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 

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

JOURNAL=Frontiers in Oncology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.642768

DOI=10.3389/fonc.2021.642768

ISSN=2234-943X

ABSTRACT=<p>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 <italic>AhR</italic> and <italic>CYP19A1</italic> 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<sup>th</sup> 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<sup>cyt</sup>) and nuclear (AhR<sup>nuc</sup>) AhR levels, intratumoral aromatase, clinicopathological features, and prognosis in different treatment groups were analyzed. Low AhR<sup>cyt</sup> levels (n=183) and positive intratumoral aromatase (n=69) were associated with estrogen receptor (ER)<sup>–</sup> status and more aggressive tumors. Genotypes were not associated with their respective protein levels. The functional <italic>AhR</italic><sup>Arg554Lys</sup> GG genotype was associated with recurrence-free survival in switch-therapy (sequential tamoxifen/aromatase inhibitors (AI) or AI/tamoxifen) treated patients (HR<sub>adj</sub> 0.42; 95% CI 0.22–0.83). High AhR<sup>cyt</sup> levels were associated with longer recurrence-free survival during the first 10 years of follow-up among tamoxifen-only treated patients (HR<sub>adj</sub> 0.40; 95% CI 0.23–0.71) compared to low AhR<sup>cyt</sup> levels, whereas an almost inverse association was seen in patients with switch-therapy (<italic>P</italic><sub>interaction</sub>=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.</p>