Risk of fatty liver after long-term use of tamoxifen in patients with breast cancer

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Abstract

Background

Few studies report the effects of tamoxifen intake and the occurrence of de novo fatty liver and the deterioration of existing fatty liver. The aim of this study was to investigate the effects of tamoxifen on fatty change of liver over time and also the impact of fatty liver on the prognosis of patients with breast cancer.

Methods

This was a single-center, retrospective study of patients who were diagnosed with primary breast cancer from January 2007 to July 2017. 911 consecutive patients were classified into three groups according to treatment method: tamoxifen group, aromatase inhibitor (AI) group, and control group.

Results

Median treatment duration was 49 months (interquartile range, IQR; 32–58) and median observational period was 85 months ( IQR; 50–118). Long-term use of tamoxifen significantly aggravated fatty liver status compared to AI or control groups [hazard ratio ( HR): 1.598, 95% confidence interval ( CI): 1.173–2.177, P = 0.003] after adjusting other factors. When analyzed separately depending on pre-existing fatty liver at baseline, tamoxifen was involved in the development of de novo fatty liver [ HR: 1.519, 95% CI: 1.100–2.098, P = 0.011) and had greater effect on fatty liver worsening ( HR: 2.103, 95% CI: 1.156–3.826, P = 0.015). However, the progression of fatty liver did not significantly affect the mortality of breast cancer patients.

Conclusions

Tamoxifen had a significant effect on the fatty liver status compared to other treatment modalities in breast cancer patients. Although fatty liver did not affect the prognosis of breast cancer, meticulous attention to cardiovascular disease or other metabolic disease should be paid when used for a long time.

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Most cited references 22

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Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group.

Michael Gnant, Adrian Harris (1998)

There have been many randomised trials of adjuvant tamoxifen among women with early breast cancer, and an updated overview of their results is presented. In 1995, information was sought on each woman in any randomised trial that began before 1990 of adjuvant tamoxifen versus no tamoxifen before recurrence. Information was obtained and analysed centrally on each of 37000 women in 55 such trials, comprising about 87% of the worldwide evidence. Compared with the previous such overview, this approximately doubles the amount of evidence from trials of about 5 years of tamoxifen and, taking all trials together, on events occurring more than 5 years after randomisation. Nearly 8000 of the women had a low, or zero, level of the oestrogen-receptor protein (ER) measured in their primary tumour. Among them, the overall effects of tamoxifen appeared to be small, and subsequent analyses of recurrence and total mortality are restricted to the remaining women (18000 with ER-positive tumours, plus nearly 12000 more with untested tumours, of which an estimated 8000 would have been ER-positive). For trials of 1 year, 2 years, and about 5 years of adjuvant tamoxifen, the proportional recurrence reductions produced among these 30000 women during about 10 years of follow-up were 21% (SD 3), 29% (SD 2), and 47% (SD 3), respectively, with a highly significant trend towards greater effect with longer treatment (chi2(1)=52.0, 2p<0.00001). The corresponding proportional mortality reductions were 12% (SD 3), 17% (SD 3), and 26% (SD 4), respectively, and again the test for trend was significant (chi2(1) = 8.8, 2p=0.003). The absolute improvement in recurrence was greater during the first 5 years, whereas the improvement in survival grew steadily larger throughout the first 10 years. The proportional mortality reductions were similar for women with node-positive and node-negative disease, but the absolute mortality reductions were greater in node-positive women. In the trials of about 5 years of adjuvant tamoxifen the absolute improvements in 10-year survival were 10.9% (SD 2.5) for node-positive (61.4% vs 50.5% survival, 2p<0.00001) and 5.6% (SD 1.3) for node-negative (78.9% vs 73.3% survival, 2p<0.00001). These benefits appeared to be largely irrespective of age, menopausal status, daily tamoxifen dose (which was generally 20 mg), and of whether chemotherapy had been given to both groups. In terms of other outcomes among all women studied (ie, including those with "ER-poor" tumours), the proportional reductions in contralateral breast cancer were 13% (SD 13), 26% (SD 9), and 47% (SD 9) in the trials of 1, 2, or about 5 years of adjuvant tamoxifen. The incidence of endometrial cancer was approximately doubled in trials of 1 or 2 years of tamoxifen and approximately quadrupled in trials of 5 years of tamoxifen (although the number of cases was small and these ratios were not significantly different from each other). The absolute decrease in contralateral breast cancer was about twice as large as the absolute increase in the incidence of endometrial cancer. Tamoxifen had no apparent effect on the incidence of colorectal cancer or, after exclusion of deaths from breast or endometrial cancer, on any of the other main categories of cause of death (total nearly 2000 such deaths; overall relative risk 0.99 [SD 0.05]). For women with tumours that have been reliably shown to be ER-negative, adjuvant tamoxifen remains a matter for research. However, some years of adjuvant tamoxifen treatment substantially improves the 10-year survival of women with ER-positive tumours and of women whose tumours are of unknown ER status, with the proportional reductions in breast cancer recurrence and in mortality appearing to be largely unaffected by other patient characteristics or treatments.

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Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis.

Eitan Amir, Saroj Niraula, Alberto Ocana … (2011)

Aromatase inhibitors are associated with consistent improvements in disease-free survival but not in overall survival. We conducted a literature-based meta-analysis of randomized trials to examine whether the relative toxicity of aromatase inhibitors compared with tamoxifen may explain this finding. We conducted a systematic review to identify randomized controlled trials that compared aromatase inhibitors and tamoxifen as primary adjuvant endocrine therapy in postmenopausal women by searching MEDLINE, EMBASE, and databases of the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium. Odds ratios (ORs), 95% confidence intervals (CIs), absolute risks, and the number needed to harm associated with one adverse event were computed for prespecified serious adverse events including cardiovascular disease, cerebrovascular disease, bone fractures, thromboembolic events, endometrial carcinoma and other second cancers not including new breast cancer. All statistical tests were two-sided. Seven trials enrolling 30,023 patients met the inclusion criteria. Longer duration of aromatase inhibitor use was associated with increased odds of developing cardiovascular disease (OR = 1.26, 95% CI = 1.10 to 1.43, P < .001; number needed to harm = 132) and bone fractures (OR = 1.47, 95% CI = 1.34 to 1.61, P < .001; number needed to harm = 46), but a decreased odds of venous thrombosis (OR = 0.55, 95% CI = 0.46 to 0.64, P < .001; number needed to harm = 79) and endometrial carcinoma (OR = 0.34, 95% CI = 0.22 to 0.53, P < .001; number needed to harm = 258). Five years of aromatase inhibitors was associated with a non-statistically significant increased odds of death without recurrence compared with 5 years of tamoxifen alone or tamoxifen for 2-3 years followed by an aromatase inhibitor for 2-3 years (OR = 1.11, 95% CI = 0.98 to 1.26, P = .09). The cumulative toxicity of aromatase inhibitors when used as up-front treatment may explain the lack of overall survival benefit despite improvements in disease-free survival. Switching from tamoxifen to aromatase inhibitors reduces this toxicity and is likely the best balance between efficacy and toxicity.

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Macrovesicular hepatic steatosis in living liver donors: use of CT for quantitative and qualitative assessment.

Seong Ho Park, Pyo Nyun Kim, Kyoung Won Kim … (2006)

To determine prospectively the diagnostic performance of unenhanced computed tomography (CT) in the assessment of macrovesicular steatosis in potential donors for living donor liver transplantation by using same-day biopsy as a reference standard. Institutional review board approval and informed consent were obtained. A total of 154 candidates, including 104 men (mean age, 30.2 years +/- 10.3 [standard deviation]) and 50 women (mean age, 31.8 years +/- 11.2), underwent same-day unenhanced CT and ultrasonography-guided liver biopsy. Histologic degree of macrovesicular steatosis was determined. Three liver attenuation indices were derived: liver-to-spleen attenuation ratio (CT(L)(/S)), difference between hepatic and splenic attenuation (CT(L)(-S)), and blood-free hepatic parenchymal attenuation (CT(LP)). Regression equations were used to quantitatively estimate the degree of macrovesicular steatosis. Limits of agreement between estimated macrovesicular steatosis and the reference standard were calculated. Receiver operating characteristic analyses were used to determine the performance of each index for qualitative diagnosis of macrovesicular steatosis of 30% or greater. The cutoff value that provided a balance between sensitivity and specificity and the highest cutoff value that yielded 100% specificity were determined. Limits of agreement were -14% to 14% for CT(L)(/S) and CT(L)(-S) and -13% to 13% for CT(LP). Performance in diagnosing macrovesicular steatosis of 30% or greater was not significantly different among indices (P > .05). Cutoff values of 0.9, -7, and 58 were determined for CT(L)(/S), CT(L)(-S), and CT(LP), respectively, and provided a balance between sensitivity and specificity. Cutoff values of 0.8, -9, and 42 were determined for CT(L)(/S), CT(L)(-S), and CT(LP), respectively, and yielded 100% specificity for all indices, with corresponding sensitivities of 82%, 82%, and 73% for CT(L)(/S), CT(L)(-S), and CT(LP), respectively. Diagnostic performance of unenhanced CT for quantitative assessment of macrovesicular steatosis is not clinically acceptable. Unenhanced CT, however, provides high performance in qualitative diagnosis of macrovesicular steatosis of 30% or greater.

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Author and article information

Contributors

Jeong-Ju Yoo: Role: ConceptualizationRole: Formal analysisRole: Writing – original draftRole: Writing – review & editing

Yong Seok Lim: Role: Investigation

Min Sung Kim: Role: InvestigationRole: Methodology

Bora Lee: Role: Formal analysisRole: MethodologyRole: ValidationRole: Visualization

Bo-Yeon Kim: Role: Supervision

Zisun Kim: Role: Conceptualization

Ji Eun Lee: Role: Methodology

Min Hee Lee: Role: Methodology

Sang Gyune Kim:

ORCID: http://orcid.org/0000-0001-8694-777X

Role: ConceptualizationRole: ValidationRole: Writing – review & editing

Young Seok Kim:

ORCID: http://orcid.org/0000-0002-7113-3623

Role: Supervision

Hakan Buyukhatipoglu: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 30 July 2020

Publication date Collection: 2020

Volume: 15

Issue: 7

Electronic Location Identifier: e0236506

Affiliations

[1 ] Division of Gastroenterology and Hepatology, Department of Internal Medicine, Soonchunhyang University School of Medicine Bucheon Hospital, Bucheon, Korea

[2 ] Department of Internal Medicine, Soonchunhyang University Gumi Hospital, Gumi, Korea

[3 ] Department of Biostatistics, Graduate School of Chung-Ang University, Seoul, Republic of Korea

[4 ] Division of Endocrinology, Department of Internal Medicine, Soonchunhyang University School of Medicine Bucheon Hospital, Bucheon, Korea

[5 ] Department of Surgery, Soonchunhyang University School of Medicine Bucheon Hospital, Bucheon, Korea

[6 ] Department of Radiology, Soonchunhyang University School of Medicine Bucheon Hospital, Bucheon, Korea

Harran Universitesi, UNITED STATES

Author notes

Competing Interests: The authors have declared that no competing interests exist.

* E-mail: mcnulty@ 123456schmc.ac.kr

Author information

Sang Gyune Kim http://orcid.org/0000-0001-8694-777X

Young Seok Kim http://orcid.org/0000-0002-7113-3623

Article

Publisher ID: PONE-D-20-05309

DOI: 10.1371/journal.pone.0236506

PMC ID: 7392315

PubMed ID: 32730287

SO-VID: 122dfa67-d757-4962-9172-70e428f5a855

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 24 February 2020

Date accepted : 7 July 2020

Page count

Figures: 2, Tables: 6, Pages: 16

Funding

The author(s) received no specific funding for this work.

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Data Availability All relevant data are within the manuscript and its Supporting Information files.

Risk of fatty liver after long-term use of tamoxifen in patients with breast cancer

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Abstract

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Most cited references 22

Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group.

Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis.

Macrovesicular hepatic steatosis in living liver donors: use of CT for quantitative and qualitative assessment.

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