Insulin Resistance Used To Assess Malignancies In Women
Overview
In this prospective multicenter real-world cohort study involving 571 patients diagnosed with female reproductive system malignancies, the prognostic significance of insulin resistance (IR) and systemic inflammation was investigated. The cohort, with a mean age of 52 years, predominantly comprised individuals with cervical cancer (55.90%).
Lipid ratios reflecting IR, such as low-density lipoprotein-cholesterol/high-density lipoprotein-cholesterol (LHR), total cholesterol/high-density lipoprotein-cholesterol (TCHR), triglyceride/high-density lipoprotein-cholesterol (TGHR), and fasting triglyceride/glucose (TyG), were utilized. Optimal cut-off values were determined, and the study employed Kaplan–Meier and Cox regression analyses to calculate hazard ratios for overall survival.
The findings revealed a negative correlation between both IR and inflammation and overall survival in female reproductive system cancer patients. Multivariate survival analysis indicated that elevated LHR, TCHR, TGHR, TyG, and neutrophil-lymphocyte ratio (NLR) were significantly associated with a worse prognosis. Among the four IR surrogate indicators, TyG emerged as the most valuable for predicting prognosis in patients with malignant tumors of the female reproductive system.
Furthermore, the combination of high TyG and high NLR demonstrated improved prognostic value, emphasizing the independent predictive capability of IR in this population. The study suggests that IR, irrespective of the specific IR substitution index, can serve as an independent predictor of prognosis in female reproductive system malignancies. The combination of TyG and NLR offers enhanced prognostic insights for women with breast cancer.
Introduction
Cervical, endometrial, and ovarian cancers, prevalent among female reproductive system malignancies, contribute significantly to global cancer morbidity and mortality. Despite advancements in cancer interventions, patient prognosis remains a challenge. Age-related hormonal fluctuations and reproductive history play pivotal roles in cancer outcomes, emphasizing the need to identify clinical features reflecting metabolic changes for improved interventions.
Patients with cancer often exhibit increased insulin resistance (IR), malnutrition, and inflammatory responses, culminating in compromised chemotherapy responses and poorer prognoses. IR, a hallmark of various health conditions, is traditionally diagnosed using the hyperinsulinemic–euglycemic glucose clamp technique, which, though gold standard, poses challenges in terms of difficulty, cost, and time consumption. As an alternative, lipid ratios (LHR, TCHR, TGHR, TyG) have gained attention as simpler markers for insulin resistance. The TyG index, in particular, has demonstrated associations with nonalcoholic fatty liver disease and bladder cancer, highlighting its potential in linking metabolic conditions to cancer risk.
The neutrophil lymphocyte ratio (NLR), an inflammatory indicator, independently predicts patient prognosis. The combined impact of IR and systemic inflammation has shown enhanced prognostic value in breast cancer. Despite these insights, limited studies focus on the prognostic implications of IR in female reproductive system cancers.
This study aims to elucidate the prognostic value of insulin resistance in female reproductive system tumors, identify key prognostic indicators of insulin resistance, and enhance patient prognosis evaluation by integrating inflammatory markers. Through this exploration, the research seeks to contribute valuable insights into clinical interventions for improved outcomes in patients with female reproductive system cancers.
Method
This prospective cohort study, part of the Investigation on Nutrition Status and its Clinical Outcome of Common Cancers (INSCOC) cohort in China, focuses on evaluating the relationship between nutritional status and clinical outcomes in patients with common cancers. The INSCOC trial, registered under ChiCTR1800020329, gathered data from multiple Chinese institutions, involving patients aged ≥18 diagnosed with solid tumors who underwent various anticancer therapies and were hospitalized for >48 hours.
Patients with active infections, immune diseases, or missing essential data were excluded. The study adhered to the Declaration of Helsinki, with ethical approval from local committees and obtaining written/oral informed consent from participants, ensuring privacy protection.
Data collection encompassed patient demographics, tumor characteristics, lifestyle factors, and nutritional risks assessed by NRS2002. Anthropometric measurements, including body mass index (BMI), categorized patients into normal (≤24 kg/m²) and overweight/obesity (>24 kg/m²). Clinical staging followed the 8th edition of the AJCC TNM system.
Serological indicators, such as albumin, cholesterol levels, triglycerides, LDL, HDL, neutrophil count, lymphocyte count, and blood glucose, were normalized within 24 hours after admission post-overnight fasting.
Assessment of insulin resistance (IR) and inflammatory status involved calculating various indices (LHR, TCHR, TGHR, TyG, and NLR) using specified formulas and optimal cut-off values determined by rank statistics.
The study’s primary endpoint was all-cause mortality, measured in months from admission to death or last follow-up. Follow-up data were collected through regular visits or telephone interviews. The rigorous methodology of this study aims to provide valuable insights into the complex interplay between nutritional status, insulin resistance, inflammation, and clinical outcomes in cancer patients.
Statistical Analysis
Continuous variables in the study are presented as mean ± standard deviation or median with interquartile range (IQR), while categorical variables are expressed as numbers and percentages. Statistical comparisons involved the independent Student T-test or nonparametric test for continuous variables and the Chi-square test or Fisher’s exact test for categorical variables. Covariates and potential confounders were selected based on previous studies.
Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for significant prognostic factors related to overall survival, employing univariate and multivariate Cox regression analyses. Subgroup and sensitivity analyses were conducted, and the association between insulin resistance (IR)-related indices and survival in female reproductive system malignancies was explored using restricted cubic splines.
Time–patient survival trends and group comparisons were depicted through Kaplan–Meier curves and log‐rank tests. The Harrell C index assessed and compared the predictive ability of IR indexes on patient survival. Additionally, the receiver operating characteristic curve was utilized to compare the prognostic value of triglyceride/high‐density lipoprotein‐cholesterol ratio (TGHR) and neutrophil lymphocyte ratio (NLR), both individually and in combination, for female reproductive system malignancies.
All statistical analyses were performed using R software, version 4.1.1, and a two‐sided p-value of <.05 was considered statistically significant. The rigorous methodology ensures robust analysis and reliable insights into the prognostic factors in the context of female reproductive system malignancies.
Result
The study included 571 patients diagnosed with female reproductive malignancies, predominantly cervical cancer (55.90%). The mean age of patients was 52.0 ± 14.0 years. Systemic chemotherapy was administered to 63.20% of patients, and 19.60% were identified as nutritionally at risk. Comparative analysis with excluded patients indicated slightly higher values for hypertension, chemotherapy, albumin, fasting blood glucose, BMI, and lower rates of surgery and nutritional risk in the study cohort.
Investigating the correlation between insulin resistance (IR) and prognosis through restricted spline curves revealed a negative association in women with reproductive system tumors. Using optimal cut-off values, higher IR levels were significantly linked to poorer prognosis. Univariate analysis demonstrated that higher IR, regardless of the index used, was associated with elevated mortality. Multivariate analysis confirmed that high values in IR indices (LHR, TCHR, TGHR, TyG) and elevated neutrophil lymphocyte ratio (NLR) were indicative of worse prognosis.
Comparison of IR surrogate measures revealed that TyG exhibited the highest prognostic value. Subgroup analysis indicated that high TyG was particularly impactful in certain patient categories. Combining IR and inflammation indicators, patients with high TyG and NLR demonstrated the worst survival. Adjusted analyses confirmed that high IR combined with high inflammatory state significantly predicted adverse prognosis, even after considering metabolic factors.
Exclusion of short-term deaths sustained the predictive power of high insulin resistance and inflammatory status on overall survival. The association was prominent in cervical cancer patients and observed, although not statistically significant, in ovarian and endometrial cancer patients. The combined prognostic ability of insulin resistance and inflammatory response indicators surpassed individual indices, as confirmed by statistical significance. The study provides valuable insights into the prognostic implications of insulin resistance and inflammation in female reproductive system malignancies.
Conclusion
In this retrospective multicenter study involving 571 women with reproductive system malignancies, the focus was on lipid ratios as predictors of insulin resistance (IR) and its impact on patient prognosis. The study revealed that 11.2%–45.5% of patients exhibited IR based on various lipid ratios. The investigation emphasized the significant association between IR, systemic inflammation, and overall survival in patients with female reproductive system malignancies. The study further highlighted that combining insulin resistance with inflammatory markers enhances prognostic predictions.
Insulin resistance, a complex disorder affecting glucose homeostasis, has been identified as a prognostic factor in various tumors, including lung, breast, and prostate cancers. However, limited research has explored the relationship between IR and prognoses in female reproductive system malignancies, making this study particularly relevant.
Systemic inflammatory biomarkers, crucial indicators of cancer, were discussed, with neutrophil-to-lymphocyte ratio (NLR) recognized as a marker of systemic inflammation. The study elucidated the role of inflammatory responses, emphasizing the impact on insulin sensitivity and promotion of insulin resistance in cancer patients.
Insulin, aside from its hypoglycemic effects, serves as a growth factor influencing cell proliferation. The occurrence of insulin resistance in cancer patients is attributed to genetic, environmental factors, and systemic inflammation. Due to the clinical challenges in achieving the gold standard for IR diagnosis, lipid ratios, such as Triglyceride and Glucose Index (TyG), have gained attention as surrogate indicators. TyG, in particular, emerged as the optimal indicator in reflecting insulin resistance status in female reproductive system malignancies, supported by previous research.
The study introduced the combination of TyG and NLR as an independent prognostic factor for these malignancies, demonstrating its significance in univariate survival analysis and after adjusting for confounders. Notably, a subgroup analysis revealed that perimenopausal women with insulin resistance experienced significantly worse prognosis compared to reproductive and postmenopausal women, suggesting a link between metabolic changes during perimenopause and insulin resistance.
While the study is the first to explore the relationship between insulin resistance, inflammation, and prognosis in Chinese female patients with reproductive system malignancies, certain limitations were acknowledged. The results, based on the Chinese population, should be verified in more diverse patient populations. Additionally, potential confounders may exist, and certain female-specific predictors, such as sex hormones, were not included in the study.
In conclusion, this study underscores the independent prognostic value of insulin resistance in female reproductive system malignancies, irrespective of the specific insulin resistance index used. The findings emphasize the importance of assessing and treating insulin resistance as a vital component in determining the prognosis of cancer patients, with potential implications for personalized therapeutic strategies.
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