Dataset Information

Prognostic and predictive role of tumour-associated macrophages in HER2 positive breast cancer.

ABSTRACT: Disease outcomes of HER2+ breast cancers have dramatically improved after targeted therapies, such as trastuzumab became available. The main mechanism of action of trastuzumab depends on immunoactivation, while immunosuppressive tumour phenotype has been linked to adverse outcomes. Current study included metastatic HER2+ breast cancer patients treated with trastuzumab (n?=?40). Immunohistochemistry was conducted to detect nitric oxide synthase 2 (iNOS) expressing M1 polarized and CD163+ M2 polarized macrophages, FoxP3+ regulatory T-cells (Tregs), CD47 and indoleamine 2,3-dioxygenase 1 (IDO1). High number of iNOS+ M1-like macrophages, both in the center of the tumour (CT) and invasive margin (IM), was significantly associated with improved survival (p?=?0.009) while high expression of IDO1 or CD47 in the malignant cells was associated with worsened prognosis (p?=?0.018, p?=?0.046). High number of CD163+ M2-like macrophages in the CT, but not in the IM, and high number of FoxP3+ Tregs in both locations showed non-significant tendencies towards poor prognosis. Moreover, high number of iNOS+ M1-like macrophages combined with high number of CD8+ T-cells in the CT was significantly associated with improved survival (p?=?0.0003), and this combined marker predicted patient's ability to remain progression-free without trastuzumab after responding to the therapy (p?=?0.003). Current study highlights the role of M1 polarized macrophages alone and in combination with CD8+ cells in HER2+ breast cancer.

SUBMITTER: Honkanen TJ

PROVIDER: S-EPMC6662906 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Prognostic and predictive role of tumour-associated macrophages in HER2 positive breast cancer.

Honkanen Tiia J TJ Tikkanen Antti A Karihtala Peeter P Mäkinen Markus M Väyrynen Juha P JP Koivunen Jussi P JP

Scientific reports 20190729 1

Disease outcomes of HER2+ breast cancers have dramatically improved after targeted therapies, such as trastuzumab became available. The main mechanism of action of trastuzumab depends on immunoactivation, while immunosuppressive tumour phenotype has been linked to adverse outcomes. Current study included metastatic HER2+ breast cancer patients treated with trastuzumab (n = 40). Immunohistochemistry was conducted to detect nitric oxide synthase 2 (iNOS) expressing M1 polarized and CD163<sup>+</su ...[more]

PMID: 31358801

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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:PurposePrognostic and predictive biomarkers to cyclin-dependent kinases 4 and 6 inhibitors are lacking. Circulating tumor DNA (ctDNA) can be used to profile these patients and dynamic changes in ctDNA could be an early predictor of treatment efficacy. Here, we conducted plasma ctDNA profiling in patients from the PEARL trial comparing palbociclib+fulvestrant versus capecitabine to investigate associations between baseline genomic landscape and on-treatment ctDNA dynamics with treatment efficacy.Experimental designCorrelative blood samples were collected at baseline [cycle 1-day 1 (C1D1)] and prior to treatment [cycle 1-day 15 (C1D15)]. Plasma ctDNA was sequenced with a custom error-corrected capture panel, with both univariate and multivariate Cox models used for treatment efficacy associations. A prespecified methodology measuring ctDNA changes in clonal mutations between C1D1 and C1D15 was used for the on-treatment ctDNA dynamic model.Results201 patients were profiled at baseline, with ctDNA detection associated with worse progression-free survival (PFS)/overall survival (OS). Detectable TP53 mutation showed worse PFS and OS in both treatment arms, even after restricting population to baseline ctDNA detection. ESR1 mutations were associated with worse OS overall, which was lost when restricting population to baseline ctDNA detection. PIK3CA mutations confer worse OS only to patients on the palbociclib+fulvestrant treatment arm. ctDNA dynamics analysis (n = 120) showed higher ctDNA suppression in the capecitabine arm. Patients without ctDNA suppression showed worse PFS in both treatment arms.ConclusionsWe show impaired survival irrespective of endocrine or chemotherapy-based treatments for patients with hormone receptor-positive/HER2-negative metastatic breast cancer harboring plasma TP53 mutations. Early ctDNA suppression may provide treatment efficacy predictions. Further validation to fully demonstrate clinical utility of ctDNA dynamics is warranted.

Dataset Information

Prognostic and predictive role of tumour-associated macrophages in HER2 positive breast cancer.

Publications

Prognostic and predictive role of tumour-associated macrophages in HER2 positive breast cancer.

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