Risk of fatty liver and hepatic fibrosis associated with long-term use of tamoxifen or anastrozole may be overestimated in patients with breast cancer

doi:10.21203/rs.3.rs-4185141/v1

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Risk of fatty liver and hepatic fibrosis associated with long-term use of tamoxifen or anastrozole may be overestimated in patients with breast cancer

https://doi.org/10.21203/rs.3.rs-4185141/v1

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Background

Nonalcoholic fatty liver disease (NAFLD) is prevalent among women with breast cancer. The impact of endocrine therapy on the severity and progression of NAFLD in the long term remains unclear.

Aims

To assess the prevalence and severity of NAFLD related to hormone therapy for breast cancer, and to investigate risk factors associated with its occurrence and progression.

Methods

Cross-sectional study recruited women with breast cancer. Abdominal ultrasound was used to detect liver steatosis, and transient elastography to evaluate fibrosis.

Results

171 patients were enrolled – mean age 58 ± 10 years and follow-up period 1-315 months (median 53, interquartile range 25–102). Comorbidities: diabetes (26.9%), hypertension (53.2%), dyslipidemia (31.0%) and obesity (70.2%). Four groups were formed: 55 (32.2%) patients unexposed to hormone therapy, 72 (42.1%) exposed only to tamoxifen, 16 (9.4%) only to anastrozole, and 28 (16.4%) to both drugs. Liver steatosis was detected in 57.9%, with no significant differences between groups (p = 0.092). Liver stiffness was similar between groups: median 5.4 kPa (p = 0.200), 12.3% with liver stiffness ≥ 8 Kpa (p = 0.568) and 5.8% ≥12 Kpa (p = 0.177). Diabetes was independently associated with steatosis, and metabolic syndrome with advanced fibrosis, even after adjustment for hormone therapy duration.

Conclusion

More than half of patients had NAFLD, and approximately 10% had advanced fibrosis. Metabolic risk factors were independently associated with occurrence and progression of NAFLD, regardless of hormone therapy exposure. The risk of NAFLD induced by tamoxifen and anastrozole seems to have been previously overestimated.

hormone therapy

steatotic liver disease

liver fibrosis

cirrhosis

elastography

Nonalcoholic fatty liver disease (NAFLD) is an overarching term encompassing the spectrum of simple hepatic steatosis and steatohepatitis, which can progress to liver fibrosis, cirrhosis, and hepatocellular carcinoma. Its global prevalence has been estimated at around 25–30% worldwide[1] and is progressively rising in parallel with the increasing prevalence of metabolic syndrome. Recently, it has been reported that a significant proportion of patients with breast cancer have NAFLD [2, 3]. Postmenopausal women experience metabolic changes such as an increase in visceral adiposity, dyslipidemia and glucose intolerance, which may play a role in NAFLD pathogenesis. However, the use of endocrine therapy directed towards breast cancer has been suggested to be a major independent risk factor for NAFLD [4, 5]. It is estimated that 40–50% of patients using tamoxifen – a selective estrogen receptor modulator – present with NAFLD [4, 6–8]. This finding was recently corroborated by a metanalysis, especially in patients with a high body-mass index (BMI) and hypercholesterolemia [9]. In fact, other modalities of hormone therapy, such as androgen inhibitors, have also been associated with NAFLD occurrence [4, 10]. The prevalence of progressive forms of NAFLD is still unknown, as the frequency of steatohepatitis and fibrosis staging has not been properly investigated in previous studies. Therefore, the clinical relevance of NAFLD in patients with breast cancer is still uncertain. This information is crucial for further recommendations on NAFLD screening, and the identification of high-risk NAFLD subgroups among patients receiving endocrine therapy could guide oncologists in deciding the best treatment options. With advances in diagnosis and treatment of breast cancer, improvement in survival rates has been observed, making the investigation of liver disease impact in the long term extremely relevant for disease management. This study aims to evaluate the prevalence and severity of NAFLD in women with breast cancer and to investigate pharmacological and metabolic risk factors associated with NAFLD occurrence and progression.

Study design and participants selection

A cross-sectional study was conducted at the oncology outpatient clinic of the Hospital das Clínicas of the Federal University of Minas Gerais, Belo Horizonte, Brazil. Female patients older than 18 years with a histopathological diagnosis of breast cancer were consecutively enrolled.

Data collected included demographics, follow-up time since cancer diagnosis, metabolic comorbidities and laboratory exams (i.e., transaminases, serum albumin, international normalized ratio, total cholesterol and lipoproteins and complete blood cell count). Patients were divided into four groups: (1) patients who had not been exposed to hormone therapy until the time of enrollment – because it was not indicated, i.e., absence of hormone receptor in cancer immunohistochemistry, or because it was indicated, but not yet initiated; (2) patients exposed only to tamoxifen, currently or previously; (3) those exposed only to anastrozole, currently or previously; and (4) those exposed to both drugs – hormone therapy modality was changed due to adverse effects or intolerance. Exposure time to hormone therapy was collected and only patients who received at least 3 months of hormone therapy were included in groups 2, 3 and 4.

An abdominal ultrasound was performed in all patients by the same examinator to detect hepatic steatosis, and a transient elastography (Fibroscan®) was performed by trained examinators to assess liver stiffness. Cutoffs of 8 kPa and 12 kPa were set for analyzing advanced fibrosis and cirrhosis, respectively, based on previous studies [11].

Exclusion criteria were as follows: alcohol related liver disease, chronic viral hepatitis B or C, current or past diagnosis of other cancer, metastatic breast cancer, right heart failure, alcohol intake > 20 g/day, aminotransferases > 5 times de upper limit of normality, inability to perform elastography with the adequate technique, refusal to undergo study’s procedures and use of other drugs known to be associated with steatotic liver disease, such as amiodarone, valproic acid and methotrexate.

This study was approved by the Federal University of Minas Gerais Ethics Committee Board (CAAE 48790721.5.0000.5149) and individual informed consent was obtained from all patients.

2.4 Transient elastography evaluation

Liver stiffness measurements were performed using a Fibroscan® 402 (Echosens, Paris, France). Experienced operators performed the exam in patients with at least three hours of fasting. Subjects assumed dorsal decubitus position with the right arm on maximal abduction. Probe size M or XL were used, as appropriate according to body-mass index status, and placed over the right liver lobe through intercostal spaces. The exam was considered adequate when, for each liver evaluation, 10 valid measurements were performed with success rate ≥ 80% and interquartile range < 30% of the median value. LSM were defined by the median value of the obtained measurements.

2.6 Statistical analysis

Analyses were performed using the software SPSS version 23.0, Armonk, NY. Shapiro-Wilk test was used to assess continuous variables for normal distribution, and those with gaussian distribution were expressed as mean ± standard deviation (SD), whereas those with skewed distribution were described as median and interquartile range (IQR). Categorical variables were expressed as absolute numbers and percentages. For univariate analysis of categorical variables, we utilized the chi-square or Fisher’s exact test, as appropriate. For continuous variables, we compared the data using the analysis of variance (ANOVA) or Student t-test if distribution was normal, and the Kruskal-Wallis or Mann-Whitney test for skewed data. Variables with clinical relevance which had p-value < 0.20 in univariate analysis were selected to logistic regression multivariate analysis by the backwards method. Absence of multicollinearity between independent variables was a prerequisite to logistic regression. Odds ratio (OR) and 95% confidence interval (95%CI) were reported. P-values < 0.05 were considered significant.

The initial cohort comprised 235 patients; however, 11 were excluded due to an inability to undergo elastography using the appropriate technique, and 53 declined to participate in an imaging examination to investigate signs of steatosis. Ultimately, 171 patients, with a mean age of 58 ± 10 years, were enrolled, and the follow-up period ranged from 1 to 315 months (median 53, IQR 25–102). Common comorbidities included diabetes mellitus (26.9%), arterial hypertension (53.2%), dyslipidemia (31.0%), and central obesity (70.2%). A detailed description of cohort characteristics is provided in Table 1.

Table 1

Cohort characteristics and comparison between patients exposed to tamoxifen, exposed to anastrozole, exposed to both drugs and non-exposed to hormone therapy
Variables	Cohort (n = 171)	Tamoxifen only (n = 72)	Anastrozole only (n = 16)	Anastrozole and tamoxifen (n = 28)	No-HT (n = 55)	P-Value
Age (yrs.)	58 ± 10	56 ± 8	68 ± 8*	59 ± 9	57 ± 11	< 0.001^†
Cancer follow-up (mo.)	53 (25–102)	61 (37–112)	41 (29–57)	75 (50–103)	25 (9–93)*	< 0.001^‡
Exposition to HT (mo.)	41 (27–60)	51 (23–60)	25 (22–32)*	57 (39–65)	–	0.002^‡
Metabolic profile:
Diabetes	46 (26.9)	18 (25.0)	7 (43.8)	7 (25.0)	14 (25.5)	0.466^§
Hypertension	91 (53.2)	32 (44.4)	11 (68.8)	31 (56.4)	17 (60.7)	0.201^§
Dyslipidemia	53 (31.0)	19 (26.4)	8 (50.0)	11 (39.3)	15 (27.3)	0.197^§
Metabolic syndrome	79 (46.2)	28 (38.9)	9 (56.3)	15 (53.6)	27 (49.1)	0.392^§
BMI (kg/m²)	29 (26–34)	29 (26–34)	29 (26–34)	30 (26–33)	29 (24–35)	0.951^‡
WC (cm)	96 ± 14	94 ± 13	103 ± 20	97 ± 12	94 ± 15	0.222^†
Central obesity	120 (70.2)	48 (66.7)	13 (81.3)	22 (78.6)	37 (67.3)	0.471^‡
Liver assessment:
Fatty liver	99 (57.9)	49 (68.1)	10 (62.5)	13 (46.4)	27 (49.1)	0.092^§
Liver stiffness (m/s)	5.4 (4.3–6.8)	5.4 (4.4–7.4)	6.1 (4.8–6.5)	5.2 (4.3–7.5)	5.2 (4.1–6.4)	0.200^‡
≥ 8 kPa	21 (12.3)	11 (15.3)	2 (12.5)	4 (14.3)	4 (7.3)	0.568^¶
≥ 12 kPa	10 (5.8)	6 (8.3)	2 (12.5)	2 (12.5)	2 (3.6)	0.177^¶
Laboratory:
AST (U/L)	27 (23–32)	26 (23–31)	28 (23–29)	28 (23–34)	28 (23–32)	0.940^‡
ALT (U/L)	20 (16–27)	21 (17–26)	20 (16–27)	21 (17–32)	20 (15–27)	0.670^‡
AP (U/L)	81 (66–103)	72 (60–86)*	107 (84–150)	85 (74–116)	84 (66–104)	< 0.001^‡
GGT (U/L)	33 (24–45)	32 (24–41)	33 (25–58)	36 (26–48)	34 (22–50)	0.391^‡
Total cholesterol (mg/dL)	212 ± 44	203 ± 39	249 ± 50	220 ± 39	211 ± 47	0.003^†
LDL-c (mg/dL)	119 (93–142)	108 (75–132)	166 (134–180)*	128 (98–139)	116 (94–152)	< 0.001^‡
HDL-c (mg/dL)	60 ± 18	64 ± 20	53 ± 9	59 ± 15	58 ± 19	0.154^†
Triglycerides (mg/dL)	136 (99–194)	127 (99–180)	165 (129–192)	133 (98–218)	139 (93–202)	0.683^‡
Data are expressed as: absolute number (percentage), mean ± standard deviation or median (interquartile range). ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; BMI, body-mass index; GGT, gamma-glutamyl transferase; HDL-c, high density lipoprotein cholesterol; HT, hormone therapy; LDL-c, low density lipoprotein cholesterol; Mo., months; WC, waist circumference; Yrs., years. Tests used: ^†ANOVA, ^‡Kruskal-Wallis, ^§Chi-square, ^¶Fisher’s exact test. *Post-hoc analysis’ associated variable.

In total, 55 (32.2%) patients did not receive hormone therapy. Of the remaining participants, 72 (42.1%) were exclusively exposed to tamoxifen for a median duration of 51 months (IQR 23–60), 16 (9.4%) exclusively to anastrozole for a median duration of 25 months (IQR 22–32), and 28 (16.4%) received both drugs for a median duration of 57 months (IQR 39–65).

Liver steatosis was detected in 57.9% of the patients, with no statistically significant differences observed among the four groups (p = 0.092). In a univariate analysis comparing women with steatotic liver versus those without steatosis (Table 2), factors associated with the occurrence of fatty liver disease included: diabetes (37.4% vs. 12.5%, p < 0.001), hypertension (63.6% vs. 38.9%, p = 0.001), dyslipidemia (38.4% vs. 20.8%, p = 0.014), metabolic syndrome (53.5% vs. 36.1%, p = 0.024), BMI (31 vs. 28 kg/m², p = 0.001), waist circumference (99 vs. 90 cm, p < 0.001), central obesity (80% vs. 40%, p < 0.001), liver stiffness (5.9 vs. 4.6 m/s, p < 0.001), alanine aminotransferase (23 vs. 19 U/L, p = 0.029), gamma-glutamyl transferase (36 vs. 28 U/L, p = 0.002) and triglycerides (146 vs. 123 mg/dL, p = 0.009). In a multivariate analysis, diabetes remained independently associated with steatotic liver, even after adjusting for the duration of exposure to hormone therapy (OR = 5.98, 95% CI 1.88–18.42, p = 0.002).

Table 2

Factors associated with fatty liver diagnosis in patients with breast cancer
Variables	Fatty liver (n = 99)	No-Fatty liver (n = 72)	Univariate analysis	Logistic regression
Variables	Fatty liver (n = 99)	No-Fatty liver (n = 72)	P-value	OR (CI95%)	P-value
Age (yrs.)	59 ± 8	56 ± 11	0.069^†
Oncologic profile
Cancer follow-up (mo.)	52 (30–103)	60 (15–102)	0.286^‡
Exposition to HT (mo.)	39 (26–63)	60 (29–60)	0.490^‡	0.99 (0.98–1.01)	0.887
Metabolic profile:
Diabetes	37 (37.4)	9 (12.5)	< 0.001^§	5.89 (1.88–18.42)	0.002
Hypertension	63 (63.6)	28 (38.9)	0.001^§
Dyslipidemia	38 (38.4)	15 (20.8)	0.014^§
Metabolic syndrome	53 (53.5)	26 (36.1)	0.024^§
BMI (kg/m²)	31 ± 6	28 ± 6	0.001^†
WC (cm)	99 (91–108)	90 (80–99)	< 0.001^‡
Central obesity	80 (80.8)	40 (55.6)	< 0.001^§
Liver assessment:
Liver stiffness (m/s)	5.9 (4.7–7.4)	4.6 (4.1–6.1)	< 0.001^‡
≥ 8 kPa	17 (17.2)	4 (5.6)	0.022^§
≥ 12 kPa	10 (10.1)	0 (0.0)	0.005^¶
Laboratory:
AST (U/L)	27 (23–32)	28 (23–32)	0.670^‡
ALT (U/L)	23 (17–29)	19 (15–25)	0.029^‡
AP (U/L)	80 (65–100)	84 (67–107)	0.339^‡
GGT (U/L)	36 (27–48)	28 (22–41)	0.002^‡
Total cholesterol (mg/dL)	210 ± 46	216 ± 41	0.408^†
LDL-c (mg/dL)	113 (88–137)	126 (102–145)	0.103^‡
HDL-c (mg/dL)	57 (45–70)	59 (48–75)	0.165^‡
Triglycerides (mg/dL)	146 (113–208)	123 (88–171)	0.009^‡
Data are expressed as: absolute number (percentage), mean ± standard deviation or median (interquartile range). ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; BMI, body-mass index; GGT, gamma-glutamyltransferase; HDL-c, high density lipoprotein cholesterol; HT, hormone therapy; LDL-c, low density lipoprotein cholesterol; Mo., months; WC, waist circumference; Yrs., years. Tests used: ^†Student’s T-test, ^‡Mann-Whitney, ^§Chi-square, ^¶Fisher’s exact test. Logistic regression was performed by backward method and the initial model included age, exposition to HT, diabetes, hypertension, dyslipidemia and central obesity.

Liver stiffness demonstrated no significant variation between groups, with a median of 5.4 kPa (p = 0.200). Additionally, 12.3% of patients exhibited liver stiffness ≥ 8 kPa (p = 0.568), and 5.8% of patients had liver stiffness ≥ 12 kPa (p = 0.177). In a univariate analysis comparing women with liver stiffness ≥ 8 kPa to those with < 8 kPa (Table 3), factors associated with advanced fibrosis were: diabetes (47.6% vs. 24%, p = 0.022), metabolic syndrome (71.4% vs. 42.7%, p = 0.018), BMI (33 vs. 29 kg/m², p = 0.005), waist circumference (105 vs. 95 cm, p = 0.001), central obesity (90.5% vs. 67.3%, p = 0.030), aspartate aminotransferase (32 vs. 26 U/L, p = 0.017), alanine aminotransferase (26 vs. 20 U/L, p = 0.012) and gamma-glutamyl transferase (47 vs. 33 U/L, p = 0.017). In a multivariate analysis, metabolic syndrome was independently associated with advanced fibrosis, even after adjusting for the duration of exposure to hormone therapy (OR = 4.63, 95%CI 1.39–15.48, p = 0.013). We also divided patients in two groups: exposed and nonexposed to hormone therapy (Supplementary Table 1). There was no difference between both groups, besides higher follow-up in the group exposed to hormone therapy.

Table 3

Factors associated with liver stiffness ≥ 8 kPa in patients with breast cancer
Variables	Liver stiffness ≥ 8 kPa (n = 21)	< 8 kPa (n = 150)	Univariate analysis	Logistic regression
Variables	Liver stiffness ≥ 8 kPa (n = 21)	< 8 kPa (n = 150)	P-value	OR (CI95%)	P-value
Age (yrs.)	60 ± 10	58 ± 10	0.396^†
Oncologic profile
Cancer follow-up (mo.)	42 (37–87)	56 (24–103)	0.910^¶
Exposition to HT (mo.)	45 (27–60)	40 (25–62)	0.852^¶	0.99 (0.98–1.01)	0.599
Metabolic profile:
Diabetes	10 (47.6)	36 (24.0)	0.022^§
Hypertension	12 (57.1)	79 (52.7)	0.700^§
Dyslipidemia	9 (42.9)	44 (29.3)	0.209^§
Metabolic syndrome	15 (71.4)	64 (42.7)	0.018^§	4.63 (1.39–15.48)	0.013
BMI (kg/m²)	33 ± 7	29 ± 6	0.005^†
WC (cm)	105 (97–121)	95 (83–102)	0.001^¶
Central obesity	19 (90.5)	101 (67.3)	0.030^§
Laboratory:
AST (U/L)	32 (25–43)	26 (23–31)	0.017^¶
ALT (U/L)	26 (23–43)	20 (16–26)	0.012^¶
AP (U/L)	89 (71–113)	81 (65–101)	0.170^¶
GGT (U/L)	47 (26–100)	33 (24–42)	0.017^¶
Total cholesterol (mg/dL)	223 (156–247)	208 (185–236)	0.928^¶
LDL-c (mg/dL)	124 (68–136)	119 (95–144)	0.526^¶
HDL-c (mg/dL)	57 (49–75)	58 (46–73)	0.844^¶
Triglycerides (mg/dL)	193 (120–235)	135 (98–186)	0.117^¶
Data are expressed as: absolute number (percentage), mean ± standard deviation or median (interquartile range). ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; BMI, body-mass index; GGT, gamma-glutamyltransferase; HDL-c, high density lipoprotein cholesterol; HT, hormone therapy; LDL-c, low density lipoprotein cholesterol; Mo., months; WC, waist circumference; Yrs., years. Tests used: ^†Student’s T-test, ^‡Mann-Whitney, ^§Chi-square, ^¶Fisher’s exact test. Logistic regression was performed by backward method and the initial model included exposition to HT and metabolic syndrome.

In this study, over fifty percent of patients with breast cancer had NAFLD, and around 10% had advanced fibrosis. Diabetes and metabolic syndrome were independently associated with the occurrence and progression of NAFLD in those patients, respectively, regardless of hormone therapy exposure. This suggests that the influence of hormone therapy on NAFLD progression may be less significant compared to the patient's metabolic profile.

Breast cancer is the most frequent malign non-skin tumor in Brazilian women, and an important cause of death [12]. The expression of estrogen receptor, observed in approximately 75% of breast cancers, serves as a valuable prognostic indicator, guiding targeted hormone therapy decisions. [13, 14]. Endocrine therapy is tailored differently for pre- and post-menopausal women, with aromatase inhibitors being the preferred choice post-menopause, unless contraindicated or poorly tolerated [15]. For premenopausal women with a low recurrence risk, a five-year therapy involving tamoxifen is recommended, while those at a high risk may be prescribed an extended 10-year therapy [16]. Given the high prevalence of breast cancer and the potential for long follow-up of survivors, investigating the hepatic effects of endocrine therapy assumes critical importance.

Previous studies have demonstrated that up to 50% of patients using tamoxifen also exhibit fatty liver [4, 6–8], a finding consistent with the observations in this study. Risk factors previously described align closely with our findings: dyslipidemia, altered fasted glucose [6, 17], high BMI and visceral fat [9, 17, 18]. While the literature remains uncertain, it is hypothesized that tamoxifen may play a multifactorial role in the development of fatty liver, involving increased synthesis of fatty acids and triglycerides, inhibition of mitochondrial fatty acid beta-oxidation, and suppression of estrogen synthesis. Additionally, enzymatic and protein polymorphisms associated with fatty liver in tamoxifen users are described in genes related to its pharmacogenetics (CYP2D6, CYP1, OATP1B1, SREBP-1, and UGT) [19–23]. However, it is still undefined whether tamoxifen have a relevant impact in NAFLD development. Even though tamoxifen is the most investigated drug, aromatase inhibitors have also been assessed for its liver-related side-effects, with lower incidence of fatty liver compared to tamoxifen [4].

Previous prospective investigations evaluating fatty liver development with endocrine therapy have indicated that most cases occur within the initial two years of follow-up [7, 8, 24], and that, after interrupting hormone therapy, the majority of cases resolve within another one to two years [7, 8]. However, a recent prospective study using controlled attenuation parameter to measure liver steatosis at three months and two years after tamoxifen therapy demonstrated a sustained prevalence of 48–51% of fatty liver, with no increase observed during both time periods [25]. This strongly aligns with our findings, suggesting that the metabolic background of patients may exert a more substantial influence on the prevalence of fatty liver than hormone therapy alone.

Breast cancer patients are commonly older women who present diseases closely related to NAFLD (i.e., diabetes, hypertension and obesity) [2, 3], since the perimenopausal period is associated with metabolic changes that favor fat storage, dyslipidemia and glucose intolerance. These changes are possibly associated with the reduction of estrogen protective effects [26] and are the reason why in this population NAFLD is so prevalent.

Steatohepatitis represents the form of NAFLD with a higher potential for the progression to chronic liver disease. However, there is a notable absence of data on the prevalence of steatohepatitis among breast cancer patients undergoing hormone therapy. Attempts have been made to estimate this prevalence, but they often rely on the elevation of aminotransferases to indicate steatohepatitis [5, 27]. It is now recognized that such an approach is inadequate, as a substantial number of patients with steatohepatitis and fibrosis may present with normal liver enzyme levels [28]. For instance, one study selected 20 patients with elevated aminotransferases for liver biopsy, revealing steatohepatitis in 15 cases [5]. This finding suggests that steatohepatitis, as a manifestation of NAFLD, can indeed occur in breast cancer patients even if liver enzyme levels appear normal.

The prediction of liver fibrosis is arguably the most crucial assessment in NAFLD [28, 29], for which noninvasive tools are widely employed. Hepatic elastography stands out as the most utilized and reliable method for predicting liver fibrosis. In our study, liver stiffness was similar between patients exposed and not exposed to hormone therapy [30]. This finding contributes to the emerging understanding that hormone therapy exposure may not be the primary factor in NAFLD development and progression, as was also demonstrated by Braal et al. [25]. On the other hand, these observations highlight a potential association with metabolic syndrome itself.

This study is subject to certain limitations. Firstly, there is heterogeneity in the distribution of patients among various endocrine therapy modalities, primarily driven by different drug indications. Consequently, women who used anastrozole were generally older. Additionally, there is a discrepancy in the follow-up duration between patients using hormone therapy and those in the non-exposed group. This difference arises from the inclusion of patients with a recent cancer diagnosis who had not initiated hormone therapy into the non-exposed group. Furthermore, the lower number of patients using only anastrozole may be attributed to the protocols of our country's public health care system, which allows tamoxifen usage for both pre and postmenopausal women.

In conclusion, among breast cancer women, more than half had NAFLD, and approximately 10% had advanced fibrosis by elastography. Common metabolic risk factors were independently associated with the occurrence and progression of NAFLD, regardless of hormone therapy exposure. The risk of NAFLD progression induced by tamoxifen and anastrozole seems to have been previously overestimated.

ANOVA, analysis of variance

IQR, interquartile range

NAFLD, nonalcoholic fatty liver disease

OR, odds ratio

SD, standard deviation

95%CI, 95% confidence interval

Data availability statement: Data is available under reasonable request

Funding statement: this study was funded by FAPEMIG (grant number APQ-00526-21)

Conflict of interest: Authors declare no conflict of interest

Ethics approval statement: This study was approved by the Federal University of Minas Gerais Ethics Committee Board (CAAE 48790721.5.0000.5149) and individual informed consent was obtained from all patients.

Author contributions:

MJN: Conceptualization, data curation, formal analysis, funding acquisition, investigation, methodology, writing – original draft. MJSDM: conceptualization, data curation, funding acquisition, investigation. GGLC: conceptualization, formal analysis, writing – review & editing. TCMFC: conceptualization, funding acquisition, investigation. AQRL: data curation, investigation. VPP: data curation, investigation. MCMB: data curation, investigation. FAG: data curation, investigation. JCV: data curation, investigation. LMM: data curation, investigation. RT: data curation, investigation. AMLR: data curation, investigation, methodology. PHCD: conceptualization, methodology. JASG: conceptualization, methodology. LCF: conceptualization, data curation, funding acquisition, investigation, methodology, writing – review & editing. CAC: conceptualization, data curation, funding acquisition, investigation, methodology, writing – review & editing.

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Risk of fatty liver and hepatic fibrosis associated with long-term use of tamoxifen or anastrozole may be overestimated in patients with breast cancer

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Abstract

Background

Aims

Methods

Results

Conclusion

INTRODUCTION

METHODS

Study design and participants selection

2.4 Transient elastography evaluation

2.6 Statistical analysis

RESULTS

DISCUSSION

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

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