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The Prognostic Impact of Intratumoral Aryl Hydrocarbon Receptor in Primary Breast Cancer Depends on the Type of Endocrine Therapy: A Population-Based Cohort Study
The aryl hydrocarbon receptor (AhR) is a master regulator of multiple pathways involved in breast cancer, and influences the estrogen receptor alpha (ER) and aromatase/CYP19A1. The purpose of this study was to elucidate the interplay between intratumoral levels of AhR and aromatase, patient characte...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174786/ https://www.ncbi.nlm.nih.gov/pubmed/34094928 http://dx.doi.org/10.3389/fonc.2021.642768 |
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author | Tryggvadottir, Helga Sandén, Emma Björner, Sofie Bressan, Alessandra Ygland Rödström, Maria Khazaei, Somayeh Edwards, Dean P. Nodin, Björn Jirström, Karin Isaksson, Karolin Borgquist, Signe Jernström, Helena |
author_facet | Tryggvadottir, Helga Sandén, Emma Björner, Sofie Bressan, Alessandra Ygland Rödström, Maria Khazaei, Somayeh Edwards, Dean P. Nodin, Björn Jirström, Karin Isaksson, Karolin Borgquist, Signe Jernström, Helena |
author_sort | Tryggvadottir, Helga |
collection | PubMed |
description | The aryl hydrocarbon receptor (AhR) is a master regulator of multiple pathways involved in breast cancer, and influences the estrogen receptor alpha (ER) and aromatase/CYP19A1. The purpose of this study was to elucidate the interplay between intratumoral levels of AhR and aromatase, patient characteristics (including AhR and CYP19A1 genotypes), clinicopathological features, and prognosis in breast cancer patients receiving adjuvant treatments. A prospective cohort of 1116 patients with primary breast cancer in Sweden, included 2002–2012, was followed until June 30(th) 2019 (median 8.7 years). Tumor‐specific AhR (n=920) and aromatase levels (n=816) were evaluated on tissue microarrays using immunohistochemistry. Associations between cytoplasmatic (AhR(cyt)) and nuclear (AhR(nuc)) AhR levels, intratumoral aromatase, clinicopathological features, and prognosis in different treatment groups were analyzed. Low AhR(cyt) levels (n=183) and positive intratumoral aromatase (n=69) were associated with estrogen receptor (ER)(–) status and more aggressive tumors. Genotypes were not associated with their respective protein levels. The functional AhR (Arg554Lys) GG genotype was associated with recurrence-free survival in switch-therapy (sequential tamoxifen/aromatase inhibitors (AI) or AI/tamoxifen) treated patients (HR(adj) 0.42; 95% CI 0.22–0.83). High AhR(cyt) levels were associated with longer recurrence-free survival during the first 10 years of follow-up among tamoxifen-only treated patients (HR(adj) 0.40; 95% CI 0.23–0.71) compared to low AhR(cyt) levels, whereas an almost inverse association was seen in patients with switch-therapy (P (interaction)=0.023). Intratumoral aromatase had little prognostic impact. These findings warrant confirmation in an independent cohort, preferably in a randomized clinical trial comparing different endocrine regimens. They might also guide the selection of breast cancer patients for clinical trials with selective AhR modulators. |
format | Online Article Text |
id | pubmed-8174786 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-81747862021-06-04 The Prognostic Impact of Intratumoral Aryl Hydrocarbon Receptor in Primary Breast Cancer Depends on the Type of Endocrine Therapy: A Population-Based Cohort Study Tryggvadottir, Helga Sandén, Emma Björner, Sofie Bressan, Alessandra Ygland Rödström, Maria Khazaei, Somayeh Edwards, Dean P. Nodin, Björn Jirström, Karin Isaksson, Karolin Borgquist, Signe Jernström, Helena Front Oncol Oncology The aryl hydrocarbon receptor (AhR) is a master regulator of multiple pathways involved in breast cancer, and influences the estrogen receptor alpha (ER) and aromatase/CYP19A1. The purpose of this study was to elucidate the interplay between intratumoral levels of AhR and aromatase, patient characteristics (including AhR and CYP19A1 genotypes), clinicopathological features, and prognosis in breast cancer patients receiving adjuvant treatments. A prospective cohort of 1116 patients with primary breast cancer in Sweden, included 2002–2012, was followed until June 30(th) 2019 (median 8.7 years). Tumor‐specific AhR (n=920) and aromatase levels (n=816) were evaluated on tissue microarrays using immunohistochemistry. Associations between cytoplasmatic (AhR(cyt)) and nuclear (AhR(nuc)) AhR levels, intratumoral aromatase, clinicopathological features, and prognosis in different treatment groups were analyzed. Low AhR(cyt) levels (n=183) and positive intratumoral aromatase (n=69) were associated with estrogen receptor (ER)(–) status and more aggressive tumors. Genotypes were not associated with their respective protein levels. The functional AhR (Arg554Lys) GG genotype was associated with recurrence-free survival in switch-therapy (sequential tamoxifen/aromatase inhibitors (AI) or AI/tamoxifen) treated patients (HR(adj) 0.42; 95% CI 0.22–0.83). High AhR(cyt) levels were associated with longer recurrence-free survival during the first 10 years of follow-up among tamoxifen-only treated patients (HR(adj) 0.40; 95% CI 0.23–0.71) compared to low AhR(cyt) levels, whereas an almost inverse association was seen in patients with switch-therapy (P (interaction)=0.023). Intratumoral aromatase had little prognostic impact. These findings warrant confirmation in an independent cohort, preferably in a randomized clinical trial comparing different endocrine regimens. They might also guide the selection of breast cancer patients for clinical trials with selective AhR modulators. Frontiers Media S.A. 2021-05-20 /pmc/articles/PMC8174786/ /pubmed/34094928 http://dx.doi.org/10.3389/fonc.2021.642768 Text en Copyright © 2021 Tryggvadottir, Sandén, Björner, Bressan, Ygland Rödström, Khazaei, Edwards, Nodin, Jirström, Isaksson, Borgquist and Jernström https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Tryggvadottir, Helga Sandén, Emma Björner, Sofie Bressan, Alessandra Ygland Rödström, Maria Khazaei, Somayeh Edwards, Dean P. Nodin, Björn Jirström, Karin Isaksson, Karolin Borgquist, Signe Jernström, Helena The Prognostic Impact of Intratumoral Aryl Hydrocarbon Receptor in Primary Breast Cancer Depends on the Type of Endocrine Therapy: A Population-Based Cohort Study |
title | The Prognostic Impact of Intratumoral Aryl Hydrocarbon Receptor in Primary Breast Cancer Depends on the Type of Endocrine Therapy: A Population-Based Cohort Study |
title_full | The Prognostic Impact of Intratumoral Aryl Hydrocarbon Receptor in Primary Breast Cancer Depends on the Type of Endocrine Therapy: A Population-Based Cohort Study |
title_fullStr | The Prognostic Impact of Intratumoral Aryl Hydrocarbon Receptor in Primary Breast Cancer Depends on the Type of Endocrine Therapy: A Population-Based Cohort Study |
title_full_unstemmed | The Prognostic Impact of Intratumoral Aryl Hydrocarbon Receptor in Primary Breast Cancer Depends on the Type of Endocrine Therapy: A Population-Based Cohort Study |
title_short | The Prognostic Impact of Intratumoral Aryl Hydrocarbon Receptor in Primary Breast Cancer Depends on the Type of Endocrine Therapy: A Population-Based Cohort Study |
title_sort | prognostic impact of intratumoral aryl hydrocarbon receptor in primary breast cancer depends on the type of endocrine therapy: a population-based cohort study |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174786/ https://www.ncbi.nlm.nih.gov/pubmed/34094928 http://dx.doi.org/10.3389/fonc.2021.642768 |
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