Biologic Sex and Obesity Shape Post-Surgical Outcomes in Pancreatic Cancer Study

As the incidence of obesity continues to rise nationally and globally, a new observational study published in Cancer reports that liver recurrence and survival outcomes in patients with pancreatic adenocarcinoma (PDAC) after upfront surgical resection appeared to differ by biologic sex and obesity.¹

In a cohort of patients with PDAC who underwent a surgery-first (upfront) approach, females with obesity were observed to have the most favorable outcomes, exhibiting superior overall survival (OS) (median OS, 37 months; 95% CI, 30–46 months) and the lowest cumulative incidence of liver recurrence at 12 (13%; 95% CI, 7.2%–20%) and 24 months (15%; 95% CI, 8.7%–23%; P =.027) post-surgery compared with those of their female counterparts without obesity and males with and without obesity.

Further, a univariate model revealed a significant association between male sex and OS (HR, 1.24; 95% CI, 1.06–1.44; P =.007); a multivariate model found that only males with obesity had significant worse OS (HR, 1.56; 95% CI, 1.12–2.18; P =.009) compared with females with obesity.

“We infer therefore that there is something protective within the obese female liver or metabolism that may limit engraftment of metastatic disease, inhibit metastatic cell growth within the liver, or augment the antitumor effects of systemic chemotherapy,” hypothesized the authors, Judge et al, on the findings.¹ The authors also pointed to possible hormonal mechanisms driving disease recurrence.

What were the study methodology and patient characteristics?

The objective of the study was to examine the association between obesity and sex and liver recurrence and overall survival (OS) in patients undergoing a surgery-first approach for pancreatic cancer.

This retrospective analysis utilized data of patients treated at Memorial Sloan Kettering Cancer Center for resected pancreatic cancer between 2012 and 2022. A total of 939 patients who underwent upfront surgery with a final pathologic diagnosis of PDAC were included for analysis, with a median age of 70 years and 73% having undergone pancreaticduodenectomy. Patients were dichotomized into male or female categories and grouped into 6 categories of body mass index (BMI; kg/m²) according to the Centers for Disease Control and Prevention and World Health Organization: underweight (BMI, <18.5), normal (BMI, 18.5–24.9), overweight (BMI, 25.0–29.9), obese class I (BMI, 30.0–34.9), obese class II (BMI, 35.0–39.9), and obese class III (BMI≥40).

Using these data, investigators constructed univariate models to evaluate association between clinical and pathologic factors and OS, defined as the period from the date of surgery until the date of death or last follow-up, as well as multivariable-adjusted models to evaluate the independent association between combined obesity and sex and OS. To account for subgroup differences in baseline hazard, investigators stratified the model by adjuvant therapy use. The models were also adjusted for baseline clinical and prognostic factors that were found to be correlated with OS in the univariate models, including vascular invasion, perineural invasion, pathologic T stage, pathologic N stage, surgical margin, and Charlson Comorbidity Index score. To assess disease recurrence, investigators reviewed surveillance or diagnostic imaging reports.

As a retrospective study, there is an inherent potential for selection bias, as well as a lack of available information in medical records. For instance, the study did not account for prediagnosis BMI as this information was not available in the dataset, which may have altered the study cohort as weight loss is common with pancreatic cancer diagnoses. Acknowledging this limitation and the potential confounding influence of weight loss, the investigators excluded patients who received neoadjuvant chemotherapy, increasing the likelihood that patients would be in good physical condition.

Nevertheless, the differences uncovered by this study highlight a novel interaction between sex and obesity in shaping outcomes, lending to future inquiries into host biology, as well as the noteworthy impact of sex and obesity on recurrence in the liver, a common site of PDAC recurrence associated with the poorest survival outcomes.²

“The impact of obesity and sex on liver recurrences may allow for personalized prognostication among patients with resected pancreatic cancer, and provides a framework for preclinical investigations into the mechanism of liver metastasis formation on the basis of clinically relevant variables, including biologic sex and obesity status,” added the investigators.¹

REFERENCES:

1. Judge SJ, Manin E, Chou J, et al. Influence of biologic sex and obesity on liver recurrence and survival in patients undergoing upfront surgery for pancreatic adenocarcinoma. Cancer. 2025;131(18). doi:https://doi.org/10.1002/cncr.70088

2. Zheng B, Kenoki Ohuchida, Yan Z, Okumura T, Takao Ohtsuka, Nakamura M. Primary Recurrence in the Lung is Related to Favorable Prognosis in Patients with Pancreatic Cancer and Postoperative Recurrence. World J Surg. 2017;41(11):2858-2866. doi:https://doi.org/10.1007/s00268-017-4068-6