Role of sex in liver tumor occurrence and clinical... : Hepatology (original) (raw)

INTRODUCTION

Increasing evidence indicates that the prevalence and clinical outcomes of several diseases, including those of the liver, differ between men and women.1 The mechanisms underlying these differences are complex and not always related to biological factors. Social determinants of liver diseases leading to gender-related inequities are increasingly recognized, together with those pertaining to vulnerable populations, such as ethnic minorities and groups with low educational levels and/or incomes.2,3 Gender-related dissimilarities may lead to differences in opportunities to receive the best treatment for advanced liver diseases, as indicated by females’ reduced access to liver transplantation (LT) and worse clinical outcomes4 and by the gender imbalance in enrollment in clinical trials assessing HCC treatments.5 Responses to pharmacological treatments for liver diseases can also be influenced by sex in terms of the drug dose required and risk of adverse drug reactions, which is usually higher for females than for males.6

Interest in the evaluation of the potential influence of sex hormones on the natural histories of many liver diseases, including primary and metastatic liver cancer, is increasing. The liver is considered to be sexually dimorphic in terms of its response to sex hormones, given the presence of both androgen receptors (ARs) and estrogen receptors (ERs), resulting in the differential expression of many genes in the liver of men and women.7 Sexual dimorphism in several pathological hepatic processes, including regeneration, fibrosis, and, potentially, the malignant transformation of hepatic and biliary cells, has been demonstrated.7 In this review, we critically highlight the main sex-based differences in the molecular mechanisms inducing liver carcinogenesis, as well as in the prevalence and prognosis of and treatment outcomes for primary and metastatic liver tumors.

ROLES OF SEX HORMONES IN LIVER FIBROSIS AND CARCINOGENESIS

The incidence of HCC skews markedly toward males, with notable gender-related differences existing among HBV-infected individuals and, less so, among patients with NASH.8 Although it occurs in an organ that is not a classical sex hormone target, HCC is influenced by this group of hormones. The physiological basis for the liver’s sensitivity to sex hormones lies in the presence of alpha and beta ERs9,10 and ARs.11 Although normally expressed at lower levels than in classical target organs, such as the breast and the uterus, ERs and ARs in the liver bind their respective ligands with the same affinity and capacity.

Advanced fibrosis and cirrhosis are the main risk factors for the development of HCC and intrahepatic cholangiocarcinoma (iCCA),8,12 and the role of estrogens in hepatic injury and repair has been well documented (Figure 1). Estrogens have potent anti-inflammatory and anti-fibrogenic effects, limiting the development of tissue scarring under chronic injury.13 Such evidence was derived from early experiments conducted with ovariectomized rats, in which the progression of fibrosis was considerably more rapid than in control animals.14 At the clinical level, premenopausal women are known to have a lower risk of fibrosis progression in chronic liver disease, regardless of its etiology. In women with chronic HCV infection, the fibrosis progression curve becomes significantly steeper and the response to antiviral therapy with interferon significantly lesser after menopause.15 Similarly, menopause increases the severity of fibrosis in patients with NAFLD. This effect has been confirmed experimentally in overfed zebrafish: female fish of reproductive age developed only steatosis, whereas menopausal female fish and male fish of reproductive age also developed fibrosis.16 In addition, an increased risk of NASH development is a well-documented side effect of the use of tamoxifen, a weak synthetic estrogen with antiestrogenic activity. These findings prompt the reconsideration of the development of hepatobiliary malignancies. They are also supported by extensive preclinical investigations using in vitro and in vivo models, which have led to the identification of cellular and molecular targets of estrogen action.17 A seminal contribution demonstrated that ERα is responsible for the protective effect of estradiol, which downregulates a proinflammatory signaling pathway and inhibits the release of IL-6 from KCs exposed to necrotic hepatocytes. These events are modulated by the myeloid differentiation primary response 88-dependent activation of NF-κB, which in turn contributes to hepatic carcinogenesis through the activation of signal transducer and activator of transcription-3 signaling. Notably, IL-6 or myeloid differentiation primary response 88 ablation was reported in 2007 to protect male mice from HCC development, providing the first mechanistic explanation for the sex difference in HCC occurrence.18 Moreover, some microRNAs expressed by HCC cells cause ER downregulation, leading to the hormonal unresponsiveness of cancer cells.19

FIGURE 1:

Estrogens and androgens influence all cells in the liver (ie, hepatocytes, endothelial cells, HSCs, and KC). Estrogens favor DNA synthesis in hepatocytes and eNOS upregulation in endothelial cells. They inhibit the release of proinflammatory cytokines and oxygen radicals from KC and HSC contraction due to decreasing endothelin levels. Androgens increase the mitogenic activity of hepatocytes and stimulate angiogenesis (sinusoidal endothelial cells). They also stimulate collagen deposition and exert pro-inflammatory action. Abbreviations: eNOS, endothelial nitric oxide synthase; NO, nitric oxide; ROS, reactive oxygen species.

IL-6-dependent signal transducer and activator of transcription-3 activation is considered to be a key event in inflammation-induced liver cancer development, and Naugler et al.18 clearly demonstrated the anti-inflammatory effect of estrogens. In chronic HBV infection, sex hormones regulate the transactivation of the HBV X protein, causing the chronic release of inflammatory cytokines in the hepatocellular microenvironment.20 In addition, estrogens reduce the transcription of the HBV gene.21 Furthermore, N′,N′-diethylnitrosamine was found to cause HCC in 100% of male mice but in only 10%–30% of their female littermates, and more hepatocyte apoptosis and necrosis was observed in male mice.18,22,23 These differences suggest that sex modulates the compensatory proliferation of hepatocytes in response to toxic damage.

Despite these compelling lines of evidence, the possibility that estrogens favor HCC development under certain conditions should be considered. Estrogens may induce the formation of free radical-mediated DNA and RNA adducts, which are potentially mutagenic. However, the failure of antiestrogens such as tamoxifen and raloxifene as HCC treatments suggests that estrogen antagonization is not effective in vivo.17 On the contrary, accumulating data indicate that endogenous and exogenously administered androgens favor the development of liver cancer through various actions at the hepatic level.24 In patients with cirrhosis, the elevation of serum testosterone levels together with the reduction of serum estrogen levels may promote the development of HCC.25 ARs have been suggested to play a major role in experimental hepatocarcinogenesis, as the incidence of carcinogen-induced HCC was lower in mice lacking these receptors in hepatocytes.26 Androgens also contribute to HBV X protein-related hepatocarcinogenesis. Although nuclear ARs are overexpressed in HCC, a second-generation AR antagonist had limited therapeutic utility due to feedback activation of the AKT/mammalian target of rapamycin pathway, which drives nuclear AR overexpression.27

More recent data suggest that sex hormones affect the development and prognosis of cholangiocarcinoma (CCA), especially iCCA. In postmenopausal women, increased 4-androstenedione concentrations were associated with a 50% decrease in the risk of liver cancer development, whereas increased sex hormone–binding globulin concentrations were associated with a 31% increase in this risk.28 The doubling of the estradiol level was associated with a 40% increase in the risk of iCCA development.28 The picture is likely more complex for these tumors. Combined postmenopausal hormone replacement formulations have been associated with an increased risk of gallbladder cancer, and estrogen-only formulations have been associated with a reduced risk of CCA.29

SEX DIFFERENCES IN BENIGN LIVER LESIONS AND THEIR NEOPLASTIC TRANSFORMATION

Sex may influence the incidence of benign liver tumors30 such as hepatocellular adenoma (HCA), which is frequently diagnosed in women aged 35–40 years and occurs at a female:male ratio of 10:1. The most relevant risk factor for HCA is the use of oral contraceptives or other steroid medications.31 The incidence of HCA is increased by 30–40-fold for long-term oral contraceptive users32,33; furthermore, the risk ratio is dose related and a small proportion of tumors regresses upon oral contraceptive withdrawal.34 The incidence of HCA in males has increased with the sports-related use of anabolic substances, including the use of anabolic androgenic steroids by bodybuilders.35–37 HCA development has also been associated with the use of androgenic steroids to treat aplastic anemia38 and paroxysmal nocturnal hemoglobinuria.39 The risk of the malignant transformation of HCA ranges from 0% to 50%, depending on factors including sex, androgen use, tumor diameter >5 cm, and the presence of genetic mutations in specific oncogenes and tumor suppressor genes.40 The activation of Wnt/β-catenin signaling has been associated with HCA progression.41 HCAs with β-catenin mutations are overrepresented in men relative to women, and about half of such cases receive the final histological diagnosis of HCC.42 Thus, the clinical course of HCA is more often benign in women than in men.43–45

The surgical resection of HCA, regardless of the tumor size, is recommended in men due to the high probability of malignant transformation.43 For women, lifestyle changes including oral contraceptive discontinuation and body weight control are recommended as first measures, unless β-catenin mutations are present. The malignant transformation of HCAs with baseline diameters <5 cm in women is uncommon, and MRI surveillance is recommended in these cases. Surgical resection of HCAs in women with diameters >5 cm despite the cessation of hormonal therapy is recommended.

Pregnancy is not contraindicated for female patients with HCAs <5 cm.40 HCA size in pregnant women should be monitored closely, with liver ultrasound performed every 6–12 weeks. Close collaboration with the obstetric team is essential when an HCA grows, as it can increase the risk of rupture.46 In the presence of an HCA <5 cm that is not exophytic or growing, no data support the need for elective cesarian section, and vaginal delivery can be planned. Surgical treatment within 24 weeks of gestation is indicated for growing lesions.47

Biliary adenofibroma is an extremely rare benign tumor (21 cases have been described) that occurs more frequently in females and has the potential for malignant transformation and recurrence when surgical excision is incomplete.48 No data on the gender-related risk of its malignant transformation are available.

Mucinous cystic neoplasm of the liver and biliary system is a rare cyst-forming epithelial neoplasm that occurs exclusively in women. It is composed of a mucin-producing epithelium associated with an underlying ovarian-type stroma. Mucinous cystic neoplasm is characterized by low-grade or high-grade epithelial dysplasia and is associated with invasive carcinoma in up to 30% of cases,49 particularly in older patients.50 Surgical resection is the treatment of choice, and the prognosis is excellent when complete excision is obtained.51

SEX DIFFERENCES IN HCC PREVALENCE, RISK FACTORS, CLINICAL PRESENTATION, AND SURVIVAL

Role of etiology

The male:female ratios for HCC incidence and mortality exceed 2.5.52–55 Despite the global decrease in overall cancer-related mortality, age-standardized mortality rates for HCC remain in the range of 3–7/100,000 for males and 1–3/100,000 for females.56 Beyond the intrinsic effects of sex hormones, this sex-based difference varies according to the etiology of the liver disease.

Viral cirrhosis

HCC is significantly more prevalent in males than in females with HBV-related and HCV-related cirrhosis, with a male:female ratio of 7:1, and it progresses more rapidly in males.15,57,58 Males are more likely to acquire HBV, have greater HBV viral loads, and develop chronic hepatitis, cirrhosis, and HCC.59 For these reasons, sex is included in almost all models for the prediction of HCC development.59,60 The sex difference in HCV-positive patients is less clear.

Alcohol consumption

Women have higher blood alcohol levels than do men after consumption of the same amount of alcohol, even considering size differences.61 Experimental animal models have shown that sex differences in alcohol metabolism are due to the following factors in females: (1) lower levels of cytochrome P450-2E1 due to growth hormone regulation62; (2) increased Kupffer cell susceptibility to endotoxins due to estrogens63,64; and (3) less expression of mitochondrial aldehyde dehydrogenase 2, a critical enzyme involved in ethanol clearance, due to modulation by sex hormones and the gut microbiota.65 Thus, the liver of females may be exposed to higher ethanol concentrations, leading to more severe liver injury, after the consumption of the same amount of alcohol as males,66–68 although the difference becomes minimal among heavy alcohol consumers (>60 g/d alcohol).69 Nevertheless, the overall prevalence of HCC is lower in women than in men, with reported rates of 15.4% and 27.8%, respectively, in the US population.70

NASH

The characteristically higher prevalence of HCC in men is less remarkable in patients with NAFLD/NASH,71–76 at least in the US, where metabolic disorders and obesity are responsible for one-third of the HCC burden70 and 38% of females are obese.77 A significantly larger proportion of women than men with NAFLD without cirrhosis develop HCC (23.3% vs. 12.4% and 17.1% vs. 9.7%, respectively)78. Moreover, LT waitlist registrations in the United Network for Organ Sharing database reflect a 2383% increase in NASH-related HCC among females between 2004 and 2016, double that among males (1172%).79

Autoimmune cirrhosis

In patients with cirrhosis due to autoimmune hepatitis, the prevalence of HCC ranges from 0.2% to 12.3%80 and is similar between sexes. Whether this is due to the greater prevalence of autoimmune hepatitis in females remains unclear, given the relative rarity of HCC in patients with this disease.

Primary biliary cholangitis

HCC develops almost exclusively in patients with primary biliary cholangitis at advanced (II and IV) stages, with an incidence of 0.8–1.8/100 person-years and 5-year cumulative incidence of up to 4%.81,82 HCC is a rare complication (4.1%) in women with primary biliary cholangitis, whereas its risk is increased (20%) in male patients.83

Clinical presentation and survival

Women are more frequently diagnosed with HCC at an older age and earlier stage of the disease than are men.84–86 Moreover, the female gender has been associated independently with better overall survival, particularly in younger HCC cohorts.54,84,85,87,88 These findings may be attributable to several factors. HCC is more likely to be diagnosed in women by surveillance than with symptom onset,84 resulting in less invasiveness at the time of diagnosis89 and lower recurrence rates.90 The small number of ARs in HCC cells91 may also be a contributing factor. In a study conducted with 1886 patients in the US, the primary HCC treatment type and median survival of patients with the disease differed, albeit not significantly, between males and females.86 However, these results should be interpreted with caution, as only 29 female patients were followed up for the maximum duration, and gender differences in treatment accessibility were not considered.86 Moreover, most (up to 72%) patients in that study and others had HBV or HCV infection.85–88 Thus, these results should not be generalized to patients with HCC of nonviral etiologies.

SEX DIFFERENCES IN RESPONSE TO CURATIVE HCC TREATMENT

Ablation, liver resection (LR), and LT are the only HCC treatments considered to be curative, and their application depends on the presence of portal hypertension, the number of nodules, and liver function.92–94 Females undergo LR and ablation more frequently than do males, likely because they present more frequently with compensated liver disease.95,96 HCC ablation is a substantially safe procedure, with most reported 3-year survival rates exceeding 90%.97 Its failure may be related to the nodule features and location, and tumor size is among the most frequently reported factors related to HCC recurrence after ablation.98,99 In a recent study, male sex was associated with greater risks of second recurrence after radiofrequency ablation, along with older age, high alpha-fetoprotein levels, the presence of multiple recurrent tumors, and early distant intrahepatic recurrence.100 A retrospective review was conducted to evaluate the value of a score based on age, male sex, albumin and bilirubin levels, and the platelet count as a predictor of late recurrence in patients with early-stage HBV-related HCC who had undergone primary radiofrequency ablation,101 but the specific weight of male sex in this score is not clear.

The main characteristics of studies examining sex differences in HCC recurrence after LR and LT are provided in Table 1. The 5-year survival rates after LR and LT for patients with HCC are about 70%–80%,93,110 but recurrence after LR is reported in 70% of cases, including in patients with single tumors. Recurrence after LR can be observed early (≤2 y) because of occult metastasis or microscopic dissemination, or late (>2 y), depending on de novo tumor development.102 Some studies have revealed no correlation of gender with HCC recurrence after LR,102–105 whereas others have shown that the recurrence rate is lower, and the disease-free survival rate is better among females than among males.106 The better prognosis for females may be related to more favorable baseline tumor biological characteristics or a lower rate of alcohol abuse relative to males.89 In 2 large multicenter studies examining early and late HCC recurrence among patients who had undergone LR in China, the late HCC recurrence rate was significantly higher in males than in females, even after adjustment for potential confounding factors such as smoking habit and alcohol consumption.106,107

TABLE 1 - Studies evaluating sex differences in HCC recurrence after surgical liver resection and liver transplantation

a_P_=0.04.

b_P_<0.001.

c_P_=0.002.

Abbreviations: F, female; LR, surgical liver resection; LT, liver transplantation; M, male; NS, not significant.

In the Model for End-Stage Liver Disease allocation system, studies have revealed sex disparities favoring men in the receipt of LT, as HCC affects men more frequently than women.111,112 In contrast, Moylan et al.113 showed that the sex disparity in the LT rate is resolved among patients with HCC, considering that HCC is an exception in the Model for End-Stage Liver Disease system. Studies in which other clinical factors are considered have revealed no sex disparity in the rate of LT for HCC.95

In the past, recipient sex did not seem to be correlated with HCC recurrence after LT.108,114,115 In a more recent study based on US National Registry Data, female sex was associated with a 25% lesser risk of HCC recurrence, even after adjustment for tumor characteristics and donor features.109 In addition, the impact of sex on the risk of post-LT HCC recurrence was independent of explant pathology, pre-LT therapies, serum alpha-fetoprotein level, and donor characteristics.109 More data are needed to confirm these results.

Figure 2 summarizes the main differences in the epidemiology, clinical features, and treatment response of HCC between males and females.

FIGURE 2:

Summary of the current knowledge of the influence of sex on the incidence, etiology, clinical presentation, and treatment response of HCC. Abbreviation: LR, liver resection; OLT, orthotopic liver transplantation; OS, overall survival.

SEX DIFFERENCES IN THE PREVALENCE AND CLINICAL OUTCOMES OF NEOPLASMS OF THE BILIARY TRACT

CCA and gallbladder cancer have a low prevalence but high overall mortality rate, probably due to late diagnosis.116 CCA is reported to be more frequent in males, and gallbladder cancer is predominant in females.117

CCA is the second most common primary liver cancer after HCC and accounts for 3% of all digestive cancer cases.118 According to the anatomical site of origin, CCA is classified as intrahepatic, perihilar, and distal. iCCA arises above the second-order bile ducts, and the point of distinction between perihilar CCA and distal CCA is the insertion of the cystic duct. Perihilar CCA and distal CCA are collectively referred to as extrahepatic cholangiocarcinoma (eCCA).119

iCCA

Age-standardized mortality rates for iCCA have increased in recent years due to the increased prevalence of its major risk factors, such as HBV and HCV infection, alcohol consumption, and NAFLD.120 The role of gender in the mortality of patients with iCCA has been examined in 14 studies.120–131 Male gender was associated with greater mortality in 11 of these studies,120–123,126,127,129–132 whereas gender had no impact on clinical outcomes in 3 studies.124,125,128

eCCA

The influence of gender on the mortality of patients with eCCA has been examined in 13 studies.120,121,124,125,128–136 The mortality rate was higher among males than among females in nine of these studies.120,121,129,131–136 Gender had no impact on mortality in three studies.124,128,130 Al Mahjoub et al.125 analyzed survival according to the eCCA subtype and found that it was significantly better among males than among females with perihilar CCA and did not differ between males and females with distal CCA.

Gallbladder cancer

Gallbladder cancer is rare and has the highest mortality rate among biliary tract cancers,124mostly in men,121 although this rate has decreased over the last 10 years. The impact of gender on the mortality of patients with this cancer has been evaluated in 8 studies,121,124,128,131,135,137–139 which have yielded conflicting results. The mortality rate was higher in males than in females in 4 studies,131,135,138,139 did not differ between sexes in 2 studies,124,128 and was higher in females than in males in 2 studies.121,137 Differences among studies in patients’ ethnicity, body weight, and residence in low-income or high-income countries make the drawing of definitive conclusions about the impact of sex on mortality from gallbladder cancer difficult.

SEX DIFFERENCES IN RESPONSE TO CCA TREATMENT

Data on sex differences in the response to CCA treatment are scarce and often derived from subanalyses of data from treatment trials or small patient series. Furthermore, most studies to date have been conducted with patients undergoing surgery, and they usually span decades, given the rarity of CCA.

Surgical treatments

Regardless of lesion location, surgical resection to obtain a negative margin while preserving adequate remnant liver size and function remains the cornerstone of CCA treatment.140,141 In many cases, complete surgical resection cannot be achieved due to the need to retain adequate remnant liver quality and volume and vascular inflow and outflow structures.142 The baseline liver volume is crucial, which may disadvantage female candidates, whose median liver volume is less than that of males. Moreover, females have larger and more advanced tumors at the time of CCA diagnosis, which influence resection margins.143,144 Nonetheless, some studies have documented a survival benefit for female patients with iCCA and eCCA145–148; however, others have revealed no association between gender and the treatment response or survival after the surgical resection of CCA149–151 (Table 2).

TABLE 2 - Studies evaluating sex differences in response to surgical liver resection for cholangiocarcinoma

a_P_<0.001.

b_P_<0.05.

cNumber of M/F who achieved 5-year survival=4/27 (_p_=0.004).

dNo significant difference in multivariate analysis (detailed M/F ns not provided).

eNumber of M/F who achieved 5-year overall survival=8/18 (not significant in multivariate analysis).

Abbreviations: CCA, cholangiocarcinoma; CT, chemotherapy; F, female; M, male; NR, not reported; OS, overall survival; RT, radiotherapy.

LT

LT is performed in patients with CCA to achieve complete tumor resection and avoid posthepatectomy liver failure.152 Whereas iCCA remains a contraindication for LT outside of clinical trials, the Mayo Clinic protocol has been adopted gradually for perihilar CCA, leading to 5-year survival rates ranging from 65% to 70% across transplant centers.153–156 The Mayo Clinic group reported that the risk factors for LT waitlist dropout due to disease progression and posttransplant recurrence were tumor related, but they did not include gender in their analysis.157 The number of patients who undergo LT for CCA remains small, and this sample spans decades, preventing precise comparison of outcomes between genders. Nevertheless, studies conducted to identify independent predictors of overall and recurrence-free survival in such patients have revealed no significant sex difference.158–162

Systemic treatments

Most patients with CCA are ineligible for LR because they have locally advanced or metastatic disease at the time of presentation and undergo systemic treatment.163 Sex has not been identified as a factor associated with the response of CCA to different treatment protocols and survival164–177 except in one study conducted in Taiwan, in which male sex was an independent predictor of poor overall survival but not of tumor response in patients treated with gemcitabine/cisplatin.178 The influence of sex on treatment response is rarely examined in clinical trials, and no sex-based recommendation for systemic therapy selection has been proposed.179 Within the limited information in the literature, of interest is the greater frequency of genetic aberrations of FGF receptor 2, a potential novel target in the management of advanced iCCA, in females than in males (13% vs. 4%) and in younger patients.180 Patients with advanced iCCA carrying these aberrations had significantly longer survival periods than did those carrying the wild type (123 vs. 37 mo).181

Current knowledge of the influence of sex on CCA occurrence, progression, and treatment efficacy is summarized in Figure 3.

FIGURE 3:

Summary of the current knowledge of the influence of sex on the occurrence, progression, and efficacy of treatment efficacy of iCCA (A) and eCCA (B). The influence of female sex is represented on the left sides of the panels and that of male sex is represented on the right. Abbreviations: iCCA, intrahepatic cholangiocarcinoma; eCCA, extrahepatic cholangiocarcinoma; , estrogens; , sex hormone-binding globulins; , estrogen-only hormone replacement therapy; , sex-related factors unproven.

SEX DIFFERENCES IN LIVER METASTASIS

Liver metastasis (LM) is the main cause of cancer-related mortality182; it significantly reduces survival relative to extrahepatic metastasis.183 Colorectal cancer (CRC) is the most common metastatic liver disease, followed by pancreatic and breast cancers.183

CRC

The prevalence of LM in patients with CRC ranges from 13% to 26%, and male sex has been identified as an independent risk factor.184–187 A recent study conducted with 4912 patients in China has shown that extrahepatic CRC metastasis was significantly more frequent among females than among males (28.2% vs. 19.8%) and that males had significantly worse survival.188

LR or ablation is being adopted increasingly with curative intent in patients with LM of CRC. Among 1325 patients in Sweden with such metastasis who received this treatment, the overall 5-year survival was 53.8% and was not influenced by sex.189 In contrast, a classification and regression tree analysis showed that the mutated Kirsten rat sarcoma genotype, female gender, lower preoperative serum carcinoembryonic antigen levels, and the absence of synchronous CRC LM were associated significantly with better overall survival after LR.190 The overall survival after systemic chemotherapy including bevacizumab did not differ significantly between males and females, although more females experienced G3/4 treatment-related side effects.191 LT for LM of CRC is an interesting option for a very select group of patients. Preliminary data from the Secondary Cancer I and II studies indicate that with LT the 5-year overall survival rate was 83%, with no significant difference between sexes.192,193 Of note, however, only 38 patients, including 17 females, were enrolled in these studies.

Pancreatic cancer

Nearly 50% of pancreatic cancer cases are diagnosed with distant metastasis, most commonly to the liver.194–196 In a recent study including 2088 patients with pancreatic cancer, Liu et al.194 showed that LM occurred more frequently in males than in females. This sex disparity has been suggested to be attributable to the male-specific upregulation of tissue inhibitor of metalloproteinases I observed in pancreatic cancer,195 which is responsible for the increased prevalence of LM and shorter survival in males. In a larger study conducted to examine the outcomes of the surgical treatment of LM of neuroendocrine tumors of pancreatic origin, the female gender, in addition to younger age and less advanced tumor stage, was identified as an independent predictor of better survival.197

Breast cancer

The incidence of LM in patients with breast cancer is third highest, following those of bone and lung metastases.198 Patients aged ≥80 years with only LM of breast cancer had the worst overall and breast cancer-specific survival among metastatic sites.199 These results were confirmed in a study conducted with 4388 women with metastatic breast cancer in Denmark, which revealed a higher mortality rate for liver-only than for brain-only metastasis.200 The role of sex in the development of LM is rarely analyzed in breast cancer studies because of the low prevalence of this cancer in males.199,201–204 In one study, the rate of LM of breast cancer was significantly lower in males than in females (10.5% vs. 24.5%).205 Regardless, breast cancer survival is significantly worse in men than in women regardless of the age at diagnosis, race, marital status, disease stage, lymph node and ER involvement, grade, geographic region, and surgery type.206

CONCLUSIONS AND FUTURE DIRECTIONS

Sex differences in the incidence, prevalence, clinical outcomes, and treatment response of many liver tumors have been reported. These data are supported by increasing knowledge of the pathogenic roles of sex hormones, which promote fibrosis progression and carcinogenesis in the liver. Importantly, females have been underrepresented in much basic and clinical research on liver diseases. Thus, renewed attention to a more sex-specific approach to diagnosis, management, and treatment of liver diseases is required, and the scientific community should focus on gaining a better understanding of the mechanisms underlying sex differences in these diseases. Current research is increasingly focused on comprehensive “omics” analysis of biological processes, including those related to sexual dimorphism. The knowledge gained thereby may contribute to the identification of novel sex-specific biomarkers and innovative targets relevant to hepatology. Greater attention needs to be paid to possible unwanted effects of hormone therapies used for gender reassignment. Few data are currently available, but such drug intervention seems to have both positive and negative effects on the cancer risk. It will be critical to investigate the possible development of liver injury in transgender persons, to monitor them for the most important risk factors for chronic liver disease and HCC, and to implement age- and natal sex-specific cancer screening.207

In conclusion, an increasing attention to a more sex-specific approach to liver disease is warranted. The efforts of the scientific community should be focused to better understand the mechanisms underlying such sex differences with the aim to eliminate sex-related inequalities in hepatology.

AUTHOR CONTRIBUTIONS

Pierluigi Toniutto and Erica Villa contributed to the study conception and design and the drafting and critical revision of the paper. Sarah Shalaby, Laura Mameli, Filomena Morisco, Martina Gambato, Valentina Cossiga, and Maria Guarino contributed to data acquisition and the drafting of the paper. Fabio Marra, Maurizia R. Brunetto, and Patrizia Burra contributed to the critical revision of the paper.

FUNDING INFORMATION

The present study was funded by the Italian Association for Cancer Research (AIRC) (IG 2020, no. 24858 to Erica Villa) and by the Italian Medicines Agency (AIFA) Independent Research Announcement (TRS-2018-00001238 to Erica Villa).

CONFLICTS OF INTEREST

Fabbio Marra consults for Roche, Eisai/MSD and Ipsen. Maurizia R. Brunetto consults for, advises, and is on the speakers’ bureau for Gilead. She advises and is on the speakers’ bureau for AbbVie. She advises Janssen and Roche. She is on the speakers’ bureau for Eisai-MSD. The remaining authors have nothing to report.

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