Novel prognostic score for endometrial cancer

doi:10.21203/rs.3.rs-4709115/v1

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Novel prognostic score for endometrial cancer

https://doi.org/10.21203/rs.3.rs-4709115/v1

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Recently, there have been an increasing number of reports on the association between inflammatory markers and the prognosis of malignant tumors. However, the current indicators have limited accuracy. We aimed to develop a new scoring system for predicting endometrial cancer recurrence using inflammatory markers, tumor markers, and histological diagnosis. Patients with primary, previously untreated, and suspected endometrial cancer who underwent surgery at the Nara Medical University Hospital between January 2007 and December 2020 were included and followed up until March 2024. Items were divided into positive and negative using scores based on cutoff values and placed into the new scoring system, the endometrial tumor-related (ETR) score. We found that positive postoperative histological examination of lymph node metastasis and myometrial invasion, high levels of carcinoembryonic antigen and D-dimer in preoperative blood tests, and a large difference in preoperative and postoperative white blood cell counts were significantly associated with recurrence. The prediction of recurrence using the ETR score was superior to that using the International Federation of Gynecology and Obstetrics staging system, which is considered the best prognostic factor for survival. The ETR score is a significant prognostic marker of recurrence in patients who have undergone lymphadenectomy, with complete surgical tumor removal.

Endometrial cancer

Recurrence

Disease-free survival rate

ETR score

D-dimer

White blood cell count

Endometrial cancer (EC) is the second most prevalent gynecological cancer after cervical cancer in women [1, 2]. The morbidity of EC has been increasing globally; in 2018, almost 90,000 deaths due to EC were reported worldwide [3]. EC is known to recur in 18% of all patients [4], and the International Federation of Gynecology and Obstetrics (FIGO) staging system is considered one of the best prognostic factors for survival [5]. The 5-year disease-free survival rates have been 85% for stage I, 75% for stage II, 45% for stage III, and 25% for stage IV [5]. In addition, the histological type of EC is known to correlate with the prognosis [6]. These include endometrioid carcinoma, serous carcinoma, clear cell carcinoma, mixed carcinoma, undifferentiated carcinoma, carcinosarcoma, other unusual types, and gastrointestinal mucinous carcinomas [6]. These histological types are divided into two groups, non-aggressive and aggressive, based on their prognostic value [6]. Non-aggressive types include endometrioid carcinoma grades 1 and 2, whereas other types are aggressive [6, 7]. EC is typically treated with surgery, including hysterectomy and bilateral salpingo-oophorectomy [8, 9]. Lymphadenectomy is also known to be associated with prognosis in patients with intermediate- and high-risk EC [8, 10, 11].

In recent years, there have been an increasing number of reports on the association between inflammatory markers and the prognosis of malignant tumors [12, 13]. The inflammatory markers used include the systemic immune inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR), all of which are calculated using blood cell counts [12–14]. The Glasgow Prognostic Score (GPS) is an inflammation-based prognostic marker calculated using C-reactive protein and albumin levels [15]. We previously reported the relationship between the SII, NLR, and PLR and the prognosis of EC in 2021 and concluded that elevated SII is a better indicator of overall survival and progression-free survival in patients with EC than PLR or NLR [12].

Current indicators have limited accuracy because they rely only on one point in time before surgery. To enhance accuracy, we aimed to develop a prediction system using preoperative and postoperative data rather than just one pretreatment point. To ensure consistency in clinical background, we focused on cases that included lymphadenectomy. We aimed to develop a new scoring system to predict EC recurrence after complete tumor removal, including lymphadenectomy.

Patients

A total of 521 patients were suspected of having EC during the study period, of whom 230 met the inclusion criteria (Fig. 1). The median patient age was 59 years (range, 23–79 years), and the median follow-up period was 84.5 months (range, 12–195 months). The patients’ peripheral blood data were collected before the operation, and the median number of days until the operation was 37 (range, 1–92 days). In addition, the postoperative blood data before the adjuvant therapy were collected, and the median number of days between the operation date and the blood test was 26 days (range, 14–59 days). The overall recurrence rate was 15.7% (n = 36). The demographic and clinical characteristics of the study cohort are shown in Table 1. The surgeries performed in the study cohort are outlined in Supplementary Table S1.

Table 1

Clinical characteristics of the study cohort.
	Total n = 230	No recurrence n = 194	Recurrence n = 36	p - value
Age (years)^a	59 (23–79)	59 (23–79)	61.5 (43–77)	0.080
BMI (kg/m²)^a	23.65 (15.1–43.5)	24.1 (15.1–43.5)	22.8 (17.6–32.8)	0.022*
Parity 0 ≥1	50 180	42 152	8 28	0.939
FIGO Stage I II III	169 23 38	152 19 23	17 4 15	< 0.001^***
Tumor subtype EM G1/G2 EM G3 CCC Serous carcinoma Carcinosarcoma Undifferentiated Mixed type Others	155 25 8 7 10 6 17 2	135 20 5 4 7 6 15 2	20 5 3 3 3 0 2 0	0.340
Myometrial invasion < 1/2 ≥ 1/2	140 90	124 70	16 20	0.028^*
Lymph vascular invasion Positive Negative	83 147	66 128	17 19	0.131
Ascites cytology Positive Negative	42 183	33 156	9 27	0.289
Lymph node metastasis Positive Negative	201 29	178 16	13 23	0.002^**
Adjuvant chemotherapy Yes No	146 84	119 75	27 9	0.098
BMI: body mass index, FIGO: The international federation of gynecology and obstetrics, EM: Endometrioid carcinoma, G1: Grade 1, G2: Grade 2, G3: Grade 3, CCC: clear cell carcinoma, ^a: median (range).
^: p < 0.05, ^: p < 0.01, ^**: p < 0.001

Candidates predicting the recurrence of EC

The results of the ROC curve based on recurrence were used to determine the value of the new scoring system in predicting EC recurrence. Candidates varied according to patient characteristics; histological findings after the surgery; and preoperative and postoperative serum data, including tumor markers, blood cell counts, differential counts of leukocytes, albumin, and D-dimer levels. The ROC analysis showed that lymph node metastasis, myometrial invasion, preoperative carcinoembryonic antigen (CEA) (ng/mL), preoperative D-dimer (µg/mL), and subtracted value of postoperative from preoperative white blood cell (WBC) counts (/µL) significantly predicted EC recurrence (Table 2).

Table 2

Cutoff values for predicting disease-free survival.
	Cut-off value	p-value	AUC	95% CI	Sensitivity	Specificity
Lymph node metastasis	-	0.013*	0.639	0.530–0.749	0.361	0.918
Myometrial invasion	-	0.014*	0.620	0.525–0.715	0.556	0.639
preoperative CEA (ng/mL)	2.4	0.010*	0.640	0.534–0.747	0.611	0.706
preoperative D-dimer (µg/mL)	1.1	0.003**	0.657	0.533–0.761	0.500	0.820
WBC (pre – post operation) (/µL)	1050	0.010*	0.637	0.533–0.741	0.750	0.572
AUC: area under the curve, CI: confidential interval, CEA: carcinoembryonic antigen, WBC: white blood cell. ^: p < 0.05, ^*: p < 0.01

Evaluation to predict the recurrence of EC using past prognostic indicators

The results of the ROC curve analysis based on recurrence were used to evaluate past prognostic indicators for predicting EC recurrence. The cutoff value was calculated using the highest Youden index. None of the past prognostic indicators showed significant differences between the recurrent and nonrecurrent groups (Table 3). However, the new scoring system, the endometrial tumor-related (ETR) score, showed significant differences between the recurrent and nonrecurrent groups (Table 3). Some of the study cohort groups had missing data for calculating the past prognostic indicators. The percentages of analyzed and missing data are shown (Supplementary Table S2).

Table 3

Cutoff values of past predictive indicators to predict disease-free survival.
	Cut-off value	p-value	AUC	95% CI	Sensitivity	Specificity
SII	574	0.102	0.593	0.482–0.704	0.706	0.508
NLR	2.72	0.070	0.599	0.492–0.706	0.618	0.608
MLR	0.41	0.500	0.537	0.429–0.645	0.147	0.931
PLR	121.9	0.084	0.587	0.488–0.686	0.941	0.286
GPS	1.5	0.215	0.569	0.460–0.678	0.194	0.948
ETR score	2.5	< 0.001	0.766	0.672–0.861	0.639	0.840
AUC: area under the curve, CI: confidential interval, PPV: positive predictive value, NPV: negative predictive value, SII: systemic immune-inflammation index, NLR: neutrophil to lymphocyte ratio, MLR: monocyte to lymphocyte ratio, PLR: platelet to lymphocyte ratio, GPS: Glasgow prognostic score, ETR score: endometrial cancer-tumor related score.

Evaluation of the new scoring system

The ROC curve showed that the new scoring system was a better prognostic tool than the FIGO staging system for predicting EC recurrence (Fig. 2). The cutoff value of the ETR score was calculated as 2.5, using the Youden index. According to this cutoff value, we considered > 3 points as the poor group, with a sensitivity of 63.9% and a specificity of 84.0% for diagnosing recurrence. In addition, we used this cutoff point to evaluate the sensitivity and specificity for predicting death. Sensitivity and specificity were 70.0% and 81.0%, respectively. Kaplan–Meier life table analysis revealed significant differences in disease-free survival and overall survival using a cutoff value of 3 (Fig. 3a and 3b). Cox regression analyses demonstrated that the ETR score was a significant independent prognostic factor affecting the disease-free survival of patients with EC (Table 4).

Table 4

Univariate and multivariate analyses predicting recurrence.
	patients	Univariate analysis		Cox multivariate analysis
	n	HR	p-value	HR	95% CI	p-value
FIGO stage ≥ Ⅲ < Ⅰ – Ⅱ	38 192	5.311	< 0.001***
Lymphovascular invasion Yes No	83 147	1.735	0.133
Ascites cytology Positive Negative	42 183	1.576	0.290
Myometrial invasion ≥ 1/2 < 1/2	90 140	2.214	0.030*
Lymph node metastasis Yes No	29 201	6.288	< 0.001***
Preoperative CEA ≥ 2.4 < 2.4	79 151	3.777	< 0.001***
Preoperative d-dimer ≥ 1.1 < 1.1	53 177	4.543	< 0.001***
Preoperative-postoperative WBC (/µL) ≥ 1,050 < 1,050	110 120	4.012	< 0.001***
ETR score ≥ 3 < 3	176 54	9.303	< 0.001***	9.017	4.127–19.701	< 0.001
HR: hazard ratio, CI: confidential interval, FIGO: The international federation of gynecology and obstetrics, CEA: carcinoembryonic antigen, WBC: white blood cell, ETR: endometrial cancer-tumor related.

In this study, we successfully developed a new scoring system, the ETR score, to predict EC recurrence after radical surgery. The score comprised lymph node metastasis, myometrial invasion, preoperative CEA levels, preoperative D-dimer levels, and WBC difference (pre–post). The strength of the ETR score is that it is easy to calculate because blood tests and histological findings have already been used worldwide.

Serum CEA, an item of the ETR score, is a diagnostic and prognostic marker of broad-spectrum malignant tumors, especially colon and rectal cancers [16, 17]. Postoperative CEA levels reflect recurrence or distant metastasis of EC [18], suggesting a relationship between EC prognosis and CEA level. In this study, preoperative CEA levels were included in the predictive scoring system for recurrence, suggesting that these values predict recurrence.

There have been reports linking high WBC counts to aggressive tumors or poor prognosis. According to a large cohort study conducted in the UK Biobank, elevated WBC counts may indicate an overly active inflammatory response, which could contribute to the eventual onset of certain types of cancer [19]. In endometrial neoplasia, WBC counts were significantly higher in patients with cancer than in those with hyperplasia, according to a study that compared the hyperplasia, EC, and control groups [20]. Based on a few reports suggesting the usefulness of pretreatment peripheral WBC counts, this difference may help predict the prognosis. Our previous study showed that this difference contributes to the prognosis of ovarian cancer by comparing presurgical and postsurgical analyses [21, 22]. This study reaffirmed the usefulness of the differences in WBC counts in predicting recurrence.

Serum D-dimer level, an item of the ETR score, is a well-known biomarker of thrombosis, such as pulmonary embolism and venous thrombosis [23]. However, it is also known as a prognostic marker for several malignancies, such as ovarian cancer [24], breast cancer [25], lung cancer [26], and other cancers [27–31]. According to a previous study, it is reasonable to include serum D-dimer levels in the new scoring system.

This study had a few limitations. First, a bias might exist owing to the nature of a retrospective and single-center study. Second, although serous and clear cell carcinomas have poor prognoses, the study cohort did not show a significant difference in histological types. Such patients ordinarily harbor an advanced stage and then receive chemotherapy rather than surgical treatment. ETR score could not reflect these small pathological groups.

In conclusion, the ETR score, which is composed of the presence of lymph node metastasis and myometrial invasion, preoperative CEA and D-dimer levels, and the difference in (pre–post) WBC levels, is a good prognostic marker for patients with EC who have undergone complete surgery. Prospective multicenter studies are warranted to validate our findings.

Patients

A list of patients with primary, previously untreated, and suspected EC who underwent surgery at the Nara Medical University Hospital between January 2007 and December 2020 was generated from our institutional registry. The patients were followed up until March 2024. Informed consent for the use of the patients’ clinical data for research was obtained from all subjects at the first hospitalization. After approval by the Ethics Review Committee of the Nara Medical Hospital, the opt-out form was provided through our institutional homepage. This study was conducted in accordance with the guidelines of the Declaration of Helsinki and was approved by the Institutional Ethics Committee of Nara Medical University Hospital (protocol code: 3603).

Patients with suspected EC were included in this study. The inclusion criteria were as follows: (1) histologically confirmed EC after surgery, (2) lymphadenectomy, and (3) did not undergo chemotherapy or radiotherapy before the first surgery. The exclusion criteria were as follows: (1) stage IV, (2) combined with other malignant tumors or hematologic diseases, (3) lost to follow-up, and (4) insufficient preoperative and postoperative serum data, which included no blood tests within 14–60 days or performed while infection occurred. Written consent for the use of the patient’s clinical data for research was obtained at the first hospitalization, and after approval by the Ethics Review Committee of the Nara Medical Hospital, the opt-out form was provided through our institutional homepage.

Collection of candidates predicting recurrence

The following data were collected through a chart review of the patients’ medical records: age; body mass index; parity; and postoperative diagnosis, including the FIGO stage, histological type, myometrial invasion, lymphovascular invasion, ascites cytology, lymph node metastasis, and distant metastasis. In addition, data concerning the use of adjuvant chemotherapy and the results of preoperative and postoperative blood tests were collected.

Examination of prognosis using past prognostic indicators

We examined the efficacy of past inflammation-based prognostic indices such as SII, NLR, MLR, PLR, and GPS. These indicators were calculated using the following formulae: SII = platelet count×neutrophil count/lymphocyte count, NLR = neutrophil count/lymphocyte count, MLR = monocyte count/lymphocyte count, and PLR = platelet count/lymphocyte count. If an elevated C-reactive protein level (> 1.0 mg/dL) and hypoalbuminemia (< 3.5 g/dL) were present, the GPS was 2. Patients with only one of these were assigned a score of 1, and those with none were assigned a score of 0.

Statistical analysis

All statistical analyses were performed using SPSS version 29.0 (IBM Corp., Armonk, NY, USA). Differences in each factor were compared using Student’s t-test or the Mann–Whitney U test after assessing whether the distribution was normal. The receiver operating characteristic (ROC) curve analysis was performed to determine the cutoff value for predicting poor prognosis. The cutoff value was based on the highest Youden index (i.e., sensitivity + specificity–1). Next, logistic regression analyses were used to assess the risk factors for recurrence and death. Kaplan–Meier life table analysis and log-rank tests were used to assess the disease-free survival and overall survival rates. A two-sided p < 0.05 was considered statistically significant. Multivariate analysis of prognostic factors for PFS and OS was performed using the Cox proportional hazard regression model.

Data availability

The data presented in this study are available on request from the corresponding author.

Acknowledgements: None

Author contributions: Conceptualization, T.M.; methodology, T.M. and N.K.; validation, T.M. and N.K.; formal analysis, T.M. and N.K.; investigation, T.M. and N.K.; resources, T.M., N.K., R.K., and F.K.; data curation, T.M., N.K., and S.S.; writing—original draft preparation, T.M. and N.K.; writing—review and editing, T.M., N.K., R.K., and F.K.; visualization, T.M., J.K., M.M., and K.W.; supervision, F.K.; project administration, F.K. All authors have read and agreed to the published version of the manuscript.

Competing interests: The authors declare no competing interests.

Cao, M., Li, H., Sun, D. & Chen, W. Cancer burden of major cancers in China: A need for sustainable actions. Cancer Commun. (Lond.)40, 205–210 (2020).
Ferlay, J. et al. Cancer incidence and mortality patterns in Europe: Estimates for 40 countries and 25 major cancers in 2018. Eur. J. Cancer103, 356–387 (2018).
Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin.68, 394–424 (2018).
Capozzi, V. A. et al. Pattern of recurrence in endometrial cancer. The murderer always returns to the scene of the crime. Eur. J. Surg. Oncol.50, 107985 (2024).
Sabater, S. et al. Does postoperative irradiation improve survival in early-stage endometrial cancer? Brachytherapy17, 912–921 (2018).
Berek, J. S. et al. FIGO staging of endometrial cancer: 2023. J. Gynecol. Oncol.34, e85 (2023).
Amant, F. et al. Endometrial cancer. Lancet366, 491–505 (2005).
Brooks, R. A. et al. Current recommendations and recent progress in endometrial cancer. CA Cancer J. Clin.69, 258–279 (2019).
Crosbie, E. J. et al. Endometrial cancer. Lancet399, 1412–1428 (2022).
Chan, J. K. et al. Therapeutic role of lymph node resection in endometrioid corpus cancer: a study of 12,333 patients. Cancer107, 1823–1830 (2006).
Todo, Y. et al. Survival effect of para-aortic lymphadenectomy in endometrial cancer (SEPAL study): a retrospective cohort analysis. Lancet375, 1165–1172 (2010).
Matsubara, S., Mabuchi, S., Takeda, Y., Kawahara, N. & Kobayashi, H. Prognostic value of pre-treatment systemic immune-inflammation index in patients with endometrial cancer. PLoS One16, e0248871 (2021).
Nøst, T. H. et al. Systemic inflammation markers and cancer incidence in the UK Biobank. Eur. J. Epidemiol.36, 841–848 (2021).
Leng, J., Wu, F. & Zhang, L. Prognostic Significance of Pretreatment Neutrophil-to- Lymphocyte Ratio, Platelet-to-Lymphocyte Ratio, or Monocyte-to-Lymphocyte Ratio in Endometrial Neoplasms: A Systematic Review and Meta-analysis. Front. Oncol.12, 734948 (2022).
Zhu, J., Wang, H., Liu, C. C., Lu, Y. & Tang, H. The Glasgow Prognostic Score (GPS) is a novel prognostic indicator in advanced epithelial ovarian cancer: a multicenter retrospective study. J. Cancer Res. Clin. Oncol.142, 2339–2345 (2016).
Kawahara, N., Miyake, R., Yamanaka, S. & Kobayashi, H. A Novel Predictive Tool for Discriminating Endometriosis Associated Ovarian Cancer from Ovarian Endometrioma: The R2 Predictive Index. Cancers (Basel)13, 3829 (2021).
Mizuno, H. et al. Optimal cutoff value of preoperative CEA and CA19-9 for prognostic significance in patients with stage II/III colon cancer. Langenbecks Arch. Surg.406, 1987–1997 (2021).
Kozakiewicz, B., Chądzyńska, M., Dmoch-Gajzlerska, E. & Stefaniak, M. Monitoring the treatment outcome in endometrial cancer patients by CEA and TATI. Tumour Biol.37, 9367–9374 (2016).
Song, M., Graubard, B. I., Loftfield, E., Rabkin, C. S. & Engels, E. A. White Blood Cell Count, Neutrophil-to-Lymphocyte Ratio, and Incident Cancer in the UK Biobank. Cancer Epidemiol. Biomarkers Prev.33, 821–829 (2024).
Acmaz, G. et al. Are neutrophil/lymphocyte and platelet/lymphocyte ratios associated with endometrial precancerous and cancerous lesions in patients with abnormal uterine bleeding? Asian Pac. J. Cancer Prev.15, 1689–1692 (2014).
Kawahara, N. et al. The prognosis predictive score around primary debulking surgery (PPSP) improves diagnostic efficacy in predicting the prognosis of ovarian cancer. Sci. Rep.12, 22636 (2022).
Kawahara, N. et al. The Prognosis Predictive Score around Neo Adjuvant Chemotherapy (PPSN) Improves Diagnostic Efficacy in Predicting the Prognosis of Epithelial Ovarian Cancer Patients. Cancers (Basel)15, 5062 (2023).
van Es, N. et al. Diagnostic management of acute pulmonary embolism: a prediction model based on a patient data meta-analysis. Eur. Heart J.44, 3073–3081 (2023).
Yamada, Y. et al. Preoperative plasma D-dimer level is a useful prognostic marker in ovarian cancer. J. Obstet. Gynaecol.40, 102–106 (2020).
Batschauer, A. P. B. et al. D-dimer as a possible prognostic marker of operable hormone receptor-negative breast cancer. Ann. Oncol.21, 1267–1272 (2010).
Chen, C. et al. Plasma D-dimer and interleukin-6 are associated with treatment response and progression-free survival in advanced NSCLC patients on anti-PD-1 therapy. Cancer Med.12, 15831–15840 (2023).
Stender, M. T., Larsen, T. B., Sørensen, H. T. & Thorlacius-Ussing, O. Preoperative plasma D-dimer predicts 1-year survival in colorectal cancer patients with absence of venous thromboembolism (VTE): a prospective clinical cohort study. J. Thromb. Haemost.10, 2027–2031 (2012).
Diao, D. et al. D-dimer: not just an indicator of venous thrombosis but a predictor of asymptomatic hematogenous metastasis in gastric cancer patients. PLoS One9, e101125 (2014).
Diao, D. et al. D-dimer is an essential accompaniment of circulating tumor cells in gastric cancer. BMC Cancer17, 56 (2017).
Wang, Y. & Wang, Z. Predictive value of plasma D-dimer levels in patients with advanced non-small-cell lung cancer. Onco Targets Ther.8, 805–808 (2015).
Bi, X. W. et al. High pretreatment D-dimer levels correlate with adverse clinical features and predict poor survival in patients with natural killer/T-cell lymphoma. PLoS One11, e0152842 (2016).

No competing interests reported.

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Novel prognostic score for endometrial cancer

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Abstract

Figures

Introduction

Results

Patients

Candidates predicting the recurrence of EC

Evaluation to predict the recurrence of EC using past prognostic indicators

Evaluation of the new scoring system

Discussion

Methods

Patients

Collection of candidates predicting recurrence

Examination of prognosis using past prognostic indicators

Statistical analysis

Declarations

References

Additional Declarations

Supplementary Files

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