Impact of Sex on the Survival of Patients With Hepatocellular Carcinoma: A Surveillance, Epidemiology, and End Results Analysis

Abstract

BACKGROUND:

Men are 4 to 8 times more likely to develop hepatocellular carcinoma (HCC) than women. Preclinical models have suggested a role for sex hormones in the development of HCC. In the current study, the authors investigated the impact of age, sex, race, and ethnicity on the survival of patients with HCC using the Surveillance, Epidemiology, and End Results (SEER) database.

METHODS:

Patients diagnosed with HCC from 1988 through 2010 were identified from the SEER registry. Hazard ratios (HR) for overall survival (OS) were derived using the Cox regression model adjusted for race, year of diagnosis, marital status, treatment, birthplace, tumor differentiation, and tumor size.

RESULTS:

A total of 39,345 patients were identified; 76% were men and 34% were women (50% white, 12% African American, 21% Asian, 16% Hispanic, and 1% Native American). The median age at the time of diagnosis was 61 years for men and 67 years for women. Approximately 84% of patients had liver-limited disease and 16% had metastatic disease. Treatment information was available for patients diagnosed after 1998 (34,674 patients): 11% received liver-directed therapy, 11% underwent surgical resection, and 7% underwent liver transplantation. The HR for the OS of women versus men was 0.83 (95% confidence interval [95% CI], 0.77–0.88) for patients aged <55 years. The protective effect of sex on OS was found to be greatest in patients aged 18 to 44 years (HR, 0.75; 95% CI, 0.65–0.86 [P<.001]), especially those with surgically resected tumors (HR, 0.68; 95% CI, 0.54–0.86 [P=.001]) and those who were African American (HR, 0.85; 95% CI, 0.78–0.92 [P<.001]). There was no survival difference between sexes noted among Hispanics or patients aged >65 years.

CONCLUSIONS:

Sex appears to be associated with survival in patients with HCC. The role of androgens and estrogens in the development and progression of HCC warrants further investigation.

INTRODUCTION

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality, with approximately 600,000 deaths occurring each year worldwide.^1,2 In the United States, HCC is the fifth and ninth leading cause of cancer-related death among men and women, respectively.³ HCC, the predominant histological subtype of liver cancer, is associated with hepatitis B virus (HBV) or hepatitis C virus, alcohol abuse, nonalcoholic fatty liver disease (NAFLD), diabetes mellitus, obesity, iron storage diseases, and aflatoxin B1 exposure.¹ Regardless of predisposing factors or geographic location, a striking sex disparity in the incidence of HCC has been consistently demonstrated, with men found to be 4 to 8 times more likely to develop the disease than women.⁴ It is from such epidemiologic observations that sex hormones were first surmised to modulate hepatocellular carcinogenesis nearly 5 decades ago.^5,6 Since then, androgens and estrogens have been shown to mediate infectious hepatitis,^7,8 hepatic fibrosis,⁹ NAFLD,¹⁰ and cirrhosis,¹¹ in addition to HCC.¹² For example, androgens have been linked to hepatic tumorigenesis in mice models¹³ and a predilection for HBV-related liver cancer in men.¹⁴ Conversely, estrogen has been shown to repress HCC growth in vitro and in vivo by upregulation of the JAK-STAT (Janus kinase/signal transducers and activators of transcription) pathway,¹⁵ suppression of interleukin-6 secretion from Kupffer cells,^16,17 decreased hepatocyte growth factor production,¹⁷ and NF-κB (nuclear factor kappalight chain-enhancer of activated B cells) inhibition.¹⁸

Sex-related discrepancies in the incidence and survival of other gastrointestinal tumors, including esophageal,¹⁹ gastric,²⁰ and colorectal cancers,²¹ have previously been demonstrated. Further supporting the protective role of estrogen is the consistent age-dependent relationship between sex and outcomes in these malignancies, with premenopausal women having improved survival compared with younger men. Moreover, racial/ethnic disparities in HCC survival have been reported,²² most likely reflecting differences in endemic risk factors, socioeconomic status, and/or health care practices across populations. In the current study, we explored the hypothesis that sex is a prognostic indicator in patients with HCC, and that this relationship is further influenced by age, race/ethnicity, and disease stage.

MATERIALS AND METHODS

Study Design

The Surveillance, Epidemiology, and End Results (SEER) research database for 1973 through 2010 (April 2013 version) was retrieved for the current study. The SEER program, which is sponsored by the National Cancer Institute, collects information regarding cancer incidence and survival from 18 population-based cancer registries, covering 28% of the US population (seer.cancer.gov/about/overview.html). The demographics, primary tumor site, tumor morphology, stage of disease at diagnosis, first course of radiation, surgical intervention, and survival of all patients newly diagnosed with cancer were systematically compiled by each registry. The SEER program oversampled Hispanics, Native Americans, and Asians/Pacific Islanders.

Study Population

We first identified patients diagnosed with HCC (International Classification of Diseases for Oncology, 3rd Edition [ICD-O-3] site code C22.0 and histologic type ICD-O-3 codes 8170–8175) between 1988 and 2010 from the SEER database (58,883 patients). Those patients diagnosed between 1973 and 1987 (4879 patients) were excluded due to insufficient information regarding staging. Disease stage was assessed by established prognostic criteria,²³ with categorization based on liver-limited disease (further classified by the number of lesions, the presence/absence of vascular invasion, and primary lesion size [<3 cm, 3–5 cm, or >5 cm]) versus metastatic disease. A total of 3611 patients with only a clinical diagnosis without radiographic or pathologic confirmation were excluded. Patients with SEER historic stage A (in situ or unstaged disease; 6464 patients), fibrolamellar histology (268 patients), diagnosis made at the time of autopsy or death (694 patients), unknown ethnicity (144 patients), unknown survival time (8040 patients), and those diagnosed at age <18 years or >90 years (616 patients) were excluded. Only patients with complete information available regarding sex, age, ethnic background, and staging were incorporated into the final analysis. Detailed exclusion criteria are shown in Figure 1. A total of 39,345 patients with HCC matching the specified eligibility criteria were included in the final analysis (Fig. 1).

Figure 1.

The subject selection algorithm is shown. Note that some patients met >1 exclusion criteria. SEER indicates Surveillance, Epidemiology, and End Results; HCC, hepatocellular carcinoma.

Statistical Analysis

The primary endpoint was overall survival (OS), defined as the interval from the date of diagnosis to the date of death. OS was censored at date of last contact, December 31, 2010, or 5 years after diagnosis, whichever came first. For censored subjects (10,608 patients), the median follow-up was 27 months, and 43% of the patients within this group had a follow-up of at least 3 years. The primary hypothesis was that women survive longer than men after a diagnosis of HCC, especially women aged <55 years. Based on previous studies,^19,21 we used an age of 55 years as a surrogate for menopause. A Cox proportional hazards regression model was performed to evaluate the impact of sex on OS when adjusting for other potential prognostic factors in the SEER database. We considered age at diagnosis, race/ethnicity, marital status, birthplace, tumor stage, tumor size, tumor grade, surgical procedure, use of radiotherapy, SEER registry site, and year of diagnosis in the multivariable Cox regression model. Detailed definitions of each variable are shown in Tables 1 and 2. A likelihood ratio test was used to test the interactions between sex, age, race, stage of disease, and treatment on OS. Departures from the proportional hazards assumption for the model were examined graphically using smoothed plots of weighted Schoenfeld residuals. No violation was detected. All analyses were performed using SAS statistical software (version 9.3; SAS Institute Inc, Cary, NC). Results were considered significant at P=.05 using 2-sided tests.

TABLE 1.

Variable Definitions and Categories

Variable	Definitions and Categories
Sex	Male and female
Age, y	18–44, 45–54, 55–64, 65–74, and ≥75
Race/ethnicity	White, African American, Asian/Pacific Islander, Hispanic (identified as having Spanish/Hispanic surname or of Spanish origin regardless the category in race/ethnicity), and Native American
Marital status at diagnosis	Not married (including never married, separated, divorced, widowed, and unknown) and married (including common-law marriage)
Birthplace	US-born, abroad low-incidence region, abroad high-incidence region, and unknown
Tumor stage	Single lesion in 1 lobe, multiple tumors, vascular invasion, and metastatic disease
Tumor size, cm	<3, 3 to <5 cm, ≥5 cm, and unknown
AJCC tumor grade/differentiation	Well differentiated (grade 1), moderately differentiated (grade 2), poorly differentiated or undifferentiated (grade 3 or 4), and not determined
Initial surgical procedure	None or unknown, local therapy (photodynamic therapy, electrocautery, fulguration, cryosurgery, laser, percutaneous ethanol injection, heat-radiofrequency ablation, or other), resection (wedge or segmental resection, lobectomy, or hepatectomy), and liver transplantation
Initial radiation	No, yes, and unknown
Year of diagnosis	4 periods: 1988 to 1997, 1998 to 2002, 2003 to 2005, and 2006 to 2010
SEER registry	18 SEER registry sites (seer.cancer.gov/registries/list.html)

Abbreviation: SEER, Surveillance, Epidemiology, and End Results.

TABLE 2.

HCC Staging Definitions

Stage	Description	Code
Single lesion in 1 lobe	Single lesion (1 lobe)	EOD extension: 10 CS extension: 100
Multiple tumors or >1 lobe involved	Multiple (satellite) tumors/nodules (1 lobe) without intrahepatic vascular invasion, including NOS; confined to liver, NOS; localized, NOS	EOD extension: 30, or 50 CS extension: 150, 170, 250, 270, and 390
Vascular invasion	Lesion(s) with intrahepatic vascular invasion or extension to extrahepatic blood vessel(s)	EOD extension: 20, 40, 60, 61, 62, 65, 70, 75, and 80 CS extension: 350, 370, 380, 400, 420, 440, 460, 600, 630, 635, 638, 639, 640, 645, 660, 700, 750, 755, 770, 800, and 810
Metastatic disease	Metastasis or distant lymph node involvement	EOD extension: 85 or EOD lymph node involvement: 6 or 7 CS metastases at diagnosis: 10–60 or CS lymph nodes: 200–800

Abbreviations: CS, collaborative stage; EOD, extent of disease, HCC, hepatocellular carcinoma; NOS, not otherwise specified.

RESULTS

Patient, Tumor, and Treatment Characteristics

Among the 39,345 subjects in the current study, 76% were men and 24% were women (male:female ratio of 3.1:1) (Table 3). The distribution by race/ethnicity included 50% white, 12% African American, 21% Asian, 16% Hispanic, and 1% Native American. With regard to disease burden, 84% of patients had liver-limited disease, 27% had unifocal disease, 20% had multiple lesions or multilobar involvement by a single lesion, and 36% had tumors with macrovascular invasion. Approximately 16% of patients had metastatic disease (Table 3). The distribution of tumor burden was similar between men and women, except for a slightly higher incidence of single lesions noted among women and of vascular invasion noted among men (both P<.001).

TABLE 3.

Demographic, Clinicopathologic, and Treatment Characteristics by Sex in Patients With HCC: SEER Data 1988 Through 2010

Characteristics	Total (N=39,345)	Men (N=29,788; 76%)	Women (N=9557; 24%)	P a
Median age (range), y	62 (18–89)	61 (18–89)	67 (18–89)	<.001
Age group, y
18–44	1888 (5%)	1455 (5%)	433 (5%)
45–54	8168 (21%)	6848 (23%)	1320 (14%)
55–64	11,941 (30%)	9656 (32%)	2285 (24%)	<.001
65–74	9902 (25%)	7064 (24%)	2838 (30%)
≥75	7446 (19%)	4765 (16%)	2681 (28%)
Race
White	19,586 (50%)	15,067 (51%)	4519 (47%)
African American	4826 (12%)	3696 (12%)	1130 (12%)
Asian	8293 (21%)	6015 (20%)	2278 (24%)	<.001
Hispanic	6236 (16%)	4719 (16%)	1517 (16%)
Native American	404 (1%)	291 (1%)	113 (1%)
Stage
Liver-limited disease
Single lesion in one lobe	10,780 (27%)	7762 (26%)	3018 (32%)
Tumor size, cm
<3	3151 (29%)	2249 (29%)	902 (30%)	.78b
3–5	3021 (28%)	2178 (28%)	843 (28%)
≥5	3682 (34%)	2660 (34%)	1022 (34%)
Unknown	926 (9%)	675 (9%)	251 (8%)
Multiple tumors/multilobar disease	8037 (20%)	6104 (20%)	1933 (20%)	<.001c
Vascular invasion	14,297 (36%)	11,007 (37%)	3290 (34%)
Metastatic disease	6231 (16%)	4915 (16%)	1316 (14%)
Treatmentd
None or unknown	24,225 (70%)	18,633 (71%)	5592 (68%)
Liver-directed therapy	3921 (11%)	2969 (11%)	952 (12%)
Surgical resection	3960 (11%)	2782 (11%)	1178 (14%)	<.001
Liver transplantation	2568 (7%)	2029 (8%)	539 (7%)

Abbreviations: HCC, hepatocellular carcinoma; SEER, Surveillance, Epidemiology, and End Results.

^aBased on Wilcoxon or chi-square test whenever appropriate.

^bFor comparison of tumor size between men and women among subjects with a single lesion in 1 lobe.

^cFor comparison of liver-limited disease (including a single lesion in 1 lobe, multiple tumors/multilobar disease, and vascular invasion) and metastatic disease between men and women.

^dAmong patients diagnosed in 1998 or later (n=34,674).

The median age at the time of diagnosis was 67 years in women and 61 years in men (P<.001) (Table 3). Among individuals between the ages of 18 to 54 years, the incidence of HCC was higher in men compared with women (28% vs 19%; P<.001). The age at diagnosis was significantly different by race (Figs. 2A and 2B) among both women and men (both P<.001). African American patients (median age of 58 years for men and 62 years for women) and Hispanic patients (median age of 59 years for men and 66 years for women) were younger at the time of diagnosis compared with white patients (median age of 62 years for men and 69 years for women) and Asian patients (median age of 62 years for men and 68 years for women) (Figs. 2A and 2B).

Figure 2.

Distribution of age at diagnosis is shown by race in (A) men and (B) women.

Detailed information regarding initial treatment was available for patients diagnsed after 1998 (34,674 patients). Of these patients, 11% received liver-directed therapy including photodynamic therapy, cryosurgery, percutaneous ethanol injection, or heat-radiofrequency ablation. Approximately 11% of patients underwent surgical resection (including wedge or segmental resection, lobectomy, or hepatectomy) and 7% underwent liver transplantation (Tables 1 and 3). The distribution of treatment options was found to be similar between men and women except for surgical resection, which was more frequent among women (44% of women vs 36% of men; P<.001) (Table 3).

OS by Sex, Race, Disease Burden, and Treatment

Survival differences by sex

On multivariate analysis, women were found to have a significantly greater median OS compared with men, independent of age, race, disease stage, or treatment (11 months vs 10 months; hazard ratio [HR], 0.93 [95% CI, 0.91–0.96]; P<.001) (Table 4). The impact of sex on OS was further investigated by age group and captured in adjusted survival curves (Table 4) (Fig. 3). Women aged 18 to 64 years had significantly longer OS than men of the same age group (P_interaction<.001) (Table 4). The HR for the OS of women versus men was 0.83 (95% CI, 0.77–0.88) for patients aged <55 years. The largest difference in OS was noted among the cohort of patients aged 18 to 44 years, in which women had a 4-month survival benefit (median OS, 14 months) relative to age-matched men (median OS, 10 months; HR, 0.75 [95% CI, 0.65–0.86]; P<.001) (Table 4). In contrast, there was no survival difference noted by sex among patients aged ≥65 years.

TABLE 4.

Association Between Sex and OS on Multivariate Analysis

	Adjusted Median OS (95% CI), Months		HR (95% CI)a	P a
Subjects	Male	Female
All	10 (10–10)	11 (11–12)	0.93 (0.91–0.96)	<.001
Age group, y
18–44	10 (9–11)	14 (12–16)	0.75 (0.65–0.86)	<.001
45–54	11 (11–12)	13 (12–15)	0.86 (0.79–0.92)	<.001
55–64	12 (11–12)	14 (13–15)	0.86 (0.81–0.91)	<.001
65–74	10 (10–11)	11 (10–12)	0.97 (0.92–1.02)	.19
≥75	8 (7–8)	7 (7–8)	1.04 (0.99–1.10)	.15
P interaction		<.001
Race
White	10 (10–10)	11 (10–11)	0.93 (0.89–0.96)	<.001
African American	8 (7–8)	9 (9–10)	0.85 (0.78–0.92)	<.001
Asian	12 (12–13)	13 (12–14)	1.00 (0.94–1.06)	.87
Hispanic	10 (10–11)	11 (10–12)	0.99 (0.92–1.07)	.79
P interaction		.017
Stage
Single lesion	26 (25–27)	29 (27–31)	0.95 (0.90–1.01)	.086
Multiple tumors	13 (13–14)	14 (13–15)	0.96 (0.90–1.03)	.24
Vascular invasion	8 (8–9)	9 (9–10)	0.91 (0.87–0.95)	<.001
Metastatic disease	4 (3–4)	4 (3–4)	0.94 (0.88–1.00)	.055
P interaction		.036
Treatment
None or unknown	7 (6–7)	7 (7–7)	0.96 (0.93–0.99)	.017
Liver-directed therapy	27 (25–28)	27 (25–30)	0.99 (0.89–1.09)	.82
Surgical resection	44 (40–46)	48 (44–54)	0.87 (0.78–0.96)	.008
Liver transplantation	60b	60b	1.06 (0.86– 1.29)	.60
P interaction		.045

Abbreviations: 95% CI, 95% confidence interval; HR, hazard ratio; OS, overall survival.

^aMen as the reference group (HR, 1).

^bEstimates were not reached.

Figure 3.

Overall survival is shown by sex and age. Survival probability curves are shown in patients aged (A) 18 to 44 years, (B) 45 to 54 years, (C) 55 to 64 years, and (D) ≥65 years. Men were used as the reference group for hazard ratios (HRs), which were adjusted for race, stage of disease, marital status, birthplace, tumor size, tumor grade, initial surgical procedure, initial radiation, and year of diagnosis and stratified by the Surveillance, Epidemiology, and End Results (SEER) registry. 95% CI indicates 95% confidence interval.

Survival differences by sex and race

Among all patients, the survival difference between sexes persisted in white patients (median OS of 10 months for men vs 11 months for women; P<.001) and African American patients (median OS of 8 months for men vs 9 months for women; P<.001) but not Asian (median OS of 12 months for men vs 13 months for women; P=.87) or Hispanic (median OS of 10 months for men vs 11 months for women; P=.79) patients (Table 4).

Women aged 18 to 54 years had significantly longer OS in every racial/ethnic group except for Hispanics (Table 5). Among patients aged ≥55 years, only African American women were found to have significantly longer OS compared with their male counterparts (HR, 0.86 [95% CI, 0.78–0.94]; P=.001). There were no significant differences noted with respect to sex and OS among Hispanic patients across all age groups.

TABLE 5.

Association Between Sex and OS Across Age Groups by Race, Stage of Disease, and Treatment on Multivariate Analysis

Subjects	No. Men/Women	Women Aged 18 to 54 Years		No. Men/Women	Women Aged ≥55 Years
		HR (95% CI)a	P a		HR (95% CI)a	P a
All	8303/1753	0.83 (0.77–0.88)	<.001	21,485/7804	0.96 (0.93–1.00)	.024
Race
White	3574/742	0.75 (0.68–0.83)	<.001	11,493/3777	0.97 (0.92–1.01)	.13
African American	1213/294	0.82 (0.71–0.96)	.013	2483/836	0.86 (0.78–0.94)	.001
Asian	1816/408	0.85 (0.74–0.97)	.015	4199/1870	1.04 (0.97–1.12)	.22
Hispanic	1608/288	1.12 (0.96–1.32)	.16	3111/1229	0.96 (0.89–1.05)	.38
Stage of disease
Single lesion	2065/519	0.89 (0.77–1.03)	.11	5697/2499	0.97 (0.91–1.03)	.29
Multiple tumors	1625/314	0.90 (0.76–1.06)	.19	4479/1619	0.98 (0.91–1.05)	.52
Vascular invasion	3163/663	0.80 (0.72–0.88)	<.001	7844/2627	0.95 (0.90–1.00)	.044
Metastatic disease	1450/257	0.78 (0.68–0.90)	<.001	3465/1059	0.99 (0.92–1.07)	.78
Treatment
None or unknown	5095/904	0.87 (0.80–0.94)	<.001	13,538/4688	0.98 (0.94–1.02)	.35
Liver-directed therapy	777/148	0.87 (0.68–1.11)	.26	2192/804	1.00 (0.89–1.12)	.96
Surgical resection	710/274	0.68 (0.54–0.86)	.001	2072/904	0.93 (0.83–1.05)	.26
Liver transplantation	900/188	1.06 (0.75–1.51)	.74	1129/351	1.00 (0.78–1.29)	.99

Abbreviations: 95% CI, 95% confidence interval; HR, hazard ratio; OS, overall survival.

^aMen as the reference group (HR, 1), adjusted for age, race, stage of disease, marital status, birthplace, tumor size, tumor grade, initial surgical procedure, initial radiation, and year of diagnosis and stratified by Surveillance, Epidemiology, and End Results (SEER) registry data among all patients.

Survival differences by sex and disease burden and treatment

The only disease burden category in which women were found to have a significantly better survival than men when including all age groups was vascular invasion (median OS of 9 months vs 8 months; P<.001) (Table 4). However, when stratified by age, women aged 18 to 54 years were found to have superior survival to men in the cohorts with vascular invasion (HR, 0.80; 95% CI, 0.72–0.88 [P<.001]) and metastatic disease (HR, 0.78; 95% CI, 0.68–0.90 [P<.001]) (Table 5).

With regard to treatment, women who underwent surgical resection were found to have a significantly improved OS compared with men (median OS of 48 months vs 44 months; HR, 0.87 [95% CI 0.78–0.96]; P=.01) (Table 4). This difference retained statistical significance at the time of stratification by age among patients with resected tumors, with women aged 18 to 54 years living longer than age-matched men (HR, 0.68; 95% CI, 0.54–0.86 [P=.001]) (Table 5). There was no difference in survival noted between sexes among those who received liver-directed therapy or transplantation (Table 4).

DISCUSSION

The higher risk of HCC in men compared with women is well established. However, to the best of our knowledge, there is limited information regarding the impact of sex on survival in patients with HCC. Using the SEER database, we evaluated the effect of sex on OS among patients with HCC, while accounting for other demographic variables and prognostic factors. Our analysis revealed an association between female sex and improved survival in patients with HCC. Although the improved survival observed in women compared with men was modest when including all age groups, the sex effect was more pronounced in younger cohorts. In the cohort of patients aged 18 to 44 years, the OS difference between men and women was >25%; this difference decreased gradually in the cohorts aged 45 to 54 years and 55 to 64 years and disappeared in patients aged ≥65 years. Although women were more likely to undergo surgical resection compared with men, women still retained a significant survival advantage compared with age-matched men in the subgroup of surgically resected patients, especially among those aged 18 to 54 years (HR, 0.68). The association between sex and survival in the absence of major differences in disease burden or broad treatment categories suggests an underlying physiologic explanation.

To our knowledge to date, the evidence regarding the influence of hormones and reproductive factors on liver cancer has been mixed. For example, although smaller clinical studies have postulated a causative role for oral contraceptives (OCPs) in the development of HCC,^24–27 other larger-scale and international investigations have failed to detect any significant relationship.^28,29 In one retrospective analysis evaluating >3000 patients, OCP use was actually found to be associated with improved survival in women with HCC,³⁰ and a recent meta-analysis has deemed the association between OCPs and HCC inconclusive.³¹ Likewise, the roles of parity,^32–35 age at menarche and menopause,^35–37 and age at first birth^32,35 remain unclear, with studies both supporting^34,35,37 and refuting^32,33,36 a correlation between estrogen exposure and the development of liver cancer.

The findings of the current study suggest that estrogen may protect against hepatocarcinogenesis and promote a more favorable biology once HCC develops. Specifically, the observed superior survival in women versus men among patients aged 18 to 44 years and 45 to 54 years suggests that menopausal status may correlate with outcomes in patients with HCC, and is concordant with other investigations revealing an inverse relationship between age at menopause and HCC risk.³⁶ Menopause, defined as 12 months of amenorrhea in women aged ≥45 years, occurs at an average age of 51.3 years, with only 10% of women becoming menopausal between ages 40 and 45 years or after age 55 years.³⁸ The survival advantage in women aged 55 to 64 years may reflect the lasting effect of estrogen on the biology of HCC, a generally indolent tumor with a prolonged period of carcinogenesis. Furthermore, hormone replacement therapy has been correlated with a lower risk of developing HCC,^36,39,40 and may contribute to the sex effect on survival in this age group. The lack of information regarding menopausal status or use of hormone therapy in the SEER database limits our ability to reach definitive conclusions in this regard.

Estrogen exerts its effects through 3 estrogen receptors (ERs): ER-alpha (ERα), ER-beta (ERβ), and G protein-coupled ER.⁴¹ Genome-wide expression and microRNA analyses in patients with HCC have shown ERα to be a tumor suppressor protein whose expression is inversely correlated with the presence of HBV infection, tumor size, and disease stage.⁴² Conversely, derangements in ER structure have been linked to the development of cirrhosis¹¹ and HCC¹² in Chinese carriers of HBV, although it should be noted that studies examining such genetic single nucleotide polymorphisms have yielded inconsistent results. Nonetheless, others have demonstrated that variant ER expression predominates in male patients with HCC and predicts worse survival, especially in those infected with HBV.^43,44 At the mechanistic level, preclinical models reveal that loss of ERα accelerates the development of diethylnitrosamine-induced HCC by promoting hepatocyte necrosis over apoptosis; the compensatory hepatocyte proliferation is concomitant with increased NF-κB-dependent transcriptional control of cytokine expression in Kupffer cells.⁴⁵ Another potential explanation is that estrogens repress HCC growth by inhibiting tumor-associated macrophages and preventing ERβ from interacting with ATP5J (also known as ATPase-coupling factor 6), a part of ATPase, thus inhibiting the JAK1-STAT6 pathway.⁴⁵ Although a detailed review of the biologic impact of estrogen on HCC is beyond the scope of this article, investigations to validate these mechanisms may offer critical information regarding novel therapeutic opportunities in this disease.

Another hypothesis for the association between female sex and improved prognosis in HCC may reside in the tumor-promoting impact of androgens. Androgens have demonstrated a synergistic oncogenic effect with HBV in men,⁴⁶ but not women,⁴⁷ with HCC. The androgen receptor (AR), located on the X chromosome, is found in higher concentrations in malignant compared with surrounding tissue, and peritumoral⁴⁸ and intratumoral⁴⁹ AR expression has been inversely correlated with recurrence rates after surgical resection of localized disease in patients with HCC.⁴⁸ Increased AR levels also have been linked to higher metastatic potential in HCC cell lines.⁵⁰ Moreover, patients with AR-negative HCC are more likely to be women and have significantly better 5-year OS.⁵¹ A possible mechanism through which androgen effects may be exerted is the Wnt signaling cascade,⁵² as evidenced by gene expression analyses⁵³ and mouse models.⁵⁴ Further investigations are warranted to elucidate the exact pathways, especially as Wnt inhibitors enter into clinical practice.

In addition to the impact of sex on survival, we explored potential interactions between sex and ethnicity. In the current analysis, women aged <55 years had superior survival to men across all ethnicities except Hispanics. This could reflect disparities in health care access and treatment patterns. One SEER investigation, for example, demonstrated that Hispanic individuals were 24% to 27% less likely than white individuals to undergo surgery for localized HCC.⁵⁵ When taking into account both local therapies and transplantation, another study found that Hispanic patients had the lowest administration of any invasive intervention.⁵⁶ Another possible explanation may be related to the difference in HCC etiology among Hispanic individuals. Hispanic patients tend to have less hepatitis-associated HCC and more hepatomas related to alcoholic cirrhosis and NAFLD,⁵⁷ which may be influenced to a different extent and manner by androgens and estrogens.

The current study has its limitations, the first of which is its retrospective nature. Moreover, the lack of information in the SEER database regarding HCC predisposing factors (eg, HBV, hepatitis C virus, NAFLD, etc), other comorbidities, socioeconomic status, and treatment rendered (other than crude initial surgical procedure and radiation) limits the strength of our conclusions because any of these factors could differ by sex. Importantly, we cannot determine the effect of menopausal status or exogenous estrogen supplementation on outcomes because this information was not available.

The results of the current study demonstrate that sex influences survival among patients with HCC. This is in agreement with preclinical data confirming androgens and estrogens as modulators of hepatic fibrosis, cirrhosis, and progression to HCC. It is also consistent with epidemiologic studies demonstrating superior outcomes in younger women with other gastrointestinal cancers. The findings of the current study should be validated in prospective studies that allow for better control of confounding factors and may present unique opportunities for biomarker development and novel therapeutics.