Nlr &amp; Brca Mutational Status In Patients With High Grade Serous Advanced Ovarian Cancer: A Large Population Study

doi:10.21203/rs.3.rs-224654/v1

Download PDF

Research Article

Nlr & Brca Mutational Status In Patients With High Grade Serous Advanced Ovarian Cancer: A Large Population Study

https://doi.org/10.21203/rs.3.rs-224654/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Laboratory-markers of the systemic inflammatory-response, such as neutrophil/lymphocyte-ratio (NLR) have been studied as prognostic factors in several tumors but in OC-patients their role is still controversial and no data about the possible correlation with the BRCA-status has been ever reported.

We consecutively enrolled a series of 397 newly diagnosed high-grade serous-advanced OC-patients. All patients were tested for BRCA-mutational-status and blood-parameters have been collected 48 hours before staging-surgery. A significant correlation of NLR with disease distribution (p<0.005) was found and patients with NLR<4 underwent primary-debulking-surgery more frequently (p-value 0.001), with a lower surgical-complexity-score (p-value 0.002).

Regarding survival-data, patients with NLR< 4 had a significant 7-month increase in mPFS (26 vs 19 months, p=0.009); focusing on the BRCA-status, among both BRCA-mutated and BRCA-wild type patients, those with lower NLR had a significantly prolonged mPFS compared to patients with NLR> 4 (BRCA-mutated: 35 vs 23 months, p= 0.03; BRCA-wt: 19 vs 16 months, p=0.05). At multivariate-analysis, independent factors of prolonged PFS were BRCA mutational status, having received complete cytoreduction and NLR< 4. Also, the strongest predictors of longer OS were BRCA-mutational status, having received complete, NLR< 4 and age.

NLR is confirmed to be a prognostic marker in OC-patients and it seems unrelated with BRCA-mutational status.

Other Public Policy

Laboratory Diagnostics

Women's studies

BRCA

NLR

OC-patients

FIGO-stage

Ovarian cancer remains the most lethal gynecological malignancy in developed countries [1].

Nearly 75% of OC affected women present with advanced disease (stage III or IV), and most of these will die from their disease, with 5-year overall survival rates around 30% [2].

Several prognostic factors have been identified to predict the outcome and guide personalized treatment of patients with advanced OC, including histological type, FIGO-stage, residual tumor after surgery, response to chemotherapy, and BRCA1/2-mutation status [3]. In addition to clinical and molecular features, recent data suggest the influence of the host-driven inflammatory response on tumors' behavior and treatments outcome [4, 5]. In fact, tumor growth and metastatic spread result from several interactions between tumoral and stromal factors, including blood vessels, inflammatory cells and the immune system, leading to a chronic inflammation status [6, 7].

Laboratory markers of systemic inflammatory response, such as white blood cell count, have been studied as prognostic and predictive factors in several tumors [8, 9]. High NLR, defined as the absolute neutrophils count divided by the absolute lymphocytes count [9–11] has shown a negative prognostic impact in stomach, colorectal cancer and other cancers [12–14]. The mechanism underlying the association between high NLR and worse outcome has not been clarified yet. Probably, neutrophilia can inhibit the immune system, by blocking the cytolytic activity of immune cells [15–16], and promotes tumour growth, by producing vascular endothelial growth factor [17, 18]. On the other hand, lymphocytopenia is frequently found in patients with advanced disease, indicating a lower immune activity against tumor antigens released by cancer cells [19, 20, 23]. Moreover, lymphocytes T seem keener to apoptosis [21, 22].

In OC, inflammation markers have shown interesting but controversial results [24]. In particular, recent trials have suggested that a high NLR is correlated with an immunosuppressive profile [25], and with poorer overall survival and could be a predictive marker for treatment efficacy [26–28].

Albeit OCs harboring a BRCA mutation are considered more immunoreactive and with a higher mutational and neoantigen loads compared with BRCA wild type tumors, no study has investigated the possible correlation between NLR values and BRCA mutational status. In light of these aspects, we investigated the relationship between BRCA status and systemic inflammatory factors in a large high-grade serous OC population.

2.1 Patients’ characteristics.

397 patients fulfilled the inclusion criteria and were evaluable for the biomarkers of interest.

Characteristics of evaluated patients are described in Table 1. The mean age at diagnosis was 60.2 years (range 27-89); 271 (68.3%) were BRCA wild-type (BRCA-WT), with 17 (4.3%) having a BRCA variant of uncertain significance (BRCA-VUS), and 127 (31.7%) had a BRCA 1/2 pathogenetic variants (BRCA-PVs). Among the latter, 79 (19.9%) patients presented with BRCA1 mutation, and 47 (11.8%) presented with BRCA2.

The association between the preoperative NLR score and clinicopathologic characteristics of EOC patients are also shown in Table 1.

Regarding the BRCA status, no significant differences were found with regard of NLR values (p-value: 0.97). The majority of patients presented as stage III of disease (282, 71.8%), without differences related to NLR value. We found a significant correlation of NLR with disease distribution, with more patients with low tumor load in Group 1 (NLR <4) versus Group 2 (NLR > 4) (44.6% vs 67.3%) (p<0.0001).

Moreover, patients in group 1 (110, 55.6%) underwent PDS more frequently than patient in group 2 (76, 38.2%) (p-value 0.001), with no statistically significant difference of complete/optimal cytoreduction in the overall population. Among patients undergoing PDS, those with lower NLR had also lower surgical complexity score (59, 54.1%) compared with those in group 2 (23, 30.7%) (p-value 0.002).

2.2 Impact of NLR on survival

The median follow-up was 24 months (range 4-47). At the time of final analysis, 210 (52.9%) of patient have recurred in the overall population, with more recurrences among group 2 (57.8%) versus group 1 (48%) respectively, p=0.03). Similarly, 105 (24.2%) patients were dead, 64 (32.2%) in group 2 and 41 (20.7%) in group 1 (p=0.007).

In the overall population, median progression free survival (mPFS) was 21 months; those with NLR < 4 had a significant 7-month increase in mPFS, compared with patients with NLR >4 (26 months vs 19 months, p=0.009, Figure. 1).

Focusing on the BRCA status, among BRCAmut patients, those with lower NLR had a significantly prolonged mPFS (35 months vs 23 months, p= 0.03, Figure 2a); similarly, among BRCA wild type patients, those with lower NLR had a slightly significant 3-month increase in mPFS, compared with patients in group 2 (19 months vs 16 months, p=0.05, Figure 2b). At multivariate analysis for PFS, independent factors of prolonged PFS were BRCA mutational status (HR 0.50, CI 95% 0.35-0.71), having received complete cytoreduction (HR 0.51, CI 95% 0.35-0.75) and NLR < 4 (HR 0.69, CI 95% 0.51-0.95) (Table 2).

Median overall survival (mOS) at 60 months was still not reached and 3 years OS was 72% in group 1 and 60% in group 2 (p=0.007). Statistically significant differences related to NLR were found in the BRCAmut (mOS not reached in both groups, p=0.05), and BRCA wild-type (mOS not reached in both groups, p=0.027) populations (Figure 3). In the multivariate analysis, the strongest predictors of longer OS were BRCA mutational status (HR 0.47, CI 95% 0.26-0.85) having received complete cytoreduction (HR 0.42, CI 95% 0.25-0.72), NLR < 4 (HR 0.58, CI 95% 0.36-0.95) and younger age (HR 1.03, CI 95% 1.01-1.06) (Table 3).

In this study, we found for the first time that high NLR (>4) has a negative prognostic role in patients with primary advanced OC, in terms of both PFS and OS, regardless of BRCA status.

Several evidences suggest that BRCA-mutated OC disease exhibits statistically significantly higher mutational and neoantigen loads and may be more immunologically “hot”/T – cell inflamed compared to BRCAwt and HR proficient ovarian cancers. Therefore, we wanted to explore whether or not, this could be predicted by a simple blood biomarker. Nevertheless, we weren’t able to find such correlation, as NLR values seem unrelated to the presence/absence of the BRCA mutation. In other words, if we assume that NLR is correlated, at least indirectly, with the immune status, based on our results, individual immunoreactivity to cancer is independent from BRCA status. As a matter of fact, we shouldn’t be surprised that BRCA, as well as HRD status, do not linearly predict response to immune checkpoint inhibitors (ICIs) [34,35] and we should consider NLR as a more reliable predictor of immunotherapy response even in OC, as it has been recently demonstrated in other cancers [36-38].

More importantly, we came up with the evidence that OC BRCA-mutated disease is not “one disease” with peculiar and good survival outcomes and that, even in presence of a BRCA mutation, the prognosis can be determined by other factors, of which NLR is one easily identifiable. Indeed, among BRCAmut patients, those with low NLR had 7 months advantage of mPFS with respect to women with high NLR.

Moreover, it is now recognized that PARPi, which are known to achieve their greatest efficacy in BRCA mutated and HRD cancer cells, can also get a response in HR proficient cancer [39]. This can be explained by both a cytotoxic activity (depending on HR deficiency), and an antitumor immune activity, that might be more relevant on HR proficient cells [40-44]. This hypothesis should be further investigated in the HR proficient population, to provide NLR as a marker able to identify those patients who can rely on their reactive antitumor-immune response to benefit from PARPi.

We also found that high NLR in patients with primary advanced OC is predictive of larger tumor burden (expressed as LPS-PIV score) and those with higher NLR have higher chances of receiving NACT instead of PDS, compared with those with lower NLR. These observations are in line with the negative prognostic value of high NLR reported in other retrospective series of different OC settings [45,46]. Finally, our data confirm that NLR at baseline has an independent prognostic impact for both PFS and OS.

The strength of our cohort relies in the collection of data from a large single-centre population consecutively enrolled in a prospective study for tissue-BRCA status investigation. Furthermore, no data about NLR according to BRCA status in OC have been published before. However, it should be recognized that neutrophils and lymphocytes counts are non-specific parameters, because they could be influenced by concomitant conditions, such as infections or inflammation. The cut-off value to discriminate between the high or low group using NLR is not clearly established. We decided to use the cut-off closer to the median value, which was 4 in our population, as it has been previously proposed [47] and considering that the more often used values are 3 or 5 [19,48]. This might be a critical limitation in the general application of our assessment, though it would reasonably not change the final findings of our analysis.

In conclusion, NLR is confirmed to be a prognostic marker in OC patients. The information obtained from our study has revealed a potential new biologic subtype of BRCA patients, correlated with inflammation status and easily detectable. Next research should be focused on the role of NLR with regard of PARPi and ICIs response, regardless of BRCA/HRD status, underlining others less common but not less effective mechanisms of action of these drugs and allowing further personalization of treatment.

4.1. Patients

Between January 2017 and December 2019, newly diagnosed high grade serous ovarian cancer (HGSOC) patients with FIGO Stage IIIC-IV, admitted at the Gynaecologic Oncology Unit, Fondazione Policlinico A. Gemelli IRCCS in Rome, were consecutively tested for the tissue/blood BRCA mutation within a prospective study [29].

All women received gynecologic oncologist counseling before BRCA testing and a signed written informed consent. BRCA-mutations were classified according to the ENIGMA BRCA1/2 Gene Variant Classification Criteria (http://www.enigmaconsortium.org/) and women with variants of uncertain significance (VUS) were considered wild-type. Tissue samples for somatic testing were obtained during surgery. Patients were included if they had a primary diagnosis of high grade serous ovarian cancer (HGSOC), they received 3 weekly carboplatin-paclitaxel as first line treatment, with or without maintenance therapy, if their BRCA mutational status was available. Their blood parameters should have been collected in the local laboratory at Fondazione Policlinico A. Gemelli IRCCS 48 hours before staging laparoscopy/laparotomy.

All women gave written informed consent for their data to be collected and analyzed for scientific purposes. The Institutional Review Board of the Catholic University of the Sacred Hear approved the study (CICOG-01-07-19/35).

4.2 Clinical data and follow-up

According to our Institutional model, patients were initially submitted to clinical evaluation, CT-scan and staging laparoscopy (S-LPS) [30] to be triaged to primary debulking surgery (PDS) or neoadjuvant chemotherapy (NACT). Intraperitoneal tumor burden was evaluated at diagnosis using a laparoscopic predictive-index value (LPS-PIV) [30], classifying women as having: low tumor load in presence of LPS-PIV < 8, and high tumor load when a LPS-PIV≥ 8 was observed. In all patients selected for PDS, maximal surgical effort was attempted, and residual tumor recorded. The Complexity of surgical procedures in patients receiving PDS was graded according to the surgical complexity score (SCS) by Aletti et al. [31]. Regardless upfront treatment strategy, all women received six cycle of carboplatin (area under the curve [AUC] 5 or 6) plus paclitaxel (175 mg/mq) every 21 day (Q3W); maintenance therapy was also administrated as indicated according to internal protocol and included Bevacizumab (15 mg/kg) in combination with chemotherapy and maintenance Q3W for 22 cycles or Olaparib 300 mg tablets orally two times per day until disease progression or toxicity for a maximum of 2 year, in BRCA mutated patients (since April 2019).

After treatment administration, patients were entered into routine follow-up program including gynecological examination, CA125 assessment and CT-scan every 6 months.

Data from medical records were consecutively collected including medical history, surgery results, treatment approach, and genetic counseling.

4.3 Statistical analysis

NLR was defined as the absolute neutrophils count divided by the absolute lymphocytes count. Neutrophils and lymphocytes count collected within 48 hours before staging laparoscopy or laparotomy were taken into consideration. A cut-off value of 4 was adopted to discriminate patients with low (NLR <4) (Group 1) versus high (NLR > 4) (Group 2) as primary analysis, according with previous published data and median value in the present series [27,32,33].

Chi-square or Fisher's exact test were used for comparison of categorical variables.

Regarding survival analysis, PFS was defined as the time relapsed between the date of diagnosis (staging laparoscopy/laparotomy) and recurrence; patients without evidence of progression disease at the time of the analysis were censored on the date of their last tumor evaluation. Overall survival (OS) was defined as the time interval between the diagnosis and death of any cause. Patients who were no longer alive at the time of the analysis or had been lost to follow-up were censored on the date of their last follow-up visit. PFS and OS were estimated by the Kaplan–Meier method, and curves were compared by the log-rank or Breslow (Generalized Wilcoxon) tests (at a significance level of 5%), as appropriate. Estimated hazard ratios (HRs) and their two-sided 95% confidence intervals (95% CIs) were calculated using the Cox proportional-hazard model. All statistical calculations were carried out using SPSS 26.0 for Mac (SPSS Inc., Chicago, IL, USA).

4.4 Ethical approval.

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

AUTHOR CONTRIBUTIONS STATEMENT

C.M. planned the study, conducted statistical analysis and drafted the manuscript. M.D drafted the manuscript, advised on results interpretation. C.B. collected data and drafted the manuscript. C.DI and S.DB collected data. B.C., L.V. and A.M. revised the manuscript. G.S. planned the study, advised on results interpretation and revised the manuscript A.F. planned the study, advised on results interpretation, drafted and revised the manuscript

All authors read and approved the final manuscript.

COMPETING INTERESTS

The authors declare no competing interests.

Cancer Statistics Center. American Cancer Society Web site. Updated 2020. Available at https:// cancerstatisticscenter.cancer.org/. Accessed May 11, 2020;
Hennessy BT, Coleman RL, Markman M. Ovarian cancer. Lancet 2009;374:1371–1382;
Lheureux S, Gourley C, Vergote I, Oza AM. Epithelial ovarian cancer. Lancet. 2019;393(10177):1240-1253. doi:10.1016/S0140-6736(18)32552-2
Bot A. Editorial:in this issue. IntRevImmunol. 2010;29(5):459–460;
Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010; 140(6): 883–899;
Balkwill F, Mantovani A. Cancer and inflammation: implications for pharmacology and therapeutics. Clin Pharmacol Ther 2010; 87(4):401–406;
Coussens LM, Werb Z. Inflammation and cancer. Nature 2002; 420(6917): 860–867;
Roxburgh CS, McMillan DC. Role of systemic inflammatory response in predicting survival in patients with primary operable cancer. Future Oncol 2010; 6(1): 149–163;
McMillan DC. Systemic inflammation, nutritional status and survival in patients with cancer. Curr Opin Clin Nutr Metab Care 2009; 12(3): 223–226;
Leitch EF, Chakrabarti M, Crozier JEM. Comparison of the prognostic value of selected markers of the systemic inflammatory response in patients with colorectal cancer. Br J Cancer 2007; 97(9): 1266–1270;
Walsh SR, Cook EJ, Goulder F et al. Neutrophil-lymphocyte ratio as a prognostic factor in colorectal cancer. J Surg Oncol 2005; 91(3): 181–184;
Lee S, Oh SY, Kim SH et al. Prognostic significance of neutrophil lympho- cyte ratio and platelet lymphocyte ratio in advanced gastric cancer patients treated with FOLFOX chemotherapy. BMC Cancer 2013; 13(1): 350;
Cheng H, Long F, Jaiswar M et al. Prognostic role of the neutrophil-to- lymphocyte ratio in pancreatic cancer: a meta-analysis. Sci Rep 2015; 5(1): 11026;
Xiao W-K, Chen D, Li S-Q et al. Prognostic significance of neutrophil- lymphocyte ratio in hepatocellular carcinoma: a meta-analysis. BMC Cancer 2014; 14(1): 117;
Petrie HT, Klassen LW, Kay HD. Inhibition of human cytotoxic T lym- phocyte activity in vitro by autologous peripheral blood granulocytes. J Immunol 1985; 134(1): 230–234.;
el-Hag A, Clark RA. Immunosuppression by activated human neutro- phils. Dependence on the myeloperoxidase system. J Immunol 1987; 139(7): 2406–2413;
Carlo E, Forni G, Musiani P. Neutrophils in the antitumoral immune response. Chem Immunol Allergy 2003; 83: 182–203;
Jabłonska E, Kiluk M, Markiewicz W et al. TNF-alpha, IL-6 and their soluble receptor serum levels and secretion by neutrophils in cancer patients. Arch Immunol Ther Exp (Warsz) 2001; 49(1): 63–69;
Chua W, Charles KA, Baracos VE, Clarke SJ. Neutrophil/lymphocyte ratio predicts chemotherapy outcomes in patients with advanced color- ectal cancer. Br J Cancer 2011; 104(8): 1288–1295;
Maltoni M, Pirovano M, Nanni O et al. Biological indices predictive of sur- vival in 519 Italian terminally ill cancer patients. Italian Multicenter Study Group on Palliative Care. J Pain Symptom Manage 1997; 13(1): 1–9;
Saito T, Kuss I, Dworacki G et al. Spontaneous ex vivo apoptosis of peripheral blood mononuclear cells in patients with head and neck can- cer. Clin Cancer Res 1999; 5(6): 1263–1273;
Dworacki G, Meidenbauer N, Kuss I et al. Decreased zeta chain expres- sion and apoptosis in CD3þ peripheral blood T lymphocytes of patients with melanoma. Clin Cancer Res 2001; 7(3 Suppl): 947s–957s;
Apetoh L, Ghiringhelli F, Tesniere A et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 2007; 13(9): 1050–1059;
Ethier JL, Desautels DN, Templeton AJ, Oza A, Amir E, Lheureux S. Is the neutrophil-to-lymphocyte ratio prognostic of survival outcomes in gynecologic cancers? A systematic review and meta-analysis. Gynecol Oncol. 2017;145(03):584–594. Doi: 10.1016/j.ygyno.2017.02.026;
Baert, T. et al. Influence of CA125, platelet count and neutrophil to lymphocyte ratio on the immune system of ovarian cancer patients. Gynecol. Oncol. 150, 31–37 (2018);
Pinto, M. P. et al. Patient inflammatory status and CD4+/CD8+ intraepithelial tumor lymphocyte infiltration are predictors of outcomes in high-grade serous ovarian cancer. Gynecol Oncol. 151, 10–17 (2018);
Farolfi, A. et al. Inflammatory indexes as prognostic and predictive factors in ovarian cancer treated with chemotherapy alone or together with bevacizumab. A multicenter, retrospective analysis by the MITO group (MITO 24). Target. Oncol. 13, 469–479 (2018);
Battaglia A, Buzzonetti A, Fossati M, et al. Translational immune correlates of indirect antibody immunization in a randomized phase II study using scheduled combination therapy with carboplatin/paclitaxel plus oregovomab in ovarian cancer patients [published correction appears in Cancer Immunol Immunother. 2020 Jul;69(7):1389]. Cancer Immunol Immunother. 2020;69(3):383-397. doi:10.1007/s00262-019-02456-z
Marchetti C, Minucci A, D'Indinosante M, et al. Feasibility of tumor testing for BRCA status in high-grade serous ovarian cancer using fresh-frozen tissue based approach. Gynecol Oncol. 2020;158(3):740-746. doi:10.1016/j.ygyno.2020.06.479;
Petrillo, G.Vizzielli, F.Fanfani,et al., Definition of a dynamic laparoscopic model for the prediction of incomplete cytoreduction in advanced epithelial ovarian cancer: proof of a concept, Gynecol. Oncol. 139 (1) (2015) 5–9;
D. Aletti, E.L. Eisenhauer, A. Santillan, A. Axtell, G. Aletti, C. Holschneider, et al., Identification of patient groups at highest risk from traditional approach to ovarian cancer treatment, Gynecol. Oncol. 120 (2011) 23–28;
Hu, X.R. Yang, Y. Xu, Y.F. Sun, C. Sun, W. Guo, et al., Systemic immune- inflammation index predicts prognosis of patients after curative resection for hepa- tocellular carcinoma, Clin. Cancer Res. 20 (2014) 6212–6222;
Passardi, E. Scarpi, L. Cavanna, M. Dall'Agata, D. Tassinari, S. Leo, et al., Inflamma- tory indexes as predictors of prognosis and bevacizumab efficacy in patients with metastatic colorectal cancer, Oncotarget 7 (2016) 33210–33219;
Matulonis UA. Ovarian Cancer. Hematol Oncol Clin North Am. 2018;32(6):xiii-xiv. doi:10.1016/j.hoc.2018.09.006;
Disis ML, Taylor MH, Kelly K, et al. Efficacy and Safety of Avelumab for Patients With Recurrent or Refractory Ovarian Cancer: Phase 1b Results From the JAVELIN Solid Tumor Trial. JAMA Oncol. 2019;5(3):393-401. doi:10.1001/jamaoncol.2018.6258;
Bagley, S.J.; Kothari, S.; Aggarwal, C.; Bauml, J.M.; Alley, E.W.; Evans, T.L.; Kosteva, J.A.; Ciunci, C.A.; Gabriel, P.E.; Thompson, J.C.; et al. Pretreatment neutrophil-to-lymphocyte ratio as a marker of outcomes in nivolumab-treated patients with advanced non-small-cell lung cancer. Lung Cancer 2017, 106, 1–7;
Mezquita, L.; Auclin, E.; Ferrara, R.; Charrier, M.; Remon, J.; Planchard, D.; Ponce, S.; Ares, L.P.; Leroy, L.; Audigier-Valette, C.; et al. Association of the Lung Immune Prognostic Index With Immune Checkpoint Inhibitor Outcomes in Patients With Advanced Non–Small Cell Lung Cancer. JAMA Oncol. 2018, 4, 351–357;
Sorich, M.J.; Rowland, A.; Karapetis, C.S.; Hopkins, A.M. Evaluation of the Lung Immune Prognostic Index for Prediction of Survival and Response in Patients Treated With Atezolizumab for NSCLC: Pooled Analysis of Clinical Trials. J. Thorac. Oncol. 2019, 14, 1440–1446. ;
González-Martín A, Pothuri B, Vergote I, et al. Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med. 2019;381(25):2391-2402. doi:10.1056/NEJMoa1910962;
Alvarado-Cruz I, Mahmoud M, Khan M et al. Differential immunomodulatory effect of PARP inhibition in BRCA1 deficient and competent tumor cells. Biochem Pharmacol. 2020 Dec 4;184:114359. doi: 10.1016/j.bcp.2020.114359. Epub ahead of print. PMID: 33285109.
Chabanon RM, Soria JC, Lord CJ et al. Beyond DNA repair: the novel immunological potential of PARP inhibitors. Mol Cell Oncol. 2019 Mar 13;6(2):1585170. doi: 10.1080/23723556.2019.1585170. PMID: 31131303; PMCID: PMC6512907.
Lee EK, Konstantinopoulos PA. Combined PARP and Immune Checkpoint Inhibition in Ovarian Cancer. Trends Cancer. 2019 Sep;5(9):524-528. doi: 10.1016/j.trecan.2019.06.004. Epub 2019 Jul 15. PMID: 31474356.
Lee EK, Konstantinopoulos PA. PARP inhibition and immune modulation: scientific rationale and perspectives for the treatment of gynecologic cancers. Ther Adv Med Oncol. 2020 Jul 24;12:1758835920944116. doi: 10.1177/1758835920944116. PMID: 32782491; PMCID: PMC7383615.
Alvarado-Cruz I, Mahmoud M, Khan M et al. Differential immunomodulatory effect of PARP inhibition in BRCA1 deficient and competent tumor cells. Biochem Pharmacol. 2020 Dec 4;184:114359. doi: 10.1016/j.bcp.2020.114359. Epub ahead of print. PMID: 33285109.
Henriksen JR, Nederby L, Donskov F, et al. Prognostic significance of baseline T cells, B cells and neutrophil-lymphocyte ratio (NLR) in recurrent ovarian cancer treated with chemotherapy. J Ovarian Res. 2020;13(1):59. Published 2020 May 15. doi:10.1186/s13048-020-00661-4;
Huang QT, Zhou L, Zeng WJ, et al. Prognostic Significance of Neutrophil-to-Lymphocyte Ratio in Ovarian Cancer: A Systematic Review and Meta-Analysis of Observational Studies. Cell Physiol Biochem. 2017;41(6):2411-2418. doi:10.1159/000475911;
Dell'Aquila E, Cremolini C, Zeppola T, et al. Prognostic and predictive role of neutrophil/lymphocytes ratio in metastatic colorectal cancer: a retrospective analysis of the TRIBE study by GONO. Ann Oncol. 2018;29(4):924-930. doi:10.1093/annonc/mdy004
Kaneko M, Nozawa H, Sasaki K et al. Elevated neutrophil to lymphocyte ratio predicts poor prognosis in advanced colorectal cancer patients receiving oxaliplatin-based chemotherapy. Oncology 2012; 82(5): 261–268.

Table 1. Characteristics of HGSOC patients by NLR.

Total

Group 1

(NLR < 4)

Group 2

(NLR > 4)

P-value

N (%)

All cases

397

196 (49.4)

201 (50.6)

Mean age at diagnosis (range, years)

60.2 (27-89)

60.8 (27-89)

59.8 (30-85)

0.837

Type of BRCA mutation

No mutation

BRCA1

BRCA2

271 (68.3)

79 (19.9)

47 (11.8)

135 (68.3)

39 (20.1)

24 (12.1)

136 (68.3)

40 (20.1)

23 (11.6)

0.97

CA125,

mean (SD), UI/mL

2632 (4265)

2085 (3152)

1973 (3190)

0.81

FIGO stage at diagnosis

III

282 (71.8)

111 (28.2)

144 (73.1)

53 (26.9)

138 (70.4)

58 (29.6)

0.31

LPS-PIV ^b

≥ 8

173 (43.9)

221 (56.1)

108 (55.4)

87 (44.6)

65 (32.7)

134 (67.3)

0.0001

Primary treatment strategy

PDS

NACT

186 (46.9)

211 (53.1)

110 (55.6)

88 (44.4)

76 (38.2)

123 (61.8)

0.001

Surgical complexity score ^c*

1-2

82 (44.6)

102 (55.4)

59 (54.1)

50 (45.9)

23 (30.7)

52 (69.3)

0.002

RT at primary surgery (PDS)

1-10 mm

>1 cm

158 (84.9)

18 (9.7)

10 (5.4)

92 (83.6)

11 (10)

7 (6.4)

66 (86.8)

7 (9.1)

3 (3.9)

0.75

WT: wild type; VUS: variants of uncertain significance; PVs: pathogenetic variants; FIGO: International Federation of Gynecology and Obstetrics; LPS-PIV: laparoscopic predictive index value; PDS: primary debulking surgery; NACT: neoadjuvant chemotherapy; RT residual tumor; NLR: neutrophile/lymphocyte ratio

^a data calculated on 393 patients due to lack of data of 4 patients

^b data calculated on 394 patients due to lack of data of 3 patients

^cdata calculated on 395 patients due to lack of data of 2 patients

^*Calculated only in women treated with PDS.

Table 2: Cox univariate and multivariate analysis for progression-free survival (PFS)
	Univariate Analysis		Multivariate analysis
Variables	HR (95% CI)	P-value	HR (95% CI)	P-value
Age	1.01 (1.00-1.03)	0.008	1.00 (0.09-1.02)	0.34
LPS-PIV <8/> 8	0.61 (0.46-0.81)	0.001	0.98 (0.64-1.52)	0.96
BRCA status mut/wt	0.43 (0.31-0.60)	0.0001	0.50 (0.35-0.71)	0.0001
PDS/NACT	0.61 (0.46-0.81)	0.001	0.79 (0.52-1.20)	0.27
RT 0/>0	0.49 (0.33-0.71)	0.0001	0.51 (0.35-0.75)	0.001
NLR < 4/ >4	0.69 (0.52-0.91)	0.01	0.69 (0.51-0.95)	0.023
LPS-PIV: laparoscopic predictive index value; mut: mutated; WT: wild type; PDS: primary debulking surgery; NACT: neoadjuvant chemotherapy; RT: residual tumor; NLR: neutrophil/lymphocyte ratio

Table 3: Cox univariate and multivariate analysis for overall-survival (OS)
	Univariate Analysis		Multivariate analysis
Variables	HR (95% CI)	P-value	HR (95% CI)	P-value
Age	1.05 (1.03-1.07)	0.0001	1.03 (1.01-1.06)	0.001
LPS-PIV <8/> 8	0.46 (0.30-0.71)	0.0001	0.81 (0.39-1.65)	0.563
BRCA status mut/wt	0.29 (0.16-0.50)	0.0001	0.47 (0.26-0.85)	0.013
PDS/NACT	0.43 (0.28-0.65)	0.0001	0.79 (0.39-1.57)	0.497
RT 0/>0	0.40 (0.24-0.68)	0.001	0.42 (0.25-0.72)	0.001
NLR < 4/ >4	0.59 (0.39-9.87)	0.008	0.58 (0.36-0.95)	0.032
LPS-PIV: laparoscopic predictive index value; mut: mutated; WT: wild type; PDS: primary debulking surgery; NACT: neoadjuvant chemotherapy; RT: residual tumor; NLR: neutrophil/lymphocyte ratio

No competing interests reported.

Download PDF

Editorial decision: Major revision
24 Mar, 2021
Reviews received at journal
05 Mar, 2021
Reviewers agreed at journal
05 Mar, 2021
Reviewers agreed at journal
04 Mar, 2021
Reviewers invited by journal
02 Mar, 2021
Editor assigned by journal
02 Mar, 2021
Editor invited by journal
10 Feb, 2021
Submission checks completed at journal
10 Feb, 2021
First submitted to journal
08 Feb, 2021

You are reading this latest preprint version

Nlr & Brca Mutational Status In Patients With High Grade Serous Advanced Ovarian Cancer: A Large Population Study

Status:

Version 1

Abstract

Figures

1. Introduction

2. Results

3. Discussion

4. Materials And Methods

Declarations

References

Tables

Additional Declarations

Status:

Version 1