Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, characterized by late-stage diagnosis, limited therapeutic options and poor prognosis. Despite advancements in oncology, the 5-year survival rate remains dismal at ~13% (1). While substantial research has focused on genetic and environmental risk factors, molecular changes and novel treatment options for PDAC, the influence of biological sex on disease incidence, progression and treatment response remains insufficiently understood.

Sex- and gender-specific factors are increasingly recognized as important determinants of disease susceptibility, progression, and treatment outcomes. Sex refers to biological attributes, while gender encompasses socially constructed roles and behaviors (2). Both biological and sociocultural components of sex and gender can profoundly influence healthcare delivery from prevention and screening to diagnosis and therapy, highlighting the need for more individualized sex- and gender-specific approaches (3,4). Despite recent efforts, women remain underrepresented in clinical studies, often due to inclusion biases related to fertility concerns and hormonal variability (5). In oncology, these disparities remain insufficiently addressed, hindering progress toward truly personalized and effective treatment strategies (6). How sex-specific factors shape disease biology and outcomes is particularly evident in colorectal cancer. Although it affects both sexes, women over the age of 65 have higher mortality rates and a lower 5-year survival rate compared with age-matched men (7). This survival disadvantage may, at least in part, be related to the higher likelihood of women developing right-sided colon cancer, which is often associated with more aggressive tumor phenotypes, and to their greater susceptibility to treatment-related toxicity (7,8). These findings underscore the clinical relevance of sex-based differences in cancer biology and outcomes and highlight opportunities to develop strategies that optimize treatment based on sex-specific factors.

By contrast, sex-specific differences in PDAC remain poorly studied, resulting in limited evidence for sex-based variations in pathophysiology and a lack of precision medicine approaches tailored to both men and women. The present review summarizes current evidence on the epidemiological, biological and clinical aspects of sex differences in PDAC. By identifying key disparities, the present review aims to highlight the need for sex-specific strategies in prevention, diagnosis and treatment, which could advance personalized and effective care, while offering approaches to improve the integration of these variables into basic and clinical research.

PDAC displays a slightly higher incidence in men than in women, with 269,709 vs. 241,283 respective new cases reported in 2022, ranking it as the 15th and 16th most common cancer in men and women, respectively (9). Globally, PDAC incidence rates are rising, with a disproportionately steeper increase observed in women. Between 1975 and 2016, incidence rates increased annually by 1.1% in women compared with 0.38% in men, highlighting a growing burden of PDAC among women (10). The highest incidence rates are reported in highly developed regions, likely due to lifestyle and environmental factors, with Western Europe currently exhibiting the highest lifetime risk of PDAC (11).

Notably, the incidence and mortality of PDAC peak at different ages between sexes: In men, the highest number of cases and deaths occurs between ages 65-69 years, whereas in women, it peaks between ages 75-79 years (12). Of particular concern is the rising incidence of PDAC among women <40 years, who now show higher rates compared with age-matched men (13,14). A study by Cavazzani et al (13) reported the greatest increase in PDAC incidence among women aged 18-26 years, with an average annual percentage change (AAPC) of 9.37% [95% confidence interval (CI), 7.36-11.41%; P<0.0001], compared with an AAPC of 4.43% in men of the same age group. Survival rates remain poor for both sexes, with a 5-year survival of ~13% (1). While the age-standardized mortality rate is higher in men overall, this varies by age group. The most pronounced sex difference in relative survival is observed in patients <44 years, with survival rates of 24.37% in women vs. 18.03% in men. However, this difference diminishes with age, and survival rates become comparable in individuals >65 years (4.68% in women vs. 4.44% in men) (15).

PDAC represents a growing global public health challenge. The disproportionately steeper rise in incidence among women, particularly at younger ages, highlights the urgent need for sex-specific strategies in prevention, early detection, and treatment.

Multiple risk factors for PDAC have been well established, including tobacco smoking, alcohol consumption, obesity, diabetes mellitus, chronic pancreatitis, and genetic predisposition (14). However, sex-based differences are often overlooked. This section provides an overview of sex-specific variations in non-genetic PDAC risk factors.

Chemotherapeutic drugs are commonly prescribed at standardized doses based on body weight or body surface area, although therapeutic efficacy is more closely related to circulating drug concentrations than to the administered dose (6). As a result, interindividual variations in drug metabolism can lead to suboptimal outcomes, including reduced efficacy or increased toxicity (6). Pharmacokinetics and pharmacodynamics differ between the sexes, yet this is often overlooked in clinical dosing strategies. Factors such as higher body fat percentage in women (42), greater renal function in men (6), and differences in muscle mass, total body water, cardiac output, and liver perfusion (4) all influence drug distribution and metabolism. A recent systematic review identified significant sex-specific pharmacokinetic differences for several drugs, including 5-fluorouracil (5-FU) and paclitaxel, both of which are integral components of standard PDAC treatment regimens (4,43). 5-FU, a key drug in the FOLFIRINOX regimen (leucovorin, 5-FU, irinotecan, and oxaliplatin) (43), is cleared >20% more rapidly in men than in women. Consequently, equivalent dosing may lead to increased toxicity in women and a potential risk of underdosing in men (44). Notably, this sex difference in clearance remains significant even after adjusting for age and dose (45). The difference may be partially explained by sex-specific variation in the activity of dihydropyrimidine dehydrogenase, the primary enzyme responsible for metabolizing 5-FU (45). In addition, genetic variants of methylenetetrahydrofolate reductase, an enzyme that influences 5-FU cytotoxicity, have demonstrated sex-dependent effects, suggesting that female patients may require lower 5-FU doses to avoid toxicity (42). In line with these findings, a study on colorectal cancer has shown that women experience a significantly higher rate of side effects from 5-FU-based therapies, both in the adjuvant and metastatic settings (4). In the treatment of colorectal cancer, increased toxicity has been reported not only in combination regimens but also with 5-FU monotherapy (4).

Sex-related pharmacokinetic differences for oxaliplatin are inconsistent. While a study has reported a 40% lower clearance in women (46), another found no significant sex-based differences (47). Data on irinotecan are similarly mixed. Certain studies suggest that women may have lower clearance, reduced volume of distribution and decreased bioavailability, potentially influencing both efficacy and toxicity (48,49). However, another investigation attributed this variability primarily to liver function, with minimal differences attributable to sex (50). Although 5-FU, irinotecan, and oxaliplatin are administered in combination in PDAC treatment, the interactions and cumulative pharmacokinetic effects of these drugs remain poorly understood. Although pharmacokinetic findings imply differing toxicity risks, few studies have systematically evaluated chemotherapy-related adverse events in PDAC by sex. Existing data are often limited by small sample sizes or single-center designs. Some report higher toxicity rates in women, such as constipation, hand-foot syndrome and epigastric pain (51), and an increased incidence of febrile neutropenia and agranulocytosis during FOLFIRINOX treatment (52). Others, including a prospective Korean study, found no significant overall differences but noted more frequent dose reductions among female patients (53), suggesting lower tolerance or heightened susceptibility to toxicity.

Gemcitabine, either as a monotherapy or in combination with nab-paclitaxel, is another well-established PDAC treatment regimen for PDAC. To date and to the best of our knowledge, no clinical evidence supports a sex-specific difference in gemcitabine pharmacokinetics (54,55). While sex has been shown to influence the clearance and toxicity of solvent-based paclitaxel (56,57), this effect is not observed with nab-paclitaxel, which displays no sex-related differences in elimination (58), suggesting a distinct pharmacological mechanism.

In summary, pharmacokinetic studies of 5-FU, irinotecan and oxaliplatin suggest that standardized dosing does not adequately account for sex-specific variability, with men at risk of potential underdosing and women at higher risk of toxicity. Major PDAC trials rarely stratify adverse events by sex, underscoring the need for comprehensive, sex-disaggregated toxicity analyses. Addressing this through novel therapy concepts is essential to optimize therapeutic efficacy, minimize adverse events and advance sex-sensitive treatment strategies in pancreatic cancer.

Few studies, albeit with large populations, have explored sex differences in treatment allocation and prognostic outcomes in PDAC. Notably, the Dutch Pancreatic Cancer Group conducted two large retrospective studies analyzing sex-based differences in tumor characteristics, treatment decisions, and survival outcomes in both stage I-III and metastatic PDAC cohorts, each including >6,000 patients (59,60). In both cohorts, female patients were older, had worse performance status but fewer comorbidities and were less likely to receive systemic chemotherapy compared with male patients. The primary reason for this disparity was a higher preference among women for best supportive care across all disease stages. No sex-based difference was observed in the likelihood of undergoing surgical resection in resectable PDAC, except among women aged ≥80 years, who were less frequently offered surgery (59,60). By contrast, two additional studies reported a lower likelihood of curative treatment planning for female patients. The first was a preliminary analysis of 100 patients from the Chemotherapy, Host Response and Molecular dynamics in Periampullary cancer (CHAMP) study, which includes both pancreatic and periampullary adenocarcinomas. The second was a nationwide Swedish cohort study of 5,677 patients with periampullary tumors, which similarly reported that fewer women were planned for curative treatment (61,62). However, in the Swedish cohort, this difference disappeared after adjustment for age and tumor location, unlike in the CHAMP study. This discrepancy may be explained by the inclusion of other periampullary tumors, such as duodenal adenocarcinomas, which have different surgical and prognostic profiles and may influence treatment decisions. The largest study to date, conducted by the American College of Surgeons and including 22,993 patients, identified male sex as a risk factor for major morbidity following pancreaticoduodenectomy (63). These findings highlight that sex disparities in treatment outcomes are not unequivocal and must be interpreted with caution. Most available studies are retrospective and heterogeneous in design, with varying inclusion criteria, treatment eras and adjustment for confounders, which limits the strength of causal inference. Observed associations between sex and prognosis in PDAC likely reflect the interplay of multiple factors, including age, performance status, comorbidities, socioeconomic status, access to specialized care and patient preferences, rather than biological sex alone. Few studies have stratified analyses or applied sensitivity models to disentangle these sociocultural and clinical variables from intrinsic biological differences. Nevertheless, several studies have identified female sex as an independent prognostic factor for improved overall survival (OS) in PDAC (59,60,64). Large cohort studies have reported a statistically significant increase, or at least a trend toward, increased OS in women, even after adjusting for confounders. However, in the end, only two studies have directly examined sex differences in response to FOLFIRINOX. A small cohort study by Hohla et al (65), which included 49 patients with unresectable PDAC, found a significantly higher disease control rate in female patients treated with FOLFIRINOX compared with males. Similarly, the PRODIGE 4/ACCORD 11 randomized trial observed a trend toward longer median OS in female patients with metastatic disease receiving FOLFIRINOX, although this did not reach statistical significance (64). These findings again raise important questions about whether differences in chemotherapy toxicity and metabolism contribute to improved survival outcomes in women, underscoring the need for prospective studies with sex-stratified analyses and standardized reporting to improve the assessment of the biological vs. sociocultural determinants of treatment response in PDAC (3).

Sex-based biological differences, particularly within the immune system, are well recognized across multiple diseases, including cancer (66-68). Generally, women exhibit stronger innate and adaptive immune responses, which has been linked to a higher prevalence of autoimmune disorders in women (66,67). The immune differences in men and women are regulated by both gonadal hormones, primarily estrogen and androgens and genetic mechanisms (66,69). Notably, stronger interferon signaling in women may result from two key mechanisms: i) Estrogen-mediated immune activation; and ii) X chromosome-linked differences. Estrogen enhances interferon production through Toll-like receptor 7 (TLR7) activation (70,71), and since TLR7 is encoded on the X chromosome, its expression and downstream immune responses are amplified in women (72). In addition, T and B cells in women demonstrate enhanced signaling and antibody responses to infections and vaccinations (67,73), which may contribute to more effective tumor immune surveillance. Estrogen further shapes the TME by modulating T cell activation and immune checkpoint expression (67,68,74). Across several cancer entities, the TMEs in women tend to display stronger immune activation than those of men (68,75).

In PDAC, the TME is a key contributor to immune evasion and poor prognosis; it is typically characterized by scarce cytotoxic T cell infiltration, abundant regulatory T cells and a dense, fibrotic stroma, which are features that also limit the response to immunotherapy (76,77). As a result, checkpoint inhibitors have shown limited efficacy in PDAC due to the inherently immunosuppressive nature of the tumor (78). Nevertheless, emerging evidence indicates that sex differences do influence immune pathways and the TME in PDAC. For example, He et al (79) identified a typically immunosuppressive subpopulation of formyl peptide receptor 2 (+) M2 macrophages that is specifically enriched in PDAC lesions from female patients. These tumor associated macrophages (TAMs), induced by estrogen, were associated with T cell exhaustion, reduced immune cell infiltration and poorer survival in women, suggesting a sex-specific immunosuppressive mechanism. In contrast to these findings, a recent study reported that female patients with PDAC exhibit higher levels of stromal biomarkers and increased tumor stiffness, both of which were associated with longer survival (80). The researchers further showed that estrogen signaling shapes the TME by driving cancer-associated fibroblasts toward a more tumor-suppressive phenotype (80). However, these estrogen-related effects were mediated not by systemic hormones but by locally produced estrogens within the tumor tissue and therefore do not fully explain the survival differences observed between women and men (80). In another study investigating patients with treatment-naive PDAC, women exhibited elevated circulating levels of C-X-C motif chemokine ligand (CXCL)9, IL-1β, IL-6, IL-10 and IL-13, supporting the notion of enhanced systemic immune activation in women (81).

Sex differences may also impact immune responses to chemotherapy. In a recent study by van Eijck et al (82), female sex was an independent prognostic factor for 5-year OS in patients with localized PDAC treated with neoadjuvant gemcitabine-based chemotherapy followed by surgery (43% OS in females vs. 22% in males). Notably, after neoadjuvant therapy, the TME in female patients showed fewer immunosuppressive M2 macrophages (CD163⁺MRC1) and a distinct transcriptomic profile with higher expression of CXCL10 and CXCL11 and lower levels of CCL2 and IL-34, suggesting an enhanced antitumor immune response (82). Although data on sex differences in immune responses in PDAC remain limited and potentially confounded by complex interactions among hormones, drugs and genetics, current evidence suggests that women may exhibit a more immunosuppressive TME characterized by a higher abundance of estrogen-influenced immunosuppressive macrophages, contrary to the expected higher immune activation in women. Notably, gemcitabine appears to induce greater macrophage plasticity in women, indicating a potential pathway for immune activation. Together, these observations highlight that sex and sex hormones uniquely shape immune activity in the TME and modulate responses to chemotherapy. Fig. 1 summarizes sex-related hormonal and genetic differences in PDAC, highlighting the distinct roles of estrogens and androgens in shaping tumor biology, immune responses and the TME in women and men. Although immune-targeted therapies have shown limited success in PDAC, emerging approaches such as neoantigen vaccination show promise and may enhance immune-based treatment strategies (83). Accounting for sex-specific immune regulation will therefore be critical as immunotherapies for PDAC continue to advance.

Research on tumor microbiota has provided compelling insights into its role in modulating the TME (84) and shaping systemic immune responses, thereby influencing various diseases (85). In PDAC, the intratumoral microbiota significantly impacts prognosis and therapeutic efficacy, most notably by altering the TME (86), influencing tumor phenotype (87), and degrading chemotherapeutic agents such as gemcitabine (88,89). However, the influence of sex on the tumor microbiota remains unclear. To date, few studies have assessed bacterial species distribution by sex in patients with PDAC and none have reported significant differences (86,90). This is further supported by comparable rates of bacterial colonization in tumor tissue across sexes (91), as well as a similar prevalence of intratumoral gram-negative bacteria in male and female patients (89). Although it should be noted that none of the studies chose the investigation of sex-specific differences as their primary endpoint.

Nonetheless, sex-specific differences in the oral and gut microbiota have been reported in patients with PDAC compared with healthy controls (92). These differences are also evident in murine models, where a recent study identified increased abundance of Ligilactobacillus and Acetatifactor in female mice with PDAC (93). While intriguing, the implications of these findings for immune modulation or tumor progression remain unclear. Further illustrating the role of microbiota in therapy, antibiotic administration has been shown to enhance gemcitabine efficacy in advanced PDAC (94), although this effect was not associated with patient sex. While current evidence does not show consistent sex-based differences in the tumor microbiota of PDAC, emerging findings in gut and oral microbiomes, as well as in preclinical models, underscore the need for further investigation. Understanding how sex may modulate the microbiome-immune-tumor axis could open new avenues for personalized therapeutic strategies.

PDAC exhibits clear sex-based differences across multiple dimensions, including incidence, risk factors, tumor biology, immune response and treatment outcomes. While men have historically shown higher incidence and mortality rates, the burden of disease is rising disproportionately in women, particularly in younger women, underscoring the importance of sex-specific research. Rising pancreatic cancer rates in young women likely result from a combination of sex-based biological vulnerability and gender-related behavioral patterns. Biologically, women appear more susceptible to the carcinogenic effects of obesity, central fat distribution and early-life smoking. Socially and behaviorally, earlier smoking initiation, rising obesity rates and increasing risky alcohol consumption intensify exposure to these factors. These combined dynamics highlight the need for targeted, sex- and gender-specific risk-prevention strategies.

Biological sex influences not only disease susceptibility but also chemotherapy pharmacokinetics, toxicity profiles, immune responses, and potentially tumor progression pathways. Women often experience greater treatment-related toxicity, while men may face subtherapeutic dosing, indicating that standardized treatment regimens may inadequately account for sex-based variability. In this context, existing therapeutic drug-monitoring approaches for agents such as 5-FU and irinotecan represent an important but underused opportunity; when applied consistently, these tools could facilitate more precise dose optimization for both sexes and help mitigate sex-related differences in exposure and toxicity. In addition, gender and sociocultural factors influence how cancer treatment is received and tolerated, yet they remain largely unaddressed in research and clinical practice. Despite accumulating evidence, most large clinical trials and translational studies still fail to stratify or analyze outcomes by sex, leaving a critical gap in our ability to personalize therapy.

To advance toward precision medicine in PDAC, sex must be systematically incorporated as a biological variable at every stage of research and clinical development. For instance, future PDAC trials should include sex as a predefined stratification factor or covariate in randomization and outcome analyses, ensuring adequate statistical power for sex-specific endpoints. Adaptive trial designs could prospectively test sex-based differences in efficacy or toxicity. Pharmacokinetic and pharmacogenomic studies should explicitly evaluate sex differences in drug metabolism, immune response, tolerance and exposure-response associations to guide individualized dosing strategies. Furthermore, translational studies should report biomarker performance and prognostic value separately for men and women, to identify sex-specific predictive signatures of response or resistance. Finally, in preclinical models, the development of sex-balanced patient-derived organoids and murine models should be considered for dissecting sex-dependent mechanisms and therapeutic vulnerabilities (Fig. 2).

It should be acknowledged that current evidence is largely derived from retrospective analyses with heterogeneous metho dologies and limited adjustment for confounders. Nevertheless, the present review highlights that sex-stratified data remain underreported in PDAC trials, and that preclinical systems rarely account for hormonal or chromosomal sex effects. Addressing these limitations will require coordinated efforts to standardize sex reporting, design prospective studies with balanced enrollment and integrate multi-omic datasets to unravel biological from sociocultural determinants of outcome. In conclusion, addressing sex disparities in PDAC is not merely a scientific objective but a prerequisite for equitable precision oncology. Incorporating sex-based insights into risk assessment, biomarker discovery and therapeutic design will be essential to optimize treatment efficacy and minimize toxicity, ultimately moving toward more personalized and effective care for all patients with PDAC.