Publications

Intratumor lactate levels reflect HER2 addiction status in HER2-positive breast cancer.

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