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. 2022 Jan;23(1):23.
doi: 10.3892/ol.2021.13141. Epub 2021 Nov 17.

mRNA expression of specific HER ligands and their association with clinical outcome in patients with metastatic breast cancer treated with trastuzumab

Vassiliki Rapti  1 , Evangelia Moirogiorgou  2 , Georgia-Angeliki Koliou  3 , Kyriaki Papadopoulou  4 , Ioannis Binas  5 , George Pentheroudakis  6   7 , Dimitrios Bafaloukos  8 , Mattheos Bobos  4 , Kyriakos Chatzopoulos  4 , Sofia Chrisafi  4 , Christos Christodoulou  5 , Irene Nicolaou  9 , Maria Sotiropoulou  10 , Christina Magkou  11 , Angelos Koutras  12 , Pavlos Papakostas  13 , Athanasios Kotsakis  14 , Evangelia Razis  15 , Amanda Psyrri  16 , Dimitrios Tryfonopoulos  1 , Dimitrios Pectasides  17 , Eleni Res  18 , Athanasios Alexopoulos  2 , Vassiliki Kotoula  4   19 , George Fountzilas  4   20   21
Affiliations

mRNA expression of specific HER ligands and their association with clinical outcome in patients with metastatic breast cancer treated with trastuzumab

Vassiliki Rapti et al. Oncol Lett. 2022 Jan.

Abstract

Prognostic and predictive biomarkers are being studied for the diagnosis and treatment of breast cancer. The present study retrospectively assessed the mRNA expression of HER family receptor ligands and of other potential prognostic biomarkers and their association with time to progression (TTP), survival and clinicopathological characteristics in patients with metastatic breast cancer (MBC) treated with trastuzumab. A total of 145 tumour tissue samples were analysed. mRNA expression analysis of the transcripts of interest was performed and the association of these markers with selected clinicopathological parameters was examined. HER2 status was centrally re-evaluated. Only 67.6% of patients were truly HER2-positive according to the central HER2 re-evaluation. Heparin binding epidermal growth factor (EGF)-like growth factor, transforming growth factor β1 (TGFB1) and thyroid hormone receptor α (THRA) mRNA expression was higher in HER2-positive patients (P=0.026, P<0.001 and P<0.001). Insulin-like growth factor binding protein 4 was correlated with retinoic acid receptor α, TGFB1 and THRA (rho=0.45, rho=0.60 and rho=0.45). In HER2-positive patients, high neuregulin 1 and high betacellulin were unfavourable factors for TTP [hazard ratio (HR) = 1.78, P=0.040 and HR=2.00, P=0.043, respectively]. In patients with de novo MBC, high EGF expression was associated with a non-significant prolongation of TTP (HR=0.52, P=0.080) and significantly longer survival (HR=0.40, P=0.020). The present study examined clinical and biological implications of specific genes and it was concluded that their expression has an impact on the outcome of trastuzumab-treated patients with MBC.

Keywords: HER ligands; HER2; biomarkers; metastatic breast cancer; trastuzumab.

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Conflict of interest statement

EM Advisory boards: Roche; GP advisory role: Roche; research funding: Roche. CC Advisory role: Roche; honoraria: Roche; advisory role: Roche. PP Advisory role: Roche; honoraria: Roche. AK Consulting or advisory role: Roche. ER Travel: Roche. AP Consultation Fees: Roche; honoraria: Roche. DP Advisory role: Roche; honoraria: Roche. GF Advisory Board: Roche.

Figures

Figure 1.
Figure 1.
Representative IHC and FISH images from IBC cases. (A and B) In the first two panels an IBC case with (A) HER2 upregulation and (B) gene amplification is shown. (C and D) IBC HER2-negative case stained by (C) IHC and (D) FISH. HER2/TOP2A/CEP17 triple-colour probe: HER2 gene probe, green; CEP17 probe, yellow. The TOP2A gene probe (red) was excluded in the images using the XCytoGen software for cytogenetics. Magnification, ×1,000. CEP17, centromeric region of chromosome 17; FISH, fluorescence in situ hybridization; IBC, invasive breast carcinoma; IHC, immunohistochemistry; TOP2A, DNA topoisomerase II α.
Figure 2.
Figure 2.
Reporting recommendations for tumour marker prognostic studies (REMARK) diagram. AREG, amphiregulin; BTC, betacellulin; EGF, epidermal growth factor; ER, oestrogen receptors; EREG, epiregulin; FFPE, formalin-fixed paraffin-embedded; HBEGF, heparin Binding EGF like growth factor; IGFBP4, insulin-like growth factor binding protein 4; IHC, immunohistochemistry; NRG1, neuregulin 1; PgR, progesterone receptors; RARA, retinoic acid receptor α; TGFA, transforming growth factor α; TGFB1, transforming growth factor β1; THRA, thyroid hormone receptor α; TILs, tumour-infiltrating lymphocytes.
Figure 3.
Figure 3.
Heatmap matrix plot showing Spearman's correlation coefficients (rho) among the examined markers in the entire cohort. The value of r ranges between −1 (light purple) and 1 (dark green) as explained in the legend corresponding to negative or positive correlations between the markers. *P<0.050, **P<0.010 and ***P<0.001, respectively. Non-significant P-values are stated explicitly. AREG, amphiregulin; BTC, betacellulin; EGF, epidermal growth factor; EREG, epiregulin; HBEGF, heparin Binding EGF like growth factor; IGFBP4, insulin-like growth factor binding protein 4; NRG1, neuregulin 1; r, Spearman's correlation coefficient; RARA, retinoic acid receptor α; TGFA, transforming growth factor α; TGFB1, transforming growth factor β1; THRA, thyroid hormone receptor α.
Figure 4.
Figure 4.
Kaplan-Meier curves with respect to TTP based on NRG1 and BTC mRNA expression in HER2-positive patients. BTC, betacellulin; NRG1, neuregulin 1; TTP, time to progression.
See this image and copyright information in PMC

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