Association between overall diet quality and postmenopausal breast cancer risk in five Finnish cohort studies

AbstractThere is limited evidence for any dietary factor, except alcohol, in breast cancer (BC) risk. Therefore, studies on a whole diet, using diet quality indices, can broaden our insight. We examined associations of the Nordic Diet (mNDI), Mediterranean diet (mMEDI) and Alternative Healthy Eating Index (mAHEI) with postmenopausal BC risk. Five Finnish cohorts were combined including 6374 postmenopausal women with dietary information. In all, 8–9 dietary components were aggregated in each index, higher total score indicating higher adherence to a healthy diet. Cox proportional hazards regression was used to estimate the combined hazard ratio (HR) and 95% confidence interval (CI) for BC risk. During an average 10-year follow-up period, 274 incident postmenopausal BC cases were diagnosed. In multivariable models, the HR for highest vs. lowest quintile of index was 0.67 (95 %CI 0.48–1.01) for mNDI, 0.88 (0.59–1.30) for mMEDI and 0.89 (0.60–1.32) for mAHEI. In this combined dataset, a borderline preventive finding of high adherence to mNDI on postmenopausal BC risk was found. Of the indices, mNDI was more based on the local food culture than the others. Although a healthy diet has beneficially been related to several chronic diseases, the link with the etiology of postmenopausal BC does not seem to be that obvious.

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Associations of Dietary Patterns with Incident Depression: The Maastricht Study

Nutrients ◽

10.3390/nu13031034 ◽

2021 ◽

Vol 13 (3) ◽

pp. 1034

Author(s):

Vincenza Gianfredi ◽

Annemarie Koster ◽

Anna Odone ◽

Andrea Amerio ◽

Carlo Signorelli ◽

...

Keyword(s):

Depressive Symptoms ◽

Dietary Patterns ◽

Proportional Hazards ◽

A Priori ◽

Preventive Measure ◽

Population Based ◽

Cox Proportional Hazards ◽

Healthy Diet ◽

Patient Health

Our aim was to assess the association between a priori defined dietary patterns and incident depressive symptoms. We used data from The Maastricht Study, a population-based cohort study (n = 2646, mean (SD) age 59.9 (8.0) years, 49.5% women; 15,188 person-years of follow-up). Level of adherence to the Dutch Healthy Diet (DHD), Mediterranean Diet, and Dietary Approaches To Stop Hypertension (DASH) were derived from a validated Food Frequency Questionnaire. Depressive symptoms were assessed at baseline and annually over seven-year-follow-up (using the 9-item Patient Health Questionnaire). We used Cox proportional hazards regression analyses to assess the association between dietary patterns and depressive symptoms. One standard deviation (SD) higher adherence in the DHD and DASH was associated with a lower hazard ratio (HR) of depressive symptoms with HRs (95%CI) of 0.78 (0.69–0.89) and 0.87 (0.77–0.98), respectively, after adjustment for sociodemographic and cardiovascular risk factors. After further adjustment for lifestyle factors, the HR per one SD higher DHD was 0.83 (0.73–0.96), whereas adherence to Mediterranean and DASH diets was not associated with incident depressive symptoms. Higher adherence to the DHD lowered risk of incident depressive symptoms. Adherence to healthy diet could be an effective non-pharmacological preventive measure to reduce the incidence of depression.

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Changes in Plant-Based Diet Quality and Total and Cause-Specific Mortality

Circulation ◽

10.1161/circulationaha.119.041014 ◽

2019 ◽

Vol 140 (12) ◽

pp. 979-991 ◽

Cited By ~ 11

Author(s):

Megu Y. Baden ◽

Gang Liu ◽

Ambika Satija ◽

Yanping Li ◽

Qi Sun ◽

...

Keyword(s):

Diet Quality ◽

Lower Risk ◽

Proportional Hazards ◽

Total Mortality ◽

Cox Proportional Hazards ◽

Environmental Benefits ◽

Health Study ◽

Specific Mortality ◽

Cvd Mortality

Background: Plant-based diets have been associated with lower risk of type 2 diabetes mellitus and cardiovascular disease (CVD) and are recommended for both health and environmental benefits. However, the association between changes in plant-based diet quality and mortality remains unclear. Methods: We investigated the associations between 12-year changes (from 1986 to 1998) in plant-based diet quality assessed by 3 plant-based diet indices (score range, 18–90)—an overall plant-based diet index (PDI), a healthful PDI, and an unhealthful PDI—and subsequent total and cause-specific mortality (1998–2014). Participants were 49 407 women in the Nurses’ Health Study (NHS) and 25 907 men in the Health Professionals Follow-Up Study (HPFS) who were free from CVD and cancer in 1998. Multivariable-adjusted Cox proportional-hazards models were used to estimate hazard ratios (HRs) and 95% CIs. Results: We documented 10 686 deaths including 2046 CVD deaths and 3091 cancer deaths in the NHS over 725 316 person-years of follow-up and 6490 deaths including 1872 CVD deaths and 1772 cancer deaths in the HPFS over 371 322 person-years of follow-up. Compared with participants whose indices remained stable, among those with the greatest increases in diet scores (highest quintile), the pooled multivariable-adjusted HRs for total mortality were 0.95 (95% CI, 0.90–1.00) for PDI, 0.90 (95% CI, 0.85–0.95) for healthful PDI, and 1.12 (95% CI, 1.07–1.18) for unhealthful PDI. Among participants with the greatest decrease (lowest quintile), the multivariable-adjusted HRs were 1.09 (95% CI, 1.04–1.15) for PDI, 1.10 (95% CI, 1.05–1.15) for healthful PDI, and 0.93 (95% CI, 0.88–0.98) for unhealthful PDI. For CVD mortality, the risk associated with a 10-point increase in each PDI was 7% lower (95% CI, 1–12%) for PDI, 9% lower (95% CI, 4–14%) for healthful PDI, and 8% higher (95% CI, 2–14%) for unhealthful PDI. There were no consistent associations between changes in plant-based diet indices and cancer mortality. Conclusions: Improving plant-based diet quality over a 12-year period was associated with a lower risk of total and CVD mortality, whereas increased consumption of an unhealthful plant-based diet was associated with a higher risk of total and CVD mortality.

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Abstract MP06: Healthy Diet Quality Is Associated With Epigenetic Age Deceleration

Circulation ◽

10.1161/circ.143.suppl_1.mp06 ◽

2021 ◽

Vol 143 (Suppl_1) ◽

Author(s):

Youjin Kim ◽

Jiantao Ma ◽

Daniel Levy

Keyword(s):

Diet Quality ◽

Healthy Eating Index ◽

Healthy Diet ◽

Mediation Effect ◽

Epigenetic Aging ◽

Epigenetic Age ◽

Heart Study ◽

Alternative Healthy Eating Index ◽

Epigenetic Age Acceleration ◽

Never Smokers

Introduction: Epigenetic age is a marker of healthy lifespan. Diet quality is known to be associated with the risk of developing chronic diseases; however, the relation between diet quality and epigenetic age remains to be investigated. Hypothesis: We tested the hypothesis that healthy diet quality is associated with favorable epigenetic age. Methods: Participants were drawn from the eighth examination of the Framingham Heart Study Offspring cohort ( n =1,995; mean age 67 years; 55% women). Diet quality was estimated using Alternative Healthy Eating Index (AHEI) and Mediterranean-style Diet Score (MDS) derived from food frequency questionnaire. A second generation of epigenetic age, DNA methylation GrimAge, was calculated. Epigenetic age acceleration (GrimAA) was derived as residual after adjustment for chronological age using linear regression model. Results and Conclusions: Higher AHEI and MDS (i.e., healthier diet) were associated with decreased GrimAA after adjusting for age, sex, body mass index, smoking, physical activity, alcohol consumption, and energy intake ( P < 0.001). We observed that the association of diet quality with GrimAA was stronger in ever-smokers (i.e., former and current smokers) compared to that in never-smokers ( P interaction < 0.001 for both scores). In ever-smokers, adjusted mean Grim AA was 3.95 years (95%CI: 3.47, 4.43) and 0.65 years (95%CI: 0.11, 1.19) in the lowest and highest AHEI quartile category, respectively, or GrimAA was reduced by 1.15 years (95%CI: 0.82, 1.48) per standard deviation (SD) increase in AHEI, P < 0.001. In never-smokers, adjusted mean GrimAA was -1.73 years (95%CI: -2.19, -1.26) and -2.37 years (95%CI: -2.80, 1.94) in the lowest and highest AHEI quartile category, respectively, or GrimAA was reduced by 0.23 years (95%CI: 0.05, 0.40) per SD increase in AHEI, P = 0.01. Similarly, for one SD increase in MDS, the GrimAA was reduced by 0.92 years (95%CI: 0.56, 1.27; P < 0.001) in ever-smokers, but by 0.19 years (95%CI: 0.01, 0.38; P = 0.04) in never-smokers. GrimAA significantly mediated the association between diet quality and all-cause mortality with the mean proportion of 37.0% for AHEI ( P mediation < 0.001) and 25.5% for MDS ( P mediation = 0.001). The mediation effect of GrimAA was more prominent in ever-smokers, which was twice the proportion found in never-smokers for both AHEI and MDS. In conclusion, higher diet quality is associated with decelerated epigenetic aging, which partially explains the beneficial relation of diet quality and healthy lifespan. These results also suggest that better diet quality could be more beneficial in ever-smokers.

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Dietary Antioxidant Vitamins and Minerals and Breast Cancer Risk: Prospective Results from the SUN Cohort

Antioxidants ◽

10.3390/antiox10030340 ◽

2021 ◽

Vol 10 (3) ◽

pp. 340

Author(s):

Cesar I. Fernandez-Lazaro ◽

Miguel Ángel Martínez-González ◽

Inmaculada Aguilera-Buenosvinos ◽

Alfredo Gea ◽

Miguel Ruiz-Canela ◽

...

Keyword(s):

Breast Cancer ◽

Vitamin E ◽

Proportional Hazards ◽

Natural Antioxidants ◽

Cox Proportional Hazards ◽

University Graduates ◽

Inverse Association ◽

The Sun ◽

Dietary Intakes

There is growing interest in natural antioxidants and their potential effects on breast cancer (BC). Epidemiological evidence, however, is inconsistent. We prospectively evaluated the association between dietary intake of vitamins A, C, and E, selenium, and zinc and BC among 9983 female participants from the SUN Project, a Mediterranean cohort of university graduates. Participants completed a food frequency questionnaire at baseline, and biennial follow-up information about incident BC diagnosis was collected. Cases were ascertained through revision of medical charts and consultation of the National Death Index. Cox proportional hazards models were used to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CI). During an average follow-up of 11.3 years, 107 incident BC cases were confirmed. The multivariable HRs (95% CI) for BC comparing extreme tertiles of energy-adjusted dietary intakes were 1.07 (0.64–1.77; Ptrend = 0.673) for vitamin A, 1.00 (0.58–1.71; Ptrend = 0.846) for vitamin C, 0.92 (0.55–1.54; Ptrend = 0.728) for vitamin E, 1.37 (0.85–2.20; Ptrend = 0.135) for selenium, and 1.01 (0.61–1.69; Ptrend = 0.939) for zinc. Stratified analyses showed an inverse association between vitamin E intake and postmenopausal BC (HRT3 vs. T1 = 0.35; 95% CI, 0.14–0.86; Ptrend = 0.027). Our results did not suggest significant protective associations between dietary vitamins A, C, and E, selenium, or zinc and BC risk.

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Risk of Endometrial Cancer and Frequencies of Invasive Endometrial Procedures in Young Breast Cancer Survivors Treated With Tamoxifen: A Nationwide Study

Frontiers in Oncology ◽

10.3389/fonc.2021.636378 ◽

2021 ◽

Vol 11 ◽

Author(s):

Soojeong Choi ◽

Young Jae Lee ◽

Jae Ho Jeong ◽

Jinhong Jung ◽

Jong Won Lee ◽

...

Keyword(s):

Breast Cancer ◽

Endometrial Cancer ◽

Cancer Survivors ◽

Breast Cancer Survivors ◽

Proportional Hazards ◽

Postmenopausal Breast Cancer ◽

Cox Proportional Hazards ◽

Close Monitoring ◽

Increased Risk ◽

Young Breast Cancer

BackgroundAlthough the guidelines recommend gynecological assessment and close monitoring for symptoms of endometrial cancer in postmenopausal breast cancer survivors taking tamoxifen (TAM), the risk of endometrial cancer in young breast cancer survivors has not yet been fully assessed. This study aimed to investigate the risk of developing endometrial cancer and the frequencies of gynecological examinations in young breast cancer survivors taking TAM in South Korea.MethodsA nationwide retrospective cohort study was conducted using the Health Insurance Review and Assessment Service claims data. Kaplan–Meier analyses and log-rank tests were used to assess the probability of endometrial cancer, benign endometrial conditions, and the probability of invasive endometrial procedure. To analyze the risk of endometrial cancer and benign endometrial conditions, we used a multivariable Cox proportional hazards regression model.ResultsBetween 2010 and 2015, 60,545 newly diagnosed female breast cancer survivors were included. The total person–years were 256,099 and 140 (0.23%) patients developed endometrial cancer during the study period. In breast cancer survivors aged ≥60 years [hazard ratio (HR), 5.037; 95% confidence interval (CI), 2.185–11.613], 50–59 years (HR, 4.343; 95% CI, 2.122–8.891), and 40–49 years (HR, 2.121; 95% CI, 1.068–4.213), TAM was associated with an increased risk of endometrial cancer. In subjects aged below 40 years, TAM did not significantly increase the risk of endometrial cancer. However, among the TAM subgroups, breast cancer survivors aged below 40 years [1.61 per 1,000 person–years (PY); HR, 12.460; 95% CI, 2.698–57.522] and aged 40–49 years (2.22 per 1,000 PY; HR, 9.667; 95% CI, 4.966–18.819) with TAM-related endometrial diseases showed significantly increased risks of endometrial cancer. Among the TAM subgroup with benign endometrial conditions, the ratios of the frequency of invasive diagnostic procedures to the incidence of endometrial cancer were higher in subjects under 40 than subjects aged 60 or more.ConclusionYoung breast cancer survivors with TAM-related benign endometrial diseases are at a higher risk of developing endometrial cancer. Gynecological surveillance should be tailored to the risk of endometrial cancer in young breast cancer survivors to improve the early detection of endometrial cancer and avoid unnecessary invasive procedures.

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Adjuvant endocrine monotherapy (ET) versus adjuvant breast radiation (RT) alone in healthy older women with stage I, estrogen receptor-positive (ER+) breast cancer: An analysis of the National Cancer Database (NCDB).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.519 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 519-519

Author(s):

Anthony H. Bui ◽

Manjeet Chadha ◽

Theresa H. Shao ◽

Naamit K. Gerber ◽

Sarah P. Cate ◽

...

Keyword(s):

Breast Cancer ◽

Older Women ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Stage I ◽

Nccn Guidelines ◽

Treatment Groups ◽

Distant Relapse ◽

Demographic Covariates

519 Background: The NCCN guidelines state that breast RT may be omitted in patients > 70 years of age with ER+, clinically node-negative, T1 breast cancer (BC) who receive adjuvant ET. Available data on older patients notes that local relapses are the most frequent site of failure, and distant relapse rates are low. The side effects of ET are not inconsequential and negatively affect QOL. The objectives of this study are to examine clinical outcomes including overall survival (OS) in women ≥70 years of age treated by lumpectomy(L)+ET and L+RT in the NCDB. Methods: The 2004-2013 NCDB includes 76,431 women ≥70 years with ER+ stage I BC who underwent L, and had a minimum one year follow up. Women who received no adjuvant therapy, both ET+RT, or any chemotherapy were excluded. To limit the analysis to healthy women, we excluded subjects with a Charlson comorbidity index > 0. We identified 24,572 patients who received either adjuvant ET monotherapy or adjuvant RT alone. Among these, 46% (11,313) received ET and 54% (13,259) breast RT. Overall median follow up was 57 months (range: 12-143 months). Analysis of OS between the 2 treatment groups was performed using Kaplan-Meier statistics and Cox proportional hazards regression; propensity weighting was used to balance covariates across the 2 treatment groups. Results: After propensity weighting, demographic covariates including age, race, insurance, and facility type were balanced between the 2 treatment groups. The median OS for ET was 125.9 months (95% CI 120.1-131.8), and 127.2 months for RT (95% CI 124.5-131.7) (p < 0.0001). The weighted hazard of death was 11.7% less in women receiving RT compared to ET (HR 0.883, 95% CI 0.834-0.936, p < 0.0001). Conclusions: To our knowledge, this is the first large study comparing RT and ET monotherapy in healthy older women with stage I, ER+ BC. The OS with RT alone is not inferior to ET alone, and in this study population is noted to be better. While this analysis has various limitations not dissimilar from other NCDB database studies, our observations are encouraging and warrant further research with prospective studies.

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Use of postmenopausal hormone therapies and risk of histology- and hormone receptor-defined breast cancer: results from a 15-year prospective analysis of NIH-AARP cohort

Breast Cancer Research ◽

10.1186/s13058-020-01365-9 ◽

2020 ◽

Vol 22 (1) ◽

Author(s):

Shao-Ming Wang ◽

Ruth M. Pfeiffer ◽

Gretchen L. Gierach ◽

Roni T. Falk

Keyword(s):

Breast Cancer ◽

Hormone Receptor ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Models ◽

Estrogen Plus Progestin ◽

Continued Use ◽

Progestin Therapy

Abstract Background Menopausal hormone therapy (MHT) increases breast cancer (BC) risk, but cohort studies largely consider use only at enrollment. Evidence is limited on how changes in MHT use alter the magnitude of risk, and whether risk varies between invasive and in situ cancer, by histology or by hormone receptor status. Methods We investigated the roles of estrogen-alone therapy (ET) and estrogen plus progestin therapy (EPT) on BC risk overall, by histology and estrogen receptor (ER) and progesterone receptor (PR) status, and on incidence of in situ disease, in the NIH-AARP cohort. Participants included 118,760 postmenopausal women (50–71 years), of whom 63.5% (n = 75,398) provided MHT use information at baseline in 1996 and in a follow-up survey in 2004, subsequent to the dissemination in 2002 of the Women’s Health Initiative trial safety concerns regarding EPT. ET analyses included 50,476 women with hysterectomy (31,439 with follow-up data); EPT analyses included 68,284 women with intact uteri (43,959 with follow-up data). Adjusted hazard ratios (HRs) were estimated using Cox proportional hazards models using age as the time metric with follow-up through 2011. Results Eight thousand three hundred thirty-three incident BC cases were accrued, 2479 in women with follow-up data. BC risk was not elevated in current ET users at baseline (HR = 1.05, 95% confidence interval [CI] CI = 0.95–1.16) but was higher in women continuing use through 2004 (HR = 1.35, 95% CI = 1.04–1.75). Ever EPT use at baseline was associated with elevated BC risk overall (HR = 1.54 (1.44–1.64), with a doubling in risk for women with 10 or more years of use, for in situ disease, and across subtypes defined by histology and ER/PR status (all p < 0.004). Risk persisted in women who continued EPT through 2004 (HR = 1.80, 95% CI = 1.39–2.32). In contrast, no association was seen in women who discontinued EPT before 2004 (HR = 1.14, 95% CI = 0.99–1.30). Conclusions ET use was not associated with BC risk in this cohort, although excess risk was suggested in women who continued use through 2004. EPT use was linked to elevated in situ and invasive BC risk, and elevated risk across invasive BC histologic and hormone receptor-defined subtypes, with the highest risk for women who continued use through the 2004 follow-up survey.

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Aspirin use and mortality in women with stage I-III breast cancer: A population-based study.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.521 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 521-521

Author(s):

Thomas Ian Barron ◽

Linda Sharp ◽

Kathleen Bennett ◽

Kala Visvanathan

Keyword(s):

Breast Cancer ◽

Exposure Duration ◽

Proportional Hazards ◽

Early Stage ◽

Cox Proportional Hazards ◽

Stage I ◽

Response Analysis ◽

Limited Information ◽

Specific Mortality

521 Background: Recent observational studies have associated aspirin (ASP) use with large reductions in breast cancer (BC) mortality. However, these studies have provided limited information on dose or duration of ASP use, key issues relevant to translation of the results into clinical practice. Methods: Linked National Cancer Registry Ireland and prescription refill data (General Medical Services Ireland, GMS) were used to identify women aged 50-80 with incident stage I-III BC (2001-2006). ASP use was defined as high or low by the median number of ASP days’ supply (85 days) in the 90 days pre-diagnosis. Full capture of ASP use is expected as the GMS provides all medications, including ASP, without charge. Hazard ratios (HR) with 95% confidence intervals (CI) for ASP use and (i) all-cause and (ii) BC-specific mortality were estimated using Cox proportional hazards models adjusted for age, stage, grade, ER, PR, HER-2 status, comorbidity and other drug exposures. Analyses were stratified by tumor stage and nodal status. Results: 2714 women with stage I-III BC were identified (median follow-up = 3.3 years), of whom 642 (23.7%) used ASP in the 90 days pre diagnosis. High and low ASP exposure groups were strongly predictive of post-diagnosis ASP exposure levels (High: mean post diagnosis exposure duration – 83% of follow-up; dose – 75mg/day in 91% of women. Low: mean post-diagnosis exposure duration – 58% of follow-up; dose – 75mg/day in 80% of women). Women with any ASP use had a non-significant reduction in all-cause (HR 0.85 95%CI 0.68, 1.06) and BC-specific (HR 0.86 95%CI 0.65, 1.15) mortality, compared to ASP unexposed women. However, in the dose response analysis high ASP exposure was associated with a significant reduction in all-cause (HR 0.70 95% CI 0.51, 0.95) and BC-specific (HR 0.63 95% CI 0.42, 0.96) mortality. No reduction was observed for low ASP exposure. The benefits of ASP exposure were greater in early stage, node negative disease. Conclusions: Only high ASP exposure was associated with a significant reduction in all cause and BC-specific mortality. These findings may explain inconsistent results from previous studies. Our findings can inform future clinical trials.

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Breast Cancer Systemic Treatments and Upper Limb Lymphedema: A Risk-Assessment Platform Encompassing Tumor-Specific Pathological Features Reveals the Potential Role of Trastuzumab

Journal of Clinical Medicine ◽

10.3390/jcm8020138 ◽

2019 ◽

Vol 8 (2) ◽

pp. 138 ◽

Cited By ~ 7

Author(s):

Marco Invernizzi ◽

Anna Michelotti ◽

Marianna Noale ◽

Gianluca Lopez ◽

Letterio Runza ◽

...

Keyword(s):

Breast Cancer ◽

Risk Assessment ◽

Proportional Hazards ◽

Growth Factor Receptor ◽

Cox Proportional Hazards ◽

Breast Cancers ◽

Pathological Features ◽

Systemic Treatments

Breast cancer related lymphedema (BCRL) is frequent but strategies for an individualized risk assessment are lacking. We aimed to define whether tumor-specific pathological features, coupled with clinical and therapeutic data, could help identify patients at risk. Data from 368 patients with node-positive breast cancers were retrospectively collected, including 75 patients with BCRL (0.4–25.6 years follow-up). BCRL was assessed during the standard follow-up oncology visits using the circumferential measurement. Clinicopathologic and therapeutic factors associated with BCRL were integrated into a Cox proportional hazards regression model. Lymphovascular invasion (LVI) was more common in BCRL patients (n = 33, 44% vs. n = 85, 29%, p = 0.01), akin extra nodal extension (ENE) of the metastasis (n = 57, 76% vs. n = 180, 61%, p = 0.02). Sentinel lymph node excision without axillary dissection and extra-axillary radiotherapy were BCRL-unrelated. A higher number of BCRL-positive patients were treated with taxane-based chemotherapy with or without trastuzumab, compared to BCRL-negative patients (p < 0.01). Treatment with trastuzumab and/or taxanes, adjusted for systemic infections, laterality, therapy, and pathological features (i.e., LVI and ENE), had a significant impact in BCRL-free survival (p < 0.01). This work offers new insights on BCRL risk stratification, where the integration of clinical, therapeutic, and tumor-specific pathological data suggests a possible role of anti-human epidermal growth factor receptor 2 (HER2) therapy in BCRL pathogenesis.

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

Breast Cancer Research ◽

10.1186/s13058-020-01347-x ◽

2020 ◽

Vol 22 (1) ◽

Author(s):

Siker Kimbung ◽

Maria Inasu ◽

Tor Stålhammar ◽

Björn Nodin ◽

Karin Elebro ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Proportional Hazards ◽

Tumor Biology ◽

Cox Proportional Hazards ◽

Receptor Expression ◽

Cancer Specific Survival ◽

Swedish Population ◽

Estrogen Receptor Positive

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.

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