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CYP27A1 expression is associated with risk of late lethal estrogen receptor-positive breast cancer in postmenopausal patients.

ABSTRACT: BACKGROUND:27-Hydroxycholesterol (27HC) stimulates estrogen receptor-positive (ER+) breast cancer (BC) progression. Inhibiting the sterol 27-hydroxylase (CYP27A1) abrogates these growth-promoting effects of 27HC in mice. However, the significance of CYP27A1 expression on BC biology and prognosis is unclear. METHODS:Intratumoral CYP27A1 expression in invasive BC was measured by immunohistochemistry in two Swedish population-based cohorts (n?=?645 and n?=?813, respectively). Cox proportional hazards models were used to evaluate the association between CYP27A1 expression and prognosis. RESULTS:CYP27A1 was highly expressed in less than 1/3 of the tumors. High CYP27A1 expression was more frequent among high-grade tumors lacking hormone receptor expression and with larger tumor sizes. Over a median of 12.2?years follow-up in cohort 1, high CYP27A1 expression was associated with impaired survival, specifically after 5 years from diagnosis among all patients [overall survival (OS), HRadjusted?=?1.93, 95%CI?=?1.26-2.97, P?=?0.003; breast cancer-specific survival (BCSS), HRadjusted?=?2.33, 95%CI?=?1.28-4.23, P?=?0.006] and among patients ??55?years presenting with ER+ tumors [OS, HRadjusted?=?1.99, 95%CI?=?1.24-3.21, P?=?0.004; BCSS, HRadjusted?=?2.78, 95%CI?=?1.41-5.51, P?=?0.003]. Among all patients in cohort 2 (median follow-up of 7.0?years), CYP27A1 expression was significantly associated with shorter OS and RFS in univariable analyses across the full follow-up period. However after adjusting for tumor characteristics and treatments, the association with survival after 5 years from diagnosis was non-significant among all patients [OS, HRadjusted?=?1.08, 95%CI?=?0.05-2.35, P?=?0.83 and RFS, HRadjusted?=?1.22, 95%CI?=?0.68-2.18, P?=?0.50] as well as among patients ??55?years presenting with ER+ tumors [OS, HRadjusted?=?0.46 95% CI = 0.11-1.98, P?=?0.30 and RFS, HRadjusted?=?0.97 95% CI = 0.44-2.10, P?=?0.93]. CONCLUSION:CYP27A1 demonstrated great potentials as a biomarker of aggressive tumor biology and late lethal disease in postmenopausal patients with ER+ BC. Future studies should investigate if the benefits of prolonged endocrine therapy and cholesterol-lowering medication in BC are modified by CYP27A1 expression.

SUBMITTER: Kimbung S

PROVIDER: S-EPMC7656740 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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CYP27A1 expression is associated with risk of late lethal estrogen receptor-positive breast cancer in postmenopausal patients.

Kimbung Siker S Inasu Maria M Stålhammar Tor T Nodin Björn B Elebro Karin K Tryggvadottir Helga H Ygland Rödström Maria M Jirström Karin K Isaksson Karolin K Jernström Helena H Borgquist Signe S

Breast cancer research : BCR 20201111 1

<h4>Background</h4>27-Hydroxycholesterol (27HC) stimulates estrogen receptor-positive (ER+) breast cancer (BC) progression. Inhibiting the sterol 27-hydroxylase (CYP27A1) abrogates these growth-promoting effects of 27HC in mice. However, the significance of CYP27A1 expression on BC biology and prognosis is unclear.<h4>Methods</h4>Intratumoral CYP27A1 expression in invasive BC was measured by immunohistochemistry in two Swedish population-based cohorts (n = 645 and n = 813, respectively). Cox pro ...[more]

PMID: 33176848

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Project description:IntroductionWe examined if a combination of proliferation markers and estrogen receptor (ER) activity could predict early versus late relapses in ER-positive breast cancer and inform the choice and length of adjuvant endocrine therapy.MethodsBaseline affymetrix gene-expression profiles from ER-positive patients who received no systemic therapy (n = 559), adjuvant tamoxifen for 5 years (cohort-1: n = 683, cohort-2: n = 282) and from 58 patients treated with neoadjuvant letrozole for 3 months (gene-expression available at baseline, 14 and 90 days) were analyzed. A proliferation score based on the expression of mitotic kinases (MKS) and an ER-related score (ERS) adopted from Oncotype DX® were calculated. The same analysis was performed using the Genomic Grade Index as proliferation marker and the luminal gene score from the PAM50 classifier as measure of estrogen-related genes. Median values were used to define low and high marker groups and four combinations were created. Relapses were grouped into time cohorts of 0-2.5, 0-5, 5-10 years.ResultsIn the overall 10 years period, the proportional hazards assumption was violated for several biomarker groups indicating time-dependent effects. In tamoxifen-treated patients Low-MKS/Low-ERS cancers had continuously increasing risk of relapse that was higher after 5 years than Low-MKS/High-ERS cancers [0 to 10 year, HR 3.36; p = 0.013]. High-MKS/High-ERS cancers had low risk of early relapse [0-2.5 years HR 0.13; p = 0.0006], but high risk of late relapse which was higher than in the High-MKS/Low-ERS group [after 5 years HR 3.86; p = 0.007]. The High-MKS/Low-ERS subset had most of the early relapses [0 to 2.5 years, HR 6.53; p < 0.0001] especially in node negative tumors and showed minimal response to neoadjuvant letrozole. These findings were qualitatively confirmed in a smaller independent cohort of tamoxifen-treated patients. Using different biomarkers provided similar results.ConclusionsEarly relapses are highest in highly proliferative/low-ERS cancers, in particular in node negative tumors. Relapses occurring after 5 years of adjuvant tamoxifen are highest among the highly-proliferative/high-ERS tumors although their risk of recurrence is modest in the first 5 years on tamoxifen. These tumors could be the best candidates for extended endocrine therapy.

Project description:Metastatic breast cancer (MBC) results in substantial morbidity and mortality for women afflicted with this disease. A majority of MBCs are hormone-responsive and estrogen receptor-positive, making endocrine therapy (ET) an integral component of systemic therapy. With a primary goal of minimizing the effects of estrogen on hormone-responsive MBC, ETs are among the first targeted treatments that aim to inhibit the influence of estrogen receptor activation on tumor proliferation. Several biochemical mechanisms have been the focus of drug development for treatment, including selective estrogen-receptor modulation, aromatase inhibition, and selective estrogen-receptor degradation. Treatments that exploit these mechanisms have improved survival and quality of life for women with MBC. However, in many cases, resistance to ET limits their effectiveness. Elucidation of the complex cellular signal cascades involved in the development of acquired resistance to ET and the interrelationship of growth factor signaling and estrogen responsiveness have characterized components of these pathways as attractive targets for drug development. Based on these insights and with the aim of overcoming hormone resistance, targeted therapies are emerging as useful treatments for MBC. This article reviews current endocrine treatments of MBC as well as recent and ongoing study of combination treatments and targeted therapies that interfere with cellular proliferation pathways as means of overcoming resistance. The Oncologist 2017;22:507-517 IMPLICATIONS FOR PRACTICE: This review provides medical oncologists and other oncology health care providers with a current understanding of the rationale for endocrine therapy in estrogen receptor-positive metastatic breast cancer and the efficacy and safety profile of available treatment options. Additionally, current concepts regarding the development of treatment resistance and the treatment strategies for overcoming resistance are discussed. Enhancing the current information and the understanding of these topics will assist clinicians in evaluating optimal treatment options for their patients.

Project description:BackgroundThe androgen receptor (AR) is an emerging prognostic marker and therapeutic target in breast cancer. AR is expressed in 60-80% of breast cancers, with higher prevalence among estrogen receptor-positive (ER+) tumors. Androgen treatment inhibits ER signaling in ER+/AR+ breast cancer cell lines, and AR expression is associated with improved survival for this subtype in epidemiologic studies. However, whether AR expression modifies the efficacy of selective ER modulators or aromatase inhibitors for ER+ cancers remains unclear.MethodsWe evaluated the prognostic and predictive value of AR expression among 3021 postmenopausal ER+ breast cancer patients in the Breast International Group (BIG) trial 1-98. The BIG 1-98 study was a four-armed, double-blind, phase III randomized clinical trial that compared 5 years of tamoxifen or letrozole monotherapy, or sequences of 2 years and 3 years treatment with one drug and then the other. AR expression was measured by immunohistochemistry and the percentage of AR-positive nuclei was quantified. The association between AR expression and prognosis was evaluated using Cox proportional hazards models. Continuous AR-by-treatment interactions were assessed using Subpopulation Treatment Effect Pattern Plots (STEPP).ResultsEighty-two percent of patients had AR+ (≥ 1%) tumors. Patients with AR+ cancers were more likely to have smaller, lower-grade tumors, with higher expression of ER and PR. AR expression was not associated with breast cancer-free interval (BCFI) (415 events) over a median 8.0 years of follow-up (p = 0.12, log-rank test). In multivariable-adjusted models, AR expression was not associated with BCFI (HR = 1.07, 95% CI 0.83-1.36, p = 0.60). The letrozole versus tamoxifen monotherapy treatment effect did not significantly differ for AR+ tumors (HR = 0.63, 95% CI 0.44-0.75, p = 0.003) and AR- tumors (HR = 0.39, 95% CI 0.21-0.72, p = 0.002) (p-heterogeneity = 0.16). STEPP analysis also suggested no heterogeneity of the treatment effect across the continuum of AR expression.ConclusionsAR expression was not associated with prognosis, nor was there heterogeneity of the letrozole versus tamoxifen treatment effect by AR expression. These findings suggest that AR expression may not be an informative biomarker for the selection of adjuvant endocrine therapy for postmenopausal women with ER+ breast cancers.Trial registrationClinicalTrials.gov , NCT00004205, Registered 27 January 2003-Retrospectively registered, https://clinicaltrials.gov/ct2/show/study/NCT00004205 .

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CYP27A1 expression is associated with risk of late lethal estrogen receptor-positive breast cancer in postmenopausal patients.

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CYP27A1 expression is associated with risk of late lethal estrogen receptor-positive breast cancer in postmenopausal patients.

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