Abstract

Background: The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are biomarkers of severe inflammation. The prognostic role of NLR and PLR in patients with high-grade epithelial ovarian cancer (HG-EOC) remains inconsistent.

Objective: This study was conducted to evaluate the prognostic value of NLR/PLR in HG-EOC patients.

Methods: We retrospectively reviewed 32 patients with HG-EOC treated at the Sultan Qaboos Comprehensive Care & Research Center, University Medical City, between January 2022 and December 2023. The clinicopathologic records and complete blood counts of the patients were analyzed.

Results: Thirty-two epithelial HG-EOC patients were included in the analysis. Median age at diagnosis was 56 years (range: 16-89). Most of the patients (44%) were diagnosed at stage III, and 53% were high grade serous ovarian cancer (HGSOC). The decrease in NLR from baseline was statistically significant at 3 months (p=0.040) and 6 months (p=0.005) of follow-up post-treatment in patients without disease recurrence. Changes in NLR and PLR were not significantly different between the BRCA wild-type and mutant groups or between the HRD and homologous recombination proficient (HRp) groups. Baseline NLR was higher in the HGSOC group compared to the other histological subtypes. Higher baseline NLR/ PLR levels were found if the CA125 was high (CA125 ≥35). Neither NLR nor PLR predicted short-term progression-free survival (PFS).

Conclusion: Assessing NLR and PLR levels is simple and inexpensive using available complete blood counts. NLR levels were higher in patients with HG-EOC and patients with CA125 ≥35. These findings suggest that NLR may serve as a treatment-response biomarker of systemic inflammation, but its prognostic utility in isolation is limited. Larger prospective studies integrating inflammatory indices with molecular biomarkers are warranted.

Keywords: Neutrophil-lymphocyte, platelet-lymphocyte ratios, epithelial ovarian cancer, prognostic significance, high-grade ovarian cancer.

INTRODUCTION

High-grade epithelial ovarian cancer (HG-EOC) is the 8th most common malignancy and the 5th leading cause of cancer-related deaths among women globally, accounting for more than 324 thousand new cases and 206 thousand deaths annually [1, 2]. The incidence rate is estimated at 10.3 per 100,000 women per year [1]. Most patients present with advanced-stage disease (IIIC/IV), as there are no specific symptoms [2]. Debulking surgery remains the mainstay of treatment. Initially, around 70% of patients respond to platinum-based chemotherapy; however, only 30-40% survive beyond 5 years [3, 4]. So far, primary screening trials have been negative [5]. There is a huge unmet need to diagnose ovarian cancer early.

Tumor biology and host response interact to induce systemic inflammation, contributing to tumor initiation, progression, angiogenesis, and immune evasion [6, 7]. Classical reviews have established inflammation as a hallmark of cancer. Simple peripheral blood indices reflecting systemic inflammation - notably the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to- lymphocyte ratio (PLR) - have attracted attention as prognostic biomarkers across many solid tumors, including ovarian cancer [8, 9]. Calculating these ratios is inexpensive and reproducible, making them attractive candidates for prognostic stratification. Mechanistically, elevated neutrophils can promote tumor progression by secreting proteases, reactive oxygen species, and pro- angiogenic factors, while relative lymphopenia signals impaired antitumor immune surveillance [10]. Similarly, thrombocytosis can protect circulating tumor cells and secrete growth factors that facilitate metastasis [11].

In HG-EOC, a growing body of observational studies and pooled analyses suggests that elevated pre-treatment NLR and PLR are associated with worse progression- free and overall survival [12-14]. Several meta-analyses and systematic reviews have reported that high NLR is associated with a significantly increased hazard of death and disease progression, and that similar relationships exist for PLR. However, effect sizes and optimal cut-off values vary between studies and cohorts [12-14]. Heterogeneity in patient selection (early vs advanced stage), timing of blood sampling (preoperative vs pre- chemotherapy), and analytical methods (single cut-off vs continuous variable) have contributed to inconsistent findings and limited clinical translation.

Given the clinical need for robust tools to aid risk stratification in HG-EOC, additional well-described cohort studies are warranted, clearly defining inclusion criteria, the timing of blood sampling, and the statistical approaches to cut-point selection. This study was conducted to evaluate the prognostic value of NLR/PLR in epithelial HG-EOC patients.

PATIENTS AND METHODS

We performed a retrospective review of electronic patient records of patients diagnosed with histologically confirmed ovarian cancer treated at the Sultan Qaboos Comprehensive Care & Research Center (University Medical City) (SQCCCRC, UMC) between January 2022 and December 2023. The institutional review board approved the study ( REF. NO. SQCCCRC- IRB&EC/135/2023/CCCRC-67-2023) with waiver of consent for retrospective data review.

This was a single-center study. Approximately 30-35 cases of ovarian cancer are diagnosed in Oman annually [15]. Cancer services are provided at two centers. During the two-year study period, nearly half of these patients were managed at our center. Consecutive patients diagnosed with ovarian cancer were included. Inclusion criteria were as follows: age ≥18 years, newly diagnosed FIGO-staged epithelial ovarian cancer, availability of pre- treatment complete blood count (CBC) within 14 days before primary cytoreductive surgery or initiation of neo- adjuvant chemotherapy, and follow-up data available for survival analysis. Patients who had active infection at the time of diagnosis, known autoimmune or hematologic disorders affecting blood counts, recent corticosteroid therapy, or a second malignancy were excluded.

Demographic, clinical, and treatment data were extracted from electronic patient records: age at diagnosis, ECOG performance status, FIGO stage, histologic subtype, preoperative CA-125, details of primary treatment (optimal vs suboptimal cytoreduction, neoadjuvant vs primary surgery, platinum-based chemotherapy regimens), and dates of progression/last follow-up/death. Pre-treatment CBC parameters (absolute neutrophil, lymphocyte, and platelet counts) were recorded and used to calculate NLR (absolute neutrophils ÷ absolute lymphocytes) and PLR (platelets ÷ absolute lymphocytes). When multiple CBCs were available within the pre-treatment window, the value closest to treatment initiation was used.

Primary endpoints were progression-free survival (PFS), defined as time from diagnosis to documented radiologic/clinical progression or death. The cut-off value for NLR was 1.5 x 10⁹/L, and that for PLR was 160 x 10⁹/L.

We used SAS software version 9.4 for all statistical analyses (SAS Institute, Cary, NC). Descriptive analysis was performed using means, standard deviations (SDs), and medians and ranges for continuous variables. Frequency and proportion were computed for the categorical variables. We examined group differences using the Wilcoxon rank-sum test for continuous variables. NLR and PLR changes at 3, 6, and 9-12 months from the baseline were examined using the Wilcoxon rank-sum test. The log-rank test was used to compare progression-free survival across subgroups. P- values ≤0.05 were considered statistically significant.

RESULTS

Thirty-two consecutively diagnosed patients with HG- EOC were included in this study. Median age at diagnosis was 56 years (range: 16-89), and median ECOG performance status was 1 (range 0-3). High-grade serous carcinoma was the predominant histological sub- type (53.1%). Most patients presented with FIGO stage III disease (43.8%), while 25% patients had stage I disease.

15 (46.9%) patients received adjuvant chemotherapy after primary debulking surgery; 8 (25%) received neoadjuvant chemotherapy followed by interval debulking surgery and adjuvant chemotherapy; and 9 (28.1%) patients received either palliative chemotherapy or best supportive care only. BRCA mutation results were available for 16 (50%) patients; 4 (25%) were positive. HRD status was available for 11 patients. Five (45.5%) patients had HRd disease (Table 1).

BRCA: BReast CAncer gene, ECOG PS: Eastern Cooperative Oncology Group Performance Status. HRD: Homologous Recombination Deficient.

NLR: Neutrophil to lymphocyte ratio; PLR Platelet to lymphocyte ratio. Both NLR and PLR were calculated before systemic treatment, and at various time points during the subsequent months for upto 1 year from diagnosis.

Baseline median NLR was 2.05x10⁹/L and demonstrated a statistically significant reduction to 1.5x10⁹/L at 3 months (median change - 0.88; p=0.040), and further down to 1.35x10⁹/L at 6 months (median change - 0.62; p=0.005) following treatment initiation. There was no further reduction between 9 and 12 months. In contrast, PLR was 174.9 × 10⁹/L at baseline, and although there was a mild reduction over the various time intervals, it did not reach statistical significance. (Table 2).

There was no significant difference between NLR (3.5 x 10⁹/L vs 1.9 x 10⁹/L) and PLR 249 x 10⁹/L vs 168 x 10⁹/L) for BRCA wild type (n=12) and BRCA mutant cases (n=4). Also, there was no significant reduction in NLR and PLR at various time points over the course of 1 year, both in BRCA wild type and BRCA mutant cases. Similarly, there was no significant difference between NLR (3.2 x 10⁹/L vs 4 x 10⁹/L) and PLR (3.2 x 10⁹/L vs 4 x 10⁹/L) for BRCA wild type, HRD (n=5), and HRP (n=6) cases. There was no significant reduction in NLR or PLR at any time point over 1 year, in either HRD or HRP cases.

Baseline NLR was significantly higher in patients with high-grade serous histology (n=17) than in patients with other epithelial subtypes (n=15) (Table 3); however, there was no significant decline in either NLR or PLR in response to treatment between the two groups. Patients with elevated baseline CA-125 (≥35 U/mL) demonstrated significantly higher baseline NLR (1.6 x 10⁹/L vs 3.3 x 10⁹/L; p=0.022) and PLR (131 x 10⁹/L vs 242 x 10⁹/L; p=0.037) (Table 4). No consistent association was observed between baseline CA-125 and clinical stage of disease at presentation.

NLR: Neutrophil to lymphocyte ratio; PLR Platelet to lymphocyte ratio; HGSOC High grade serous ovarian cancer.

NLR: Neutrophil to lymphocyte ratio; PLR Platelet to lymphocyte ratio. Both NLR and PLR were calculated before systemic treatment, and at various time points during the subsequent months for upto 1 year from diagnosis, and a comparison was made for patients whose baseline CA125 was within the normal limits (<35IU/L), or high (>35IU/L). significance was set at <0.05.

NLR: Neutrophil to lymphocyte ratio; PLR Platelet to lymphocyte ratio.

One-year progression-free survival was 100% in patients with CA125 <35 IU/L and Stage I-II. However, one-year PFS was not associated with CA125 (p=0.351) and stage (p=0.235). Neither NLR (p=0.270) nor PLR (p=0.270) was significantly associated with one-year PFS (Table 5).

DISCUSSION

In this single-institution cohort of patients with HG-EOC, we demonstrated a significant early post-treatment reduction in NLR, while PLR remained largely unchanged. These findings suggest that NLR may reflect short-term modulation of systemic inflammation following treatment, whereas PLR appears less dynamic in this setting.

Elevated baseline NLR has been consistently associated with inferior survival outcomes in HG-EOC across multiple retrospective series and meta-analyses [12, 13]. However, most published studies have relied on static baseline measurements and have provided limited longitudinal evaluation. Our observation of an early decline in NLR following treatment aligns with prior reports suggesting that chemotherapy and cytoreductive surgery may partially reverse tumor-driven systemic inflammation. However, the converse may also happen [16]. The induction of tumor/host-reactive responses by chemotherapy may be counterbalanced by its therapeutic efficacy. The lack of sustained significance beyond six months may reflect treatment heterogeneity, evolving disease biology, or limited statistical power due to attrition in longitudinal sampling.

Notably, NLR and PLR were not associated with BRCA mutation or HRD status in our cohort. While homologous recombination deficiency is a strong predictor of chemosensitivity and response to PARP inhibitors, its relationship with host inflammatory markers remains poorly defined [17]. Prior studies have similarly reported weak or inconsistent correlations between inflammatory indices and molecular subtypes, suggesting that systemic inflammation may represent a parallel rather than a downstream biological axis.

Baseline NLR was significantly higher in high-grade serous carcinoma than in other epithelial subtypes, consistent with translational studies demonstrating a more immunosuppressive, neutrophil-rich tumor microenvironment in serous ovarian cancer [18]. The association between elevated CA-125 and higher baseline NLR and PLR further supports a link between tumor burden and systemic inflammatory response [19, 20]. Furthermore, serum NLR combined with CA125 has been shown to improve the diagnostic and prognostic efficiency in patients with ovarian cancer [21].

Despite these associations, neither NLR nor PLR predicted short-term progression-free survival. This finding contrasts with pooled analyses reporting prognostic significance for both markers. Still, it is likely influenced by limited sample size, short follow-up, and the dominant prognostic impact of residual disease and treatment response.

CONCLUSION

NLR demonstrates significant early post-treatment modulation in patients with HG-EOC, whereas PLR does not. Baseline inflammatory markers correlate with histologic subtype and tumor burden but do not independently predict short-term PFS. These findings suggest that NLR may serve as a treatment-responsive biomarker of systemic inflammation, but its prognostic utility in isolation is limited. Larger prospective studies integrating inflammatory indices with molecular and chemosensitivity biomarkers are warranted.

ETHICS APPROVAL

The study was approved by the Institutional Review Board (REF. NO. SQCCCRC- IRB&EC/135/2023/CCCRC-67-2023). All procedures performed in studies involving human participants were conducted in accordance with the ethical standards of the institutional and/or national research committee and the Helsinki Declaration.

CONSENT FOR PUBLICATION

Not applicable.

AVAILABILITY OF DATA

The data is available with the first and the corresponding author.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

ACKNOWLEDGEMENTS

We acknowledge all medical, nursing, and technical staff involved in patient care.

AUTHORS' CONTRIBUTION

1. AZ: Conceptualization, data curation, analysis, writing the initial draft, and review of the manuscript.

GENERATIVE AI AND AI-ASSISTED TECHNOLOGIES IN THE WRITING PROCESS

During the preparation of this work, the authors used ChatGPT (GPT-3.5, OpenAI) to generate language suggestions and perform minor proofreading in some sections of the manuscript. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article.

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