High hepatocyte growth factor expression in primary tumor predicts better overall survival in male breast cancer

Si-Qi Qiu; Johan van Rooijen; Hilde H Nienhuis; Bert van der Vegt; Hetty Timmer-Bosscha; Elise van Leeuwen-Stok; Annemiek M E Walenkamp; Carolien H M van Deurzen; Geertruida H de Bock; Elisabeth G E de Vries; Carolien P Schröder

doi:10.1186/s13058-020-01266-x

High hepatocyte growth factor expression in primary tumor predicts better overall survival in male breast cancer

Si-Qi Qiu
, Johan van Rooijen
, Hilde H Nienhuis
, Bert van der Vegt
, Hetty Timmer-Bosscha
, Elise van Leeuwen-Stok
, Annemiek M E Walenkamp
, Carolien H M van Deurzen
, Geertruida H de Bock
, Elisabeth G E de Vries
, Carolien P Schröder^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

BACKGROUND: Breast cancer is rare in men, but management is focused on tumor characteristics commonly found in female breast cancer. The tumor microenvironment of male breast cancer is less well understood, and insight may improve male breast cancer management. The hepatocyte growth factor (HGF)/c-MET axis and the stromal cell-derived factor-1 (CXCL12)/C-X-C chemokine receptor type 4 (CXCR4) axis are prognostic in women with breast cancer. We aimed to investigate these factors in male breast cancer and correlate them with patient survival.

METHODS: From 841 Dutch males with breast cancer who were enrolled in the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program (NCT01101425) and diagnosed between 1990 and 2010, archival primary tumor samples were collected. Tissue microarrays were constructed with 3 cores per sample and used for immunohistochemical analysis of HGF, c-MET, CXCL12, and CXCR4. Overall survival (OS) of the patients without metastases (M0) was analyzed using the Kaplan-Meier method. The value of the markers regarding OS was determined using univariable and multivariable Cox regression analyses, providing hazard ratios (HRs) and 95% confidence intervals (95% CIs).

RESULTS: Of 720 out of 841 patients, sufficient tissue was available for analysis; 487 out of 720 patients had M0 disease. Patients with high HGF expression and high CXCL12 expression had a superior OS (low vs high expression of both markers, 7.5 vs 13.0 years, hazard ratio [HR] 0.64, 95% CI 0.49-0.84, P = 0.001 [HGF]; 9.1 vs 15.3 years, HR 0.63, 95% CI 0.45-0.87, P = 0.005 [CXCL12]). Multivariate analysis identified HGF as an independent predictor for OS (HR 0.64, 95% CI 0.47-0.88, P = 0.001).

CONCLUSIONS: HGF and CXCL12 tumor expression appear to identify male breast cancer patients with a relatively good prognosis. Possibly, this could support male breast cancer-specific management strategies in the future.

Original language	English
Article number	30
Journal	Breast Cancer Research
Volume	22
Issue number	1
DOIs	https://doi.org/10.1186/s13058-020-01266-x
Publication status	Published - 18 Mar 2020
Externally published	Yes

Keywords

Aged
Biomarkers, Tumor/metabolism
Breast Neoplasms, Male/metabolism
Chemokine CXCL12/metabolism
Hepatocyte Growth Factor/metabolism
Humans
Male
Middle Aged
Prognosis
Retrospective Studies
Signal Transduction
Survival Rate
Tumor Microenvironment

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10.1186/s13058-020-01266-x

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Qiu, S.-Q., van Rooijen, J., Nienhuis, H. H., van der Vegt, B., Timmer-Bosscha, H., van Leeuwen-Stok, E., Walenkamp, A. M. E., van Deurzen, C. H. M., de Bock, G. H., de Vries, E. G. E., & Schröder, C. P. (2020). High hepatocyte growth factor expression in primary tumor predicts better overall survival in male breast cancer. Breast Cancer Research, 22(1), Article 30. https://doi.org/10.1186/s13058-020-01266-x

@article{4b14f38dfd8b494d9ff9e5cf7a5cf5cd,

title = "High hepatocyte growth factor expression in primary tumor predicts better overall survival in male breast cancer",

abstract = "BACKGROUND: Breast cancer is rare in men, but management is focused on tumor characteristics commonly found in female breast cancer. The tumor microenvironment of male breast cancer is less well understood, and insight may improve male breast cancer management. The hepatocyte growth factor (HGF)/c-MET axis and the stromal cell-derived factor-1 (CXCL12)/C-X-C chemokine receptor type 4 (CXCR4) axis are prognostic in women with breast cancer. We aimed to investigate these factors in male breast cancer and correlate them with patient survival.METHODS: From 841 Dutch males with breast cancer who were enrolled in the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program (NCT01101425) and diagnosed between 1990 and 2010, archival primary tumor samples were collected. Tissue microarrays were constructed with 3 cores per sample and used for immunohistochemical analysis of HGF, c-MET, CXCL12, and CXCR4. Overall survival (OS) of the patients without metastases (M0) was analyzed using the Kaplan-Meier method. The value of the markers regarding OS was determined using univariable and multivariable Cox regression analyses, providing hazard ratios (HRs) and 95\% confidence intervals (95\% CIs).RESULTS: Of 720 out of 841 patients, sufficient tissue was available for analysis; 487 out of 720 patients had M0 disease. Patients with high HGF expression and high CXCL12 expression had a superior OS (low vs high expression of both markers, 7.5 vs 13.0 years, hazard ratio [HR] 0.64, 95\% CI 0.49-0.84, P = 0.001 [HGF]; 9.1 vs 15.3 years, HR 0.63, 95\% CI 0.45-0.87, P = 0.005 [CXCL12]). Multivariate analysis identified HGF as an independent predictor for OS (HR 0.64, 95\% CI 0.47-0.88, P = 0.001).CONCLUSIONS: HGF and CXCL12 tumor expression appear to identify male breast cancer patients with a relatively good prognosis. Possibly, this could support male breast cancer-specific management strategies in the future.",

keywords = "Aged, Biomarkers, Tumor/metabolism, Breast Neoplasms, Male/metabolism, Chemokine CXCL12/metabolism, Hepatocyte Growth Factor/metabolism, Humans, Male, Middle Aged, Prognosis, Retrospective Studies, Signal Transduction, Survival Rate, Tumor Microenvironment",

author = "Si-Qi Qiu and \{van Rooijen\}, Johan and Nienhuis, \{Hilde H\} and \{van der Vegt\}, Bert and Hetty Timmer-Bosscha and \{van Leeuwen-Stok\}, Elise and Walenkamp, \{Annemiek M E\} and \{van Deurzen\}, \{Carolien H M\} and \{de Bock\}, \{Geertruida H\} and \{de Vries\}, \{Elisabeth G E\} and Schr{\"o}der, \{Carolien P\}",

note = "Publisher Copyright: {\textcopyright} 2020 The Author(s).",

year = "2020",

month = mar,

day = "18",

doi = "10.1186/s13058-020-01266-x",

language = "English",

volume = "22",

journal = "Breast Cancer Research",

issn = "1465-5411",

publisher = "BioMed Central Ltd.",

number = "1",

}

Qiu, S-Q, van Rooijen, J, Nienhuis, HH, van der Vegt, B, Timmer-Bosscha, H, van Leeuwen-Stok, E, Walenkamp, AME, van Deurzen, CHM, de Bock, GH, de Vries, EGE & Schröder, CP 2020, 'High hepatocyte growth factor expression in primary tumor predicts better overall survival in male breast cancer', Breast Cancer Research, vol. 22, no. 1, 30. https://doi.org/10.1186/s13058-020-01266-x

TY - JOUR

T1 - High hepatocyte growth factor expression in primary tumor predicts better overall survival in male breast cancer

AU - Qiu, Si-Qi

AU - van Rooijen, Johan

AU - Nienhuis, Hilde H

AU - van der Vegt, Bert

AU - Timmer-Bosscha, Hetty

AU - van Leeuwen-Stok, Elise

AU - Walenkamp, Annemiek M E

AU - van Deurzen, Carolien H M

AU - de Bock, Geertruida H

AU - de Vries, Elisabeth G E

AU - Schröder, Carolien P

PY - 2020/3/18

Y1 - 2020/3/18

N2 - BACKGROUND: Breast cancer is rare in men, but management is focused on tumor characteristics commonly found in female breast cancer. The tumor microenvironment of male breast cancer is less well understood, and insight may improve male breast cancer management. The hepatocyte growth factor (HGF)/c-MET axis and the stromal cell-derived factor-1 (CXCL12)/C-X-C chemokine receptor type 4 (CXCR4) axis are prognostic in women with breast cancer. We aimed to investigate these factors in male breast cancer and correlate them with patient survival.METHODS: From 841 Dutch males with breast cancer who were enrolled in the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program (NCT01101425) and diagnosed between 1990 and 2010, archival primary tumor samples were collected. Tissue microarrays were constructed with 3 cores per sample and used for immunohistochemical analysis of HGF, c-MET, CXCL12, and CXCR4. Overall survival (OS) of the patients without metastases (M0) was analyzed using the Kaplan-Meier method. The value of the markers regarding OS was determined using univariable and multivariable Cox regression analyses, providing hazard ratios (HRs) and 95% confidence intervals (95% CIs).RESULTS: Of 720 out of 841 patients, sufficient tissue was available for analysis; 487 out of 720 patients had M0 disease. Patients with high HGF expression and high CXCL12 expression had a superior OS (low vs high expression of both markers, 7.5 vs 13.0 years, hazard ratio [HR] 0.64, 95% CI 0.49-0.84, P = 0.001 [HGF]; 9.1 vs 15.3 years, HR 0.63, 95% CI 0.45-0.87, P = 0.005 [CXCL12]). Multivariate analysis identified HGF as an independent predictor for OS (HR 0.64, 95% CI 0.47-0.88, P = 0.001).CONCLUSIONS: HGF and CXCL12 tumor expression appear to identify male breast cancer patients with a relatively good prognosis. Possibly, this could support male breast cancer-specific management strategies in the future.

AB - BACKGROUND: Breast cancer is rare in men, but management is focused on tumor characteristics commonly found in female breast cancer. The tumor microenvironment of male breast cancer is less well understood, and insight may improve male breast cancer management. The hepatocyte growth factor (HGF)/c-MET axis and the stromal cell-derived factor-1 (CXCL12)/C-X-C chemokine receptor type 4 (CXCR4) axis are prognostic in women with breast cancer. We aimed to investigate these factors in male breast cancer and correlate them with patient survival.METHODS: From 841 Dutch males with breast cancer who were enrolled in the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program (NCT01101425) and diagnosed between 1990 and 2010, archival primary tumor samples were collected. Tissue microarrays were constructed with 3 cores per sample and used for immunohistochemical analysis of HGF, c-MET, CXCL12, and CXCR4. Overall survival (OS) of the patients without metastases (M0) was analyzed using the Kaplan-Meier method. The value of the markers regarding OS was determined using univariable and multivariable Cox regression analyses, providing hazard ratios (HRs) and 95% confidence intervals (95% CIs).RESULTS: Of 720 out of 841 patients, sufficient tissue was available for analysis; 487 out of 720 patients had M0 disease. Patients with high HGF expression and high CXCL12 expression had a superior OS (low vs high expression of both markers, 7.5 vs 13.0 years, hazard ratio [HR] 0.64, 95% CI 0.49-0.84, P = 0.001 [HGF]; 9.1 vs 15.3 years, HR 0.63, 95% CI 0.45-0.87, P = 0.005 [CXCL12]). Multivariate analysis identified HGF as an independent predictor for OS (HR 0.64, 95% CI 0.47-0.88, P = 0.001).CONCLUSIONS: HGF and CXCL12 tumor expression appear to identify male breast cancer patients with a relatively good prognosis. Possibly, this could support male breast cancer-specific management strategies in the future.

KW - Aged

KW - Biomarkers, Tumor/metabolism

KW - Breast Neoplasms, Male/metabolism

KW - Chemokine CXCL12/metabolism

KW - Hepatocyte Growth Factor/metabolism

KW - Humans

KW - Male

KW - Middle Aged

KW - Prognosis

KW - Retrospective Studies

KW - Signal Transduction

KW - Survival Rate

KW - Tumor Microenvironment

U2 - 10.1186/s13058-020-01266-x

DO - 10.1186/s13058-020-01266-x

M3 - Article

C2 - 32188473

SN - 1465-5411

VL - 22

JO - Breast Cancer Research

JF - Breast Cancer Research

IS - 1

M1 - 30

ER -

High hepatocyte growth factor expression in primary tumor predicts better overall survival in male breast cancer

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