No impact of neutrophil-to-lymphocyte ratio on pathological response to neoadjuvant chemotherapy in Turkish women with breast cancer

No impact of neutrophil-to-lymphocyte ratio on pathological response to neoadjuvant chemotherapy in Turkish women with breast cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article No impact of neutrophil-to-lymphocyte ratio on pathological response to neoadjuvant chemotherapy in Turkish women with breast cancer Erdem Cubukcu, Ahmet Sahin, Birol Ocak, Adem Deligonul, Turkkan Evrensel, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-156091/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Jul, 2021 Read the published version in Scientific Reports → Version 1 posted 9 You are reading this latest preprint version Abstract A low neutrophil-to-lymphocyte ratio (NLR) reflects a systemic milieu characterized by reduced inflammation and increase immune system activation – potentially favoring a better response to therapy in solid malignancies. This retrospective study of collected data aimed to assess whether NLR may predict pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) in Turkish women with breast cancer. The study sample consisted of 406 patients with breast cancer who were scheduled to undergo NAC before attempting cytoreductive surgery. A pretreatment complete blood count was obtained in the week preceding NAC, and the NLR was calculated from absolute counts of neutrophils and lymphocytes. The Miller-Payne system was used to grade response to NAC. Secondary outcome measures included disease-free survival (DFS) and overall survival (OS). Patients were divided into two groups (high versus low) according to the optimal cutoff value (NLR = 1.95; low NLR ≤ 1.95, high NLR > 1.95). The rate of pCR in the low NLR group (22.3%) was similar to that observed in the high NLR group (19.8%; P = 0.20). Moreover, there were no significant differences in DFS and OS of patients in the high and low NLR groups. Based on our results, pretreatment NLR seems to have no significant predictive value in Turkish women with breast cancer who received NAC. However, prospective studies will surely provide deeper insights into the prognostic significance of NLR in this clinical setting. Oncology Cancer Biology Breast cancer neoadjuvant chemotherapy pathological complete response neutrophil-to-lymphocyte ratio disease-free survival Figures Figure 1 Introduction Malignancies originating in the mammary gland are the most common type of cancer in women 1 . The lifetime risk of breast cancer for a woman has been calculated at around 1-in-7 to 1-in-10 2 , indicating that approximately 10% of the female population will be diagnosed with breast cancer during their lifetime 1 , 2 . Neoadjuvant chemotherapy (NAC) − consisting of chemotherapy delivered before local treatment (surgery) − has become the standard of care in patients with locally advanced breast cancer 3 . In addition, downstaging of the primary tumor in patients with earlier stages of breast cancer may facilitate breast-conserving therapy and offer the opportunity to downstage the axilla – ultimately obviating the need for axillary treatment in some patients 4 . The overarching goal of NAC is to achieve pathological complete response (pCR) – which is, in turn, associated with a lower recurrence rate and more favorable survival outcomes 5 . Unfortunately, there is considerable interindividual variation in response to NAC amongst women with breast cancer, and several variables have been investigated in relation to this variability 6 . Inflammation has been shown to promote tumor initiation and progression, whereas escape from immune surveillance may favor cancer invasiveness 7 . There is also evidence that high tumor infiltration by neutrophils has an adverse prognostic significance, whereas tumor-infiltrating lymphocytes portend more favorable outcomes 8 , especially in triple-negative and epidermal growth factor receptor (HER) 2-positive breast cancer 9 . The neutrophil-to-lymphocyte ratio (NLR) – has been extensively investigated in relation to prognosis in patients with different solid malignancies, including breast cancer 9 . In general, a low NLR reflects a systemic milieu characterized by reduced inflammation and increase immune system activation – potentially favoring a better response to therapy 8 , 9 . Recently, Graziano et al. 10 have shown that the combined presence of a low NLR and a low platelet-to-lymphocyte ratio is predictive of pCR in Italian women with breast cancer treated with NAC. However, the question as to whether NLR may predict pCR to NAC as well as survival endpoints in Turkish women remains open. We, therefore, designed the current study to address these issues specifically. Results The general characteristics of the entire study sample (n = 406) before and after categorization according to low (n = 184) or high (n = 222) NLR are shown in Table 1 . The two NLR groups did not differ significantly in terms of age and histopathology. There was a trend toward more frequent postmenopausal patients (P = 0.06) in the low NLR group (53.3% versus 48.3% in the high NLR group). With respect to treatment modalities, there were no intergroup differences with regard to the use of chemotherapy, radiotherapy, type of surgery, hormone therapy, and trastuzumab. Table 2 and Table 3 depict the pre- and post-treatment variables in different NLR groups. None of these variables showed significant intergroup differences. Table 1 General characteristics of the study patients in different neutrophil-to-lymphocyte ratio groups (low versus high) Characteristic Entire cohort (n = 406) Neutrophil-to-lymphocyte ratio P Low (n = 184) High (n = 222) Median age, years (minimum-maximum) 48.2 (22.0-83.5) 49.7 (23.9–77.4) 46.5 (22.0-83.5) 0.07 Menopausal status, n (%) Premenopausal Postmenopausal 210 (51.7) 196 (48.3) 86 (46.7) 98 (53.3) 124 (51.7) 98 (48.3) 0.06 Surgery, n (%) Breast conservative surgery Mastectomy 305 (75.1) 101 (24.9) 144 (78.3) 40 (21.7) 161 (75.1) 61 (24.9) 0.18 Histopathology, n (%) Invasive ductal carcinoma Other histology types* 369 (90.9) 37 (9.1) 167 (90.8) 17 (9.2) 202 (91.0) 20 (9.0) 0.93 Chemotherapy, n (%) Anthracycline regimens Taxane regimes Anthracycline plus taxane 97 (23.9) 20 (4.9) 289 (71.2) 42 (22.8) 7 (3.8) 135 (73.4) 55 (24.8) 13 (5.9) 154 (69.3) 0.53 Hormone therapy, n (%) No Yes 97 (24.0) 308 (76.0) 45 (24.5) 139 (75.5) 52 (23.5) 169 (76.5) 0.83 Radiotherapy, n (%) No Yes 7 (1.7) 399 (98.3) 2 (1.1) 182 (98.9) 5 (2.3) 217 (97.7) 0.46 Trastuzumab, n (%) No Yes 296 (73.1) 109 (26.9) 129 (70.1) 55 (29.9) 167 (75.6) 54 (8.6) 0.19 *Including lobular, mucinous, papillary, metaplastic, and mixed tumors. Data are given as counts (percentages) unless otherwise indicated. Table 2 Pre-treatment variables in different neutrophil-to-lymphocyte ratio groups (low versus high) Characteristic Entire cohort (n = 406) Neutrophil-to-lymphocyte ratio P Low (n = 184) High (n = 222) Clinical T stage, n (%) T1 T2 T3 T4 81 (20.5) 202 (51.1) 26 (6.6) 86 (21.8) 36 (20.5) 96 (54.5) 8 (4.5) 36 (20.5) 45 (20.5) 106 (48.4) 18 (8.2) 50 (22.8) 0.39 Clinical Node status, n (%) Negative Positive 161 (40.4) 238 (59.6) 76 (42.0) 105 (58.0) 85 (39.0) 133 (61.0) 0.54 ER expression, n (%) Negative Positive Unknown 101 (24.9) 288 (70.9) 17 (4.2) 49 (27.7) 128 (72.3) 52 (24.5) 160 (75.5) 0.48 PR expression, n (%) Negative Positive Unknown 152 (37.4) 237 (58.4) 17 (4.2) 70 (39.5) 107 (60.5) 82 (38.7) 130 (61.3) 0.86 HER-2 expression, n (%) 0.52 Negative Positive Unknown 291 (71.7) 97 (23.9) 18 (4.4) 130 (73.4) 47 (26.6) 161 (76.3) 50 (23.7) Ki-67 expression, n (%) ≤ 15% > 15% Unknown 95 (23.4) 263 (64.8) 48 (11.2) 42 (25.6) 122 (74.4) 53 (27.3) 141 (72.7) 0.72 Data are given as counts (percentages). Table 3 Post-treatment variables in different neutrophil-to-lymphocyte ratio groups (low versus high) Characteristic Entire cohort (n = 406) Neutrophil-to-lymphocyte ratio P Low (n = 184) High (n = 222) pT stage, n (%) T0 T1 T2 T3 T4 Unknown 85 (20.9) 185 (45.6) 93 (22.9) 29 (7.1) 5 (1.2) 9 (2.2) 41 (22.7) 84 (46.4) 44 (24.3) 11 (6.1) 1 (0.6) 44 (20.4) 101 (46.8) 49 (5.7) 18 (8.3) 4 (1.9) 0.65 pN, n (%) Negative Positive Unknown 194 (47.8) 204 (50.2) 8 (2.0) 91 (50.6) 89 (49.4) 103 (47.2) 115 (52.8) 0.51 ER expression, n (%) Negative Positive Unknown* 51 (12.6) 259 (63.8) 96 (23.6) 24 (17.6) 112 (82.4) 27 (15.5) 147 (84.5) 0.62 PR expression, n (%) Negative Positive Unknown* 103 (25.4) 207 (51.0) 96 (23.6) 45 (33.1) 91 (66.9) 58 (33.3) 116 (66.7) 0.96 HER-2 expression, n (%) 0.93 Negative Positive Unknown* 254 (62.6) 53 (13.1) 99 (24.4) 112 (83.0) 23 (17.0) 142 (82.6) 30 (17.4) Ki-67 expression, n (%) ≤ 15% > 15% Unknown* 208 (51.2) 90 (22.2) 108 (26.6) 91 (70.5) 38 (29.5) 117 (69.2) 52 (30.8) 0.81 Tumor grade, n (%) 1 2 3 Unknown* 38 (9.4) 216 (53.2) 52 (12.8) 100 (24.6) 20 (14.6) 95 (69.3) 22 (16.1) 18 (10.7) 121 (71.6) 30 (17.8) 0.57 *Unknown includes pathological complete response and missing data. Data are given as counts (percentages). Outcomes Table 4 shows patients’ response to NAC according to the Miller-Payne system in the two NLR groups. No significant intergroup difference was evident (P = 0.20), and the rate of pCR in the low NLR group (22.3%) was similar to that observed in the high NLR group (19.8%). The median follow-up time was 53.3 months (range: 11.4 − 194.4 months). Median DFS and OS were not reached. 12-, 36-, and 60-months disease-free survival rates were 94.6%, 86.1%, 77.8%, respectively. 12-, 36-, and 60-months overall survival rates were 99.8%, 96.3%, 90.3%, respectively. The DFS of patients in the high and low NLR groups was similar (P = 0.091; Fig. 1 A). Similarly, the OS of patients in the high and low NLR groups did not differ significantly (P = 0.181; Fig. 1 B). Table 4 Pathological response to neoadjuvant chemotherapy according to the Miller-Payne grading system of the study patients in different neutrophil-to-lymphocyte ratio groups (low versus high) Miller-Payne grade, n (%) Entire cohort (n = 406) Neutrophil-to-lymphocyte ratio P Low (n = 184) High (n = 222) 1 2 3 4 5 6 (1.5) 58 (14.3) 167 (41.1) 90 (22.2) 85 (20.9) 5 (2.7) 21 (11.4) 75 (40.8) 42 (22.8) 41 (22.3) 1 (0.5) 37 (31.7) 92 (41.4) 48 (20.6) 44 (19.8) 0.20 Data are given as counts (percentages). Discussion Previous studies have shown that numerous factors – including age, genetic polymorphisms, as well as ER, PR, and HER2 expression status – may be predictive of response to NAC in women with breast cancer 6 . For example, HER2-positive and triple-negative breast malignancies generally show good responses to NAC 6 . However, some of these variables become available only following detailed pathological investigations. There is, therefore, an urgent need for reliable prognostic tools grounded on simple pretreatment variables. In this scenario, some readily available parameters originated from routine complete blood count have been extensively investigated to predict treatment response 7 , 9 . In general, white blood cell count reflects an individual’s systemic and/or local inflammatory status 8 . Neutrophils are known to produce cytokines, chemokines, and growth factors that may promote angiogenesis as well as tumor cell proliferation and migration. In contrast, lymphocytes are responsible for antitumor-specific immune response – including T-lymphocyte tumor infiltration and cytotoxic T-lymphocyte-mediated antitumor activity 8 , 10 . Starting from these premises, it can be expected that a high NLR – an index that reflects the balance between inflammation and immunoreaction in cancer – would predict a lower response to treatment and less favorable outcomes 9 . However, we did not observe any significant association between pretreatment NLR and pCR to NAC in Turkish women with breast malignancies. Further, NLR was not predictive of DFS and OS in this patient group, although there was a non-significant trend toward a better DFS in patients with low NLR. We cannot exclude that the cutoff value might affect the predictive and prognostic performances of NAC. Notably, such cutoffs may be dependent on the specific patient population and/or ethnicity. The optimal cutoff for NLR in our study was 1.95, being lower than that previously reported by Azab et al. 11 These authors demonstrated that patients with breast cancer in the highest NLR quartile (> 3.3) had higher 1- and 5-year mortality rates than those in the lowest NLR quartile ( 2.06 before chemotherapy had higher rates of pCR. However, negative results have been published as well. Suppan at al. 13 failed to demonstrate an association between NLR and response to neoadjuvant chemo- or hormone therapy in a study of 247 Austrian women. Similar results have been reported by Erylmaz et al. 14 in research conducted on 78 Turkish women. As described above, the optimal methods of selecting NLR cutoff values remain unclear, and this methodological caveat may yield conflicting results. Further, the potential existence of inflammatory co-morbidities may have confounded the predictive value of NLR and could have played a role in the discrepant findings published in the literature. Some limitations of our study merit comment, including the retrospective design and the inclusion of women of Turkish descent only. Furthermore, we did not perform subgroup analyses according to breast cancer subtypes. Based on our results, pretreatment NLR seems to have no significant predictive value in Turkish women with breast cancer who received NAC. However, prospective studies will surely provide deeper insights into the prognostic significance of NLR in this clinical setting. Materials And Methods Study patients and variable collection This is a retrospective analysis of collected data. The study sample consisted of 406 consecutive Turkish women with breast cancer scheduled to undergo NAC before attempting cytoreductive surgery at the Department of Oncology or the Department of General Surgery, Uludag University Medical Center (Bursa, Turkey). The following variables were extracted from clinical records in all participants: age; menopausal status; surgical approach; pre- and post-treatment pathological stage; histology type; pre- and post-treatment tumor stage; pre- and post-treatment axillary lymph node status; pre- and post-treatment expression of estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki67; post-treatment tumor grade; use of chemo-, radio- and hormonal therapy; and use of trastuzumab. The staging of the patients was carried out according to the American Joint Committee on Cancer (AJCC) Staging Manual, eighth edition. A pretreatment complete blood count was obtained in the week preceding NAC, and the NLR was calculated from absolute counts of neutrophils and lymphocytes. Ethical statement The study protocol complied with the tenets of the Helsinki declaration. The Clinical Research Ethics Committee of the Bursa Uludag University Faculty of Medicine approved the study and all exemptions from informed consent due to the retrospective nature (Approval number: 2020-8/43). Outcomes The primary outcome measure was pCR to NAC. The Miller-Payne system 15 was used to grade response to NAC, as follows: grade 1, no change or some alteration to individual malignant cells, but no reduction in overall cellularity (pNR); grade 2, minor loss of tumor cells, but overall cellularity still high; up to 30% loss (pPR); grade 3, between an estimated 30% and 90% reduction in tumor cells (pPR); grade 4, marked disappearance of tumor cells such that only small clusters or widely dispersed individual cells remain; 90% loss of tumor cells (almost pCR); and grade 5, no malignant cells identifiable in sections from the site of the tumor; only vascular fibroelastotic stroma remains, often containing macrophages; however, ductal carcinoma in situ may be present (pCR). Secondary outcome measures included disease-free survival (DFS) and overall survival (OS). DFS and OS were calculated as the time (in months) from the date of breast cancer diagnosis to the date of disease recurrence and death, respectively. Statistical analysis The optimal cutoff point for NLR was determined using receiver operating characteristic (ROC) curve analysis taking disease recurrence as the endpoint of interest. Patients were divided into two groups (high versus low) according to the optimal cutoff value (NLR = 1.95; low NLR ≤ 1.95, high NLR >1.95). The general characteristics of the study patients are presented using descriptive statistics (median, ranges, counts, and percentages). Intergroup differences were assessed with the Mann-Whitney U test (continuous variables) or the chi-square test (categorical variables). Survival curves were plotted using the Kaplan-Meier method and compared with the log-rank test. All calculations were performed with SPSS, version 22.0 (IBM, Armonk, NY, USA). Two-tailed p values <0.05 were considered statistically significant. Declarations Ethical statement The study protocol complied with the tenets of the Helsinki declaration. The Clinical Research Ethics Committee of the Bursa Uludag University Faculty of Medicine approved the study and all exemptions from informed consent due to the retrospective nature (Approval number: 2020-8/43). COMPETING INTERESTS The authors declare no competing interests. AUTHOR CONTRIBUTIONS E.C. conceived the study design, A.B.S, B.O, K.S., and G.Y. collected the data, A.B.S. performed statistical analyses. E.C. wrote the manuscript. T.E., A.D., S.T., M.S.G., and S.C. edited the manuscript. All authors have read and approved the final manuscript. ACKNOWLEDGMENTS None. References Winters, S., Martin, C., Murphy, D. & Shokar, N. K. Breast Cancer Epidemiology, Prevention, and Screening. Progress in Molecular Biology and Translational Science. 151 , 1–32 Elsevier B.V. (2017). Rojas, K. & Stuckey, A. Breast Cancer Epidemiology and Risk Factors. Clin. Obstet. Gynecol. 59 , 651–672 (2016). Doval, D. C., Dutta, K., Batra, U. & Talwar, V. Neoadjuvant chemotherapy in breast cancer: review of literature. J. Indian Med. Assoc. 111 , 629–631 (2013). Mathew, J. et al. Neoadjuvant chemotherapy for locally advanced breast cancer: A review of the literature and future directions. European Journal of Surgical Oncology. 35 , 113–122 (2009). Spring, L. M. et al. Pathologic Complete Response after Neoadjuvant Chemotherapy and Impact on Breast Cancer Recurrence and Survival: A Comprehensive Meta-analysis. Clin. Cancer Res. 26 , 2838–2848 (2020). Parekh, T., Dodwell, D., Sharma, N. & Shaaban, A. M. Radiological and Pathological Predictors of Response to Neoadjuvant Chemotherapy in Breast Cancer: A Brief Literature Review. Pathobiology. 82 , 124–132 (2015). Guthrie, G. J. K. et al. The systemic inflammation-based neutrophil-lymphocyte ratio: Experience in patients with cancer. Critical Reviews in Oncology/Hematology. 88 , 218–230 (2013). Dupré, A. & Malik, H. Z. Inflammation and cancer: What a surgical oncologist should know. European Journal of Surgical Oncology. 44 , 566–570 (2018). Ethier, J. L., Desautels, D., Templeton, A., Shah, P. S. & Amir, E. Prognostic role of neutrophil-to-lymphocyte ratio in breast cancer: A systematic review and meta-analysis. Breast Cancer Res. 19 , (2017). Graziano, V. et al. Combination of peripheral neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio is predictive of pathological complete response after neoadjuvant chemotherapy in breast cancer patients. Breast. 44 , 33–38 (2019). Azab, B. et al. Usefulness of the neutrophil-to-lymphocyte ratio in predicting short- and long-term mortality in breast cancer patients. Ann. Surg. Oncol. 19 , 217–224 (2012). Chen, J. et al. Prognostic value of neutrophil-to-lymphocyte ratio in breast cancer. FEBS Open Bio. 5 , 502–507 (2015). Suppan, C. et al. Neutrophil/Lymphocyte ratio has no predictive or prognostic value in breast cancer patients undergoing preoperative systemic therapy. BMC Cancer 15 , (2015). Eryilmaz, M. K. et al. The neutrophil to lymphocyte ratio has a high negative predictive value for pathologic complete response in locally advanced breast cancer patients receiving neoadjuvant chemotherapy. Asian Pacific J. Cancer Prev. 15 , 7737–7740 (2014). Miller, A. B., Hoogstraten, B., Staquet, M. & Winkler, A. Reporting results of cancer treatment. Cancer. 47 , 207–214 (1981). Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-156091","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":13577693,"identity":"53ba1c67-01c7-4cde-8810-03eaab4d007e","order_by":0,"name":"Erdem Cubukcu","email":"","orcid":"","institution":"Uludağ University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Erdem","middleName":"","lastName":"Cubukcu","suffix":""},{"id":13577694,"identity":"f470d95d-fc20-4757-a7b5-c9df2c9395bb","order_by":1,"name":"Ahmet Sahin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA50lEQVRIiWNgGAWjYDACCQYGZgYDBjkGdjAbCA4QqcUYSMK1MDYQ1sLAkNhAtBb+2e0PPxcU3EnfcJjH8MaPXwxyfDcS2B9X4LPkzhlj6RkGz3KBWowte/sYjCVvJDA2nsFnzY0cBmkeg8MgLWYSvD0MiRtAWvC5TP5G+uPfQC3pBkAtkn97GOoJajG4kWAGsiUBpEWa5wdDggEhLYZ3zphZA7UYzjzMVmwt2yBhOPPMw8aZ+LTI3W5/fJvnz2F5vuPNG2+++WMDZCQf+IhPCypgbANFDYGYRAN/SFE8CkbBKBgFIwUAACyZUZpQANW8AAAAAElFTkSuQmCC","orcid":"","institution":"Uludağ University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Ahmet","middleName":"","lastName":"Sahin","suffix":""},{"id":13577695,"identity":"18cdcc86-cdb0-4b08-b5dc-e4dd1dc353f1","order_by":2,"name":"Birol Ocak","email":"","orcid":"","institution":"Uludağ University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Birol","middleName":"","lastName":"Ocak","suffix":""},{"id":13577696,"identity":"10f77827-a0d0-4bc0-966b-eed5aa9b8dba","order_by":3,"name":"Adem Deligonul","email":"","orcid":"","institution":"Uludağ University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Adem","middleName":"","lastName":"Deligonul","suffix":""},{"id":13577697,"identity":"3bf8025a-f3ed-4f16-8fce-38699625c6c3","order_by":4,"name":"Turkkan Evrensel","email":"","orcid":"","institution":"Uludağ University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Turkkan","middleName":"","lastName":"Evrensel","suffix":""},{"id":13577698,"identity":"c8b17ca1-a01b-4285-82ae-e805855925e8","order_by":5,"name":"Sahsine Tolunay","email":"","orcid":"","institution":"Uludağ University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sahsine","middleName":"","lastName":"Tolunay","suffix":""},{"id":13577699,"identity":"63a11880-c960-4473-a58d-5bd45a0f731d","order_by":6,"name":"Mustafa Sehsuvar Gokgoz","email":"","orcid":"","institution":"Uludağ University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mustafa","middleName":"Sehsuvar","lastName":"Gokgoz","suffix":""},{"id":13577700,"identity":"3709d66f-5724-41e8-aba7-ac7d29fcef54","order_by":7,"name":"Sibel Cetintas","email":"","orcid":"","institution":"Uludağ University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sibel","middleName":"","lastName":"Cetintas","suffix":""},{"id":13577701,"identity":"f08d1793-d68b-46f8-aa17-12db498dd062","order_by":8,"name":"Gorkem Yarbas","email":"","orcid":"","institution":"Uludağ University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Gorkem","middleName":"","lastName":"Yarbas","suffix":""},{"id":13577702,"identity":"6d680bd5-bf2b-48de-88c2-7c865d8e925c","order_by":9,"name":"Kazım Senol","email":"","orcid":"","institution":"Uludağ University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kazım","middleName":"","lastName":"Senol","suffix":""}],"badges":[],"createdAt":"2021-01-26 17:47:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-156091/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-156091/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-021-94184-7","type":"published","date":"2021-07-19T15:04:47+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":6365609,"identity":"b3ac8f14-51e1-4900-ab8f-3a62519a0684","added_by":"auto","created_at":"2021-02-25 21:15:27","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":71683,"visible":true,"origin":"","legend":"Kaplan-Meier plots of survival endpoints in different neutrophil-to-lymphocyte ratio groups (low versus high): (A) disease-free survival; (B) overall survival.","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-156091/v1/36d6a9444b399b39b093c469.jpg"},{"id":13672143,"identity":"06bb2ed4-70c4-428b-a7b6-795fbc8dba1f","added_by":"auto","created_at":"2021-09-17 11:12:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":509421,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-156091/v1/a5773324-c5f0-4f44-aca3-f8aba4360f54.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"No impact of neutrophil-to-lymphocyte ratio on pathological response to neoadjuvant chemotherapy in Turkish women with breast cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMalignancies originating in the mammary gland are the most common type of cancer in women\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. The lifetime risk of breast cancer for a woman has been calculated at around 1-in-7 to 1-in-10\u003csup\u003e2\u003c/sup\u003e, indicating that approximately 10% of the female population will be diagnosed with breast cancer during their lifetime\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eNeoadjuvant chemotherapy (NAC)\u0026thinsp;\u0026minus;\u0026thinsp;consisting of chemotherapy delivered before local treatment (surgery)\u0026thinsp;\u0026minus;\u0026thinsp;has become the standard of care in patients with locally advanced breast cancer\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. In addition, downstaging of the primary tumor in patients with earlier stages of breast cancer may facilitate breast-conserving therapy and offer the opportunity to downstage the axilla \u0026ndash; ultimately obviating the need for axillary treatment in some patients\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. The overarching goal of NAC is to achieve pathological complete response (pCR) \u0026ndash; which is, in turn, associated with a lower recurrence rate and more favorable survival outcomes\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Unfortunately, there is considerable interindividual variation in response to NAC amongst women with breast cancer, and several variables have been investigated in relation to this variability\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eInflammation has been shown to promote tumor initiation and progression, whereas escape from immune surveillance may favor cancer invasiveness\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. There is also evidence that high tumor infiltration by neutrophils has an adverse prognostic significance, whereas tumor-infiltrating lymphocytes portend more favorable outcomes\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e, especially in triple-negative and epidermal growth factor receptor (HER) 2-positive breast cancer\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. The neutrophil-to-lymphocyte ratio (NLR) \u0026ndash; has been extensively investigated in relation to prognosis in patients with different solid malignancies, including breast cancer\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. In general, a low NLR reflects a systemic milieu characterized by reduced inflammation and increase immune system activation \u0026ndash; potentially favoring a better response to therapy\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Recently, Graziano et al.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e have shown that the combined presence of a low NLR and a low platelet-to-lymphocyte ratio is predictive of pCR in Italian women with breast cancer treated with NAC. However, the question as to whether NLR may predict pCR to NAC as well as survival endpoints in Turkish women remains open. We, therefore, designed the current study to address these issues specifically.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe general characteristics of the entire study sample (n\u0026thinsp;=\u0026thinsp;406) before and after categorization according to low (n\u0026thinsp;=\u0026thinsp;184) or high (n\u0026thinsp;=\u0026thinsp;222) NLR are shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. The two NLR groups did not differ significantly in terms of age and histopathology. There was a trend toward more frequent postmenopausal patients (P\u0026thinsp;=\u0026thinsp;0.06) in the low NLR group (53.3% versus 48.3% in the high NLR group). With respect to treatment modalities, there were no intergroup differences with regard to the use of chemotherapy, radiotherapy, type of surgery, hormone therapy, and trastuzumab. Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e depict the pre- and post-treatment variables in different NLR groups. None of these variables showed significant intergroup differences.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eGeneral characteristics of the study patients in different neutrophil-to-lymphocyte ratio groups (low \u003cem\u003eversus\u003c/em\u003e high)\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eCharacteristic\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eEntire cohort\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;406)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eNeutrophil-to-lymphocyte ratio\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLow\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(n\u0026thinsp;=\u0026thinsp;184)\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eHigh\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(n\u0026thinsp;=\u0026thinsp;222)\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eMedian age, years\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(minimum-maximum)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e48.2\u003c/p\u003e\n\u003cp\u003e(22.0-83.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e49.7\u003c/p\u003e\n\u003cp\u003e(23.9\u0026ndash;77.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e46.5\u003c/p\u003e\n\u003cp\u003e(22.0-83.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.07\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eMenopausal status, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePremenopausal\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePostmenopausal\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e210 (51.7)\u003c/p\u003e\n\u003cp\u003e196 (48.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e86 (46.7)\u003c/p\u003e\n\u003cp\u003e98 (53.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e124 (51.7)\u003c/p\u003e\n\u003cp\u003e98 (48.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.06\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eSurgery, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eBreast conservative surgery\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMastectomy\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e305 (75.1)\u003c/p\u003e\n\u003cp\u003e101 (24.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e144 (78.3)\u003c/p\u003e\n\u003cp\u003e40 (21.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e161 (75.1)\u003c/p\u003e\n\u003cp\u003e61 (24.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.18\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eHistopathology, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eInvasive ductal carcinoma\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eOther histology types*\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e369 (90.9)\u003c/p\u003e\n\u003cp\u003e37 (9.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e167 (90.8)\u003c/p\u003e\n\u003cp\u003e17 (9.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e202 (91.0)\u003c/p\u003e\n\u003cp\u003e20 (9.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.93\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eChemotherapy, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAnthracycline regimens\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTaxane regimes\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAnthracycline plus taxane\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e97 (23.9)\u003c/p\u003e\n\u003cp\u003e20 (4.9)\u003c/p\u003e\n\u003cp\u003e289 (71.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e42 (22.8)\u003c/p\u003e\n\u003cp\u003e7 (3.8)\u003c/p\u003e\n\u003cp\u003e135 (73.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e55 (24.8)\u003c/p\u003e\n\u003cp\u003e13 (5.9)\u003c/p\u003e\n\u003cp\u003e154 (69.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.53\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eHormone therapy, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eNo\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eYes\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e97 (24.0)\u003c/p\u003e\n\u003cp\u003e308 (76.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e45 (24.5)\u003c/p\u003e\n\u003cp\u003e139 (75.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e52 (23.5)\u003c/p\u003e\n\u003cp\u003e169 (76.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.83\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eRadiotherapy, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eNo\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eYes\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (1.7)\u003c/p\u003e\n\u003cp\u003e399 (98.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (1.1)\u003c/p\u003e\n\u003cp\u003e182 (98.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (2.3)\u003c/p\u003e\n\u003cp\u003e217 (97.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.46\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eTrastuzumab, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eNo\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eYes\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e296 (73.1)\u003c/p\u003e\n\u003cp\u003e109 (26.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e129 (70.1)\u003c/p\u003e\n\u003cp\u003e55 (29.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e167 (75.6)\u003c/p\u003e\n\u003cp\u003e54 (8.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.19\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003e*Including lobular, mucinous, papillary, metaplastic, and mixed tumors. Data are given as counts (percentages) unless otherwise indicated.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003ePre-treatment variables in different neutrophil-to-lymphocyte ratio groups (low \u003cem\u003eversus\u003c/em\u003e high)\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eCharacteristic\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eEntire cohort\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;406)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eNeutrophil-to-lymphocyte ratio\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLow\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(n\u0026thinsp;=\u0026thinsp;184)\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eHigh\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(n\u0026thinsp;=\u0026thinsp;222)\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eClinical T stage, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eT1\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eT2\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eT3\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eT4\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e81 (20.5)\u003c/p\u003e\n\u003cp\u003e202 (51.1)\u003c/p\u003e\n\u003cp\u003e26 (6.6)\u003c/p\u003e\n\u003cp\u003e86 (21.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e36 (20.5)\u003c/p\u003e\n\u003cp\u003e96 (54.5)\u003c/p\u003e\n\u003cp\u003e8 (4.5)\u003c/p\u003e\n\u003cp\u003e36 (20.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e45 (20.5)\u003c/p\u003e\n\u003cp\u003e106 (48.4)\u003c/p\u003e\n\u003cp\u003e18 (8.2)\u003c/p\u003e\n\u003cp\u003e50 (22.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.39\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Node status, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eNegative\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePositive\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e161 (40.4)\u003c/p\u003e\n\u003cp\u003e238 (59.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e76 (42.0)\u003c/p\u003e\n\u003cp\u003e105 (58.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e85 (39.0)\u003c/p\u003e\n\u003cp\u003e133 (61.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.54\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eER expression, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eNegative\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePositive\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eUnknown\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e101 (24.9)\u003c/p\u003e\n\u003cp\u003e288 (70.9)\u003c/p\u003e\n\u003cp\u003e17 (4.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e49 (27.7)\u003c/p\u003e\n\u003cp\u003e128 (72.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e52 (24.5)\u003c/p\u003e\n\u003cp\u003e160 (75.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.48\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePR expression, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eNegative\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePositive\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eUnknown\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e152 (37.4)\u003c/p\u003e\n\u003cp\u003e237 (58.4)\u003c/p\u003e\n\u003cp\u003e17 (4.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e70 (39.5)\u003c/p\u003e\n\u003cp\u003e107 (60.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e82 (38.7)\u003c/p\u003e\n\u003cp\u003e130 (61.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.86\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eHER-2 expression, n (%)\u003c/strong\u003e0.52\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eNegative\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePositive\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eUnknown\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e291 (71.7)\u003c/p\u003e\n\u003cp\u003e97 (23.9)\u003c/p\u003e\n\u003cp\u003e18 (4.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e130 (73.4)\u003c/p\u003e\n\u003cp\u003e47 (26.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e161 (76.3)\u003c/p\u003e\n\u003cp\u003e50 (23.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eKi-67 expression, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026le;\u0026thinsp;15%\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026gt;\u0026thinsp;15%\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eUnknown\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e95 (23.4)\u003c/p\u003e\n\u003cp\u003e263 (64.8)\u003c/p\u003e\n\u003cp\u003e48 (11.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e42 (25.6)\u003c/p\u003e\n\u003cp\u003e122 (74.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e53 (27.3)\u003c/p\u003e\n\u003cp\u003e141 (72.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.72\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eData are given as counts (percentages).\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003ePost-treatment variables in different neutrophil-to-lymphocyte ratio groups (low \u003cem\u003eversus\u003c/em\u003e high)\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eCharacteristic\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eEntire cohort\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;406)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eNeutrophil-to-lymphocyte ratio\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLow\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(n\u0026thinsp;=\u0026thinsp;184)\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eHigh\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(n\u0026thinsp;=\u0026thinsp;222)\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003epT stage, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eT0\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eT1\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eT2\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eT3\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eT4\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eUnknown\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e85 (20.9)\u003c/p\u003e\n\u003cp\u003e185 (45.6)\u003c/p\u003e\n\u003cp\u003e93 (22.9)\u003c/p\u003e\n\u003cp\u003e29 (7.1)\u003c/p\u003e\n\u003cp\u003e5 (1.2)\u003c/p\u003e\n\u003cp\u003e9 (2.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e41 (22.7)\u003c/p\u003e\n\u003cp\u003e84 (46.4)\u003c/p\u003e\n\u003cp\u003e44 (24.3)\u003c/p\u003e\n\u003cp\u003e11 (6.1)\u003c/p\u003e\n\u003cp\u003e1 (0.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e44 (20.4)\u003c/p\u003e\n\u003cp\u003e101 (46.8)\u003c/p\u003e\n\u003cp\u003e49 (5.7)\u003c/p\u003e\n\u003cp\u003e18 (8.3)\u003c/p\u003e\n\u003cp\u003e4 (1.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.65\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003epN, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eNegative\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePositive\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eUnknown\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e194 (47.8)\u003c/p\u003e\n\u003cp\u003e204 (50.2)\u003c/p\u003e\n\u003cp\u003e8 (2.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e91 (50.6)\u003c/p\u003e\n\u003cp\u003e89 (49.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e103 (47.2)\u003c/p\u003e\n\u003cp\u003e115 (52.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.51\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eER expression, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eNegative\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePositive\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eUnknown*\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e51 (12.6)\u003c/p\u003e\n\u003cp\u003e259 (63.8)\u003c/p\u003e\n\u003cp\u003e96 (23.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e24 (17.6)\u003c/p\u003e\n\u003cp\u003e112 (82.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27 (15.5)\u003c/p\u003e\n\u003cp\u003e147 (84.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.62\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePR expression, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eNegative\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePositive\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eUnknown*\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e103 (25.4)\u003c/p\u003e\n\u003cp\u003e207 (51.0)\u003c/p\u003e\n\u003cp\u003e96 (23.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e45 (33.1)\u003c/p\u003e\n\u003cp\u003e91 (66.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e58 (33.3)\u003c/p\u003e\n\u003cp\u003e116 (66.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.96\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eHER-2 expression, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003e0.93\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eNegative\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePositive\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eUnknown*\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e254 (62.6)\u003c/p\u003e\n\u003cp\u003e53 (13.1)\u003c/p\u003e\n\u003cp\u003e99 (24.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e112 (83.0)\u003c/p\u003e\n\u003cp\u003e23 (17.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e142 (82.6)\u003c/p\u003e\n\u003cp\u003e30 (17.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eKi-67 expression, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026le;\u0026thinsp;15%\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026gt;\u0026thinsp;15%\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eUnknown*\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e208 (51.2)\u003c/p\u003e\n\u003cp\u003e90 (22.2)\u003c/p\u003e\n\u003cp\u003e108 (26.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e91 (70.5)\u003c/p\u003e\n\u003cp\u003e38 (29.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e117 (69.2)\u003c/p\u003e\n\u003cp\u003e52 (30.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.81\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eTumor grade, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e1\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e2\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e3\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eUnknown*\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e38 (9.4)\u003c/p\u003e\n\u003cp\u003e216 (53.2)\u003c/p\u003e\n\u003cp\u003e52 (12.8)\u003c/p\u003e\n\u003cp\u003e100 (24.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e20 (14.6)\u003c/p\u003e\n\u003cp\u003e95 (69.3)\u003c/p\u003e\n\u003cp\u003e22 (16.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18 (10.7)\u003c/p\u003e\n\u003cp\u003e121 (71.6)\u003c/p\u003e\n\u003cp\u003e30 (17.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.57\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"6\"\u003e*Unknown includes pathological complete response and missing data. Data are given as counts (percentages).\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e shows patients\u0026rsquo; response to NAC according to the Miller-Payne system in the two NLR groups. No significant intergroup difference was evident (P\u0026thinsp;=\u0026thinsp;0.20), and the rate of pCR in the low NLR group (22.3%) was similar to that observed in the high NLR group (19.8%). The median follow-up time was 53.3 months (range: 11.4\u0026thinsp;\u0026minus;\u0026thinsp;194.4 months). Median DFS and OS were not reached. 12-, 36-, and 60-months disease-free survival rates were 94.6%, 86.1%, 77.8%, respectively. 12-, 36-, and 60-months overall survival rates were 99.8%, 96.3%, 90.3%, respectively. The DFS of patients in the high and low NLR groups was similar (P\u0026thinsp;=\u0026thinsp;0.091; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eA). Similarly, the OS of patients in the high and low NLR groups did not differ significantly (P\u0026thinsp;=\u0026thinsp;0.181; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eB).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab4\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003ePathological response to neoadjuvant chemotherapy according to the Miller-Payne grading system of the study patients in different neutrophil-to-lymphocyte ratio groups (low \u003cem\u003eversus\u003c/em\u003e high)\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMiller-Payne grade, n (%)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eEntire cohort\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;406)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eNeutrophil-to-lymphocyte ratio\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLow\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(n\u0026thinsp;=\u0026thinsp;184)\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eHigh\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(n\u0026thinsp;=\u0026thinsp;222)\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (1.5)\u003c/p\u003e\n\u003cp\u003e58 (14.3)\u003c/p\u003e\n\u003cp\u003e167 (41.1)\u003c/p\u003e\n\u003cp\u003e90 (22.2)\u003c/p\u003e\n\u003cp\u003e85 (20.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (2.7)\u003c/p\u003e\n\u003cp\u003e21 (11.4)\u003c/p\u003e\n\u003cp\u003e75 (40.8)\u003c/p\u003e\n\u003cp\u003e42 (22.8)\u003c/p\u003e\n\u003cp\u003e41 (22.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (0.5)\u003c/p\u003e\n\u003cp\u003e37 (31.7)\u003c/p\u003e\n\u003cp\u003e92 (41.4)\u003c/p\u003e\n\u003cp\u003e48 (20.6)\u003c/p\u003e\n\u003cp\u003e44 (19.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.20\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eData are given as counts (percentages).\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003ePrevious studies have shown that numerous factors \u0026ndash; including age, genetic polymorphisms, as well as ER, PR, and HER2 expression status \u0026ndash; may be predictive of response to NAC in women with breast cancer\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. For example, HER2-positive and triple-negative breast malignancies generally show good responses to NAC\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. However, some of these variables become available only following detailed pathological investigations. There is, therefore, an urgent need for reliable prognostic tools grounded on simple pretreatment variables. In this scenario, some readily available parameters originated from routine complete blood count have been extensively investigated to predict treatment response\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. In general, white blood cell count reflects an individual\u0026rsquo;s systemic and/or local inflammatory status\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Neutrophils are known to produce cytokines, chemokines, and growth factors that may promote angiogenesis as well as tumor cell proliferation and migration. In contrast, lymphocytes are responsible for antitumor-specific immune response \u0026ndash; including T-lymphocyte tumor infiltration and cytotoxic T-lymphocyte-mediated antitumor activity\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Starting from these premises, it can be expected that a high NLR \u0026ndash; an index that reflects the balance between inflammation and immunoreaction in cancer \u0026ndash; would predict a lower response to treatment and less favorable outcomes\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. However, we did not observe any significant association between pretreatment NLR and pCR to NAC in Turkish women with breast malignancies. Further, NLR was not predictive of DFS and OS in this patient group, although there was a non-significant trend toward a better DFS in patients with low NLR. We cannot exclude that the cutoff value might affect the predictive and prognostic performances of NAC. Notably, such cutoffs may be dependent on the specific patient population and/or ethnicity. The optimal cutoff for NLR in our study was 1.95, being lower than that previously reported by Azab et al.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e These authors demonstrated that patients with breast cancer in the highest NLR quartile (\u0026gt;\u0026thinsp;3.3) had higher 1- and 5-year mortality rates than those in the lowest NLR quartile (\u0026lt;\u0026thinsp;1.8)\u003csup\u003e11\u003c/sup\u003e. In a study of 215 Chinese women, Chen et al.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e shown that women who had an NLR\u0026thinsp;\u0026gt;\u0026thinsp;2.06 before chemotherapy had higher rates of pCR. However, negative results have been published as well. Suppan at al.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e failed to demonstrate an association between NLR and response to neoadjuvant chemo- or hormone therapy in a study of 247 Austrian women. Similar results have been reported by Erylmaz et al.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e in research conducted on 78 Turkish women. As described above, the optimal methods of selecting NLR cutoff values remain unclear, and this methodological caveat may yield conflicting results. Further, the potential existence of inflammatory co-morbidities may have confounded the predictive value of NLR and could have played a role in the discrepant findings published in the literature.\u003c/p\u003e\n\u003cp\u003eSome limitations of our study merit comment, including the retrospective design and the inclusion of women of Turkish descent only. Furthermore, we did not perform subgroup analyses according to breast cancer subtypes.\u003c/p\u003e\n\u003cp\u003eBased on our results, pretreatment NLR seems to have no significant predictive value in Turkish women with breast cancer who received NAC. However, prospective studies will surely provide deeper insights into the prognostic significance of NLR in this clinical setting.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n\u003cp\u003e\u003cstrong\u003eStudy patients and variable collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is a retrospective analysis of collected data. The study sample consisted of 406 consecutive Turkish women with breast cancer scheduled to undergo NAC before attempting cytoreductive surgery at the Department of Oncology or the Department of General Surgery, Uludag University Medical Center (Bursa, Turkey). The following variables were extracted from clinical records in all participants: age; menopausal status; surgical approach; pre- and post-treatment pathological stage; histology type; pre- and post-treatment tumor stage; pre- and post-treatment axillary lymph node status; pre- and post-treatment expression of estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki67; post-treatment tumor grade; use of chemo-, radio- and hormonal therapy; and use of trastuzumab.\u003c/p\u003e\n\u003cdiv class=\"Ethics-ToolTip\"\u003eThe staging of the patients was carried out according to the American Joint Committee on Cancer (AJCC) Staging Manual, eighth edition.\u003c/div\u003e\n\u003cp\u003eA pretreatment complete blood count was obtained in the week preceding NAC, and the NLR was calculated from absolute counts of neutrophils and lymphocytes.\u003c/p\u003e\n\u003c/div\u003e\u003cp\u003e\u003cstrong\u003eEthical statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol complied with the tenets of the Helsinki declaration. The Clinical Research Ethics Committee of the Bursa Uludag University Faculty of Medicine approved the study and all exemptions from informed consent due to the retrospective nature (Approval number: 2020-8/43).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcome measure was pCR to NAC. The Miller-Payne system\u003csup\u003e15\u003c/sup\u003e was used to grade response to NAC, as follows: grade 1, no change or some alteration to individual malignant cells, but no reduction in overall cellularity (pNR); grade 2, minor loss of tumor cells, but overall cellularity still high; up to 30% loss (pPR); grade 3, between an estimated 30% and 90% reduction in tumor cells (pPR); grade 4, marked disappearance of tumor cells such that only small clusters or widely dispersed individual cells remain; 90% loss of tumor cells (almost pCR); and grade 5, no malignant cells identifiable in sections from the site of the tumor; only vascular fibroelastotic stroma remains, often containing macrophages; however, ductal carcinoma in situ may be present (pCR). Secondary outcome measures included disease-free survival (DFS) and overall survival (OS). DFS and OS were calculated as the time (in months) from the date of breast cancer diagnosis to the date of disease recurrence and death, respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe optimal cutoff point for NLR was determined using receiver operating characteristic (ROC) curve analysis taking disease recurrence as the endpoint of interest. Patients were divided into two groups (high versus low) according to the optimal cutoff value (NLR = 1.95; low NLR \u0026le; 1.95, high NLR \u0026gt;1.95). The general characteristics of the study patients are presented using descriptive statistics (median, ranges, counts, and percentages). Intergroup differences were assessed with the Mann-Whitney U test (continuous variables) or the chi-square test (categorical variables). Survival curves were plotted using the Kaplan-Meier method and compared with the log-rank test. All calculations were performed with SPSS, version 22.0 (IBM, Armonk, NY, USA). Two-tailed p values \u0026lt;0.05 were considered statistically significant.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol complied with the tenets of the Helsinki declaration.\u003c/p\u003e\n\u003cp class=\"Ethics-ToolTip\"\u003eThe Clinical Research Ethics Committee of the Bursa Uludag University Faculty of Medicine approved the study and all exemptions from informed consent due to the retrospective nature (Approval number: 2020-8/43).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCOMPETING INTERESTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eE.C. conceived the study design, A.B.S, B.O, K.S., and G.Y. collected the data, A.B.S. performed statistical analyses. E.C. wrote the manuscript. T.E., A.D., S.T., M.S.G., and S.C. edited the manuscript.\u003c/p\u003e\n\u003cp class=\"Ethics-ToolTip\"\u003eAll authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACKNOWLEDGMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWinters, S., Martin, C., Murphy, D. \u0026amp; Shokar, N. K. Breast Cancer Epidemiology, Prevention, and Screening. \u003cem\u003eProgress in Molecular Biology and Translational Science.\u003c/em\u003e \u003cb\u003e151\u003c/b\u003e, 1\u0026ndash;32 Elsevier B.V. (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRojas, K. \u0026amp; Stuckey, A. Breast Cancer Epidemiology and Risk Factors. \u003cem\u003eClin. Obstet. Gynecol.\u003c/em\u003e \u003cb\u003e59\u003c/b\u003e, 651\u0026ndash;672 (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDoval, D. C., Dutta, K., Batra, U. \u0026amp; Talwar, V. Neoadjuvant chemotherapy in breast cancer: review of literature. \u003cem\u003eJ. Indian Med. Assoc.\u003c/em\u003e \u003cb\u003e111\u003c/b\u003e, 629\u0026ndash;631 (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMathew, J. \u003cem\u003eet al.\u003c/em\u003e Neoadjuvant chemotherapy for locally advanced breast cancer: A review of the literature and future directions. \u003cem\u003eEuropean Journal of Surgical Oncology.\u003c/em\u003e \u003cb\u003e35\u003c/b\u003e, 113\u0026ndash;122 (2009).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpring, L. M. \u003cem\u003eet al.\u003c/em\u003e Pathologic Complete Response after Neoadjuvant Chemotherapy and Impact on Breast Cancer Recurrence and Survival: A Comprehensive Meta-analysis. \u003cem\u003eClin. Cancer Res.\u003c/em\u003e \u003cb\u003e26\u003c/b\u003e, 2838\u0026ndash;2848 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eParekh, T., Dodwell, D., Sharma, N. \u0026amp; Shaaban, A. M. Radiological and Pathological Predictors of Response to Neoadjuvant Chemotherapy in Breast Cancer: A Brief Literature Review. \u003cem\u003ePathobiology.\u003c/em\u003e \u003cb\u003e82\u003c/b\u003e, 124\u0026ndash;132 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuthrie, G. J. K. \u003cem\u003eet al.\u003c/em\u003e The systemic inflammation-based neutrophil-lymphocyte ratio: Experience in patients with cancer. \u003cem\u003eCritical Reviews in Oncology/Hematology.\u003c/em\u003e \u003cb\u003e88\u003c/b\u003e, 218\u0026ndash;230 (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDupr\u0026eacute;, A. \u0026amp; Malik, H. Z. Inflammation and cancer: What a surgical oncologist should know. \u003cem\u003eEuropean Journal of Surgical Oncology.\u003c/em\u003e \u003cb\u003e44\u003c/b\u003e, 566\u0026ndash;570 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEthier, J. L., Desautels, D., Templeton, A., Shah, P. S. \u0026amp; Amir, E. Prognostic role of neutrophil-to-lymphocyte ratio in breast cancer: A systematic review and meta-analysis.\u003cem\u003eBreast Cancer Res.\u003c/em\u003e\u003cb\u003e19\u003c/b\u003e, (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGraziano, V. \u003cem\u003eet al.\u003c/em\u003e Combination of peripheral neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio is predictive of pathological complete response after neoadjuvant chemotherapy in breast cancer patients. \u003cem\u003eBreast.\u003c/em\u003e \u003cb\u003e44\u003c/b\u003e, 33\u0026ndash;38 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAzab, B. \u003cem\u003eet al.\u003c/em\u003e Usefulness of the neutrophil-to-lymphocyte ratio in predicting short- and long-term mortality in breast cancer patients. \u003cem\u003eAnn. Surg. Oncol.\u003c/em\u003e \u003cb\u003e19\u003c/b\u003e, 217\u0026ndash;224 (2012).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen, J. \u003cem\u003eet al.\u003c/em\u003e Prognostic value of neutrophil-to-lymphocyte ratio in breast cancer. \u003cem\u003eFEBS Open Bio.\u003c/em\u003e \u003cb\u003e5\u003c/b\u003e, 502\u0026ndash;507 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSuppan, C. \u003cem\u003eet al.\u003c/em\u003e Neutrophil/Lymphocyte ratio has no predictive or prognostic value in breast cancer patients undergoing preoperative systemic therapy.\u003cem\u003eBMC Cancer\u003c/em\u003e\u003cb\u003e15\u003c/b\u003e, (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEryilmaz, M. K. \u003cem\u003eet al.\u003c/em\u003e The neutrophil to lymphocyte ratio has a high negative predictive value for pathologic complete response in locally advanced breast cancer patients receiving neoadjuvant chemotherapy. \u003cem\u003eAsian Pacific J. Cancer Prev.\u003c/em\u003e \u003cb\u003e15\u003c/b\u003e, 7737\u0026ndash;7740 (2014).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiller, A. B., Hoogstraten, B., Staquet, M. \u0026amp; Winkler, A. Reporting results of cancer treatment. \u003cem\u003eCancer.\u003c/em\u003e \u003cb\u003e47\u003c/b\u003e, 207\u0026ndash;214 (1981).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Breast cancer, neoadjuvant chemotherapy, pathological complete response, neutrophil-to-lymphocyte ratio, disease-free survival","lastPublishedDoi":"10.21203/rs.3.rs-156091/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-156091/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eA low neutrophil-to-lymphocyte ratio (NLR) reflects a systemic milieu characterized by reduced inflammation and increase immune system activation \u0026ndash; potentially favoring a better response to therapy in solid malignancies. This retrospective study of collected data aimed to assess whether NLR may predict pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) in Turkish women with breast cancer. The study sample consisted of 406 patients with breast cancer who were scheduled to undergo NAC before attempting cytoreductive surgery. A pretreatment complete blood count was obtained in the week preceding NAC, and the NLR was calculated from absolute counts of neutrophils and lymphocytes. The Miller-Payne system was used to grade response to NAC. Secondary outcome measures included disease-free survival (DFS) and overall survival (OS). Patients were divided into two groups (high versus low) according to the optimal cutoff value (NLR\u0026thinsp;=\u0026thinsp;1.95; low NLR\u0026thinsp;\u0026le;\u0026thinsp;1.95, high NLR\u0026thinsp;\u0026gt;\u0026thinsp;1.95). The rate of pCR in the low NLR group (22.3%) was similar to that observed in the high NLR group (19.8%; P\u0026thinsp;=\u0026thinsp;0.20). Moreover, there were no significant differences in DFS and OS of patients in the high and low NLR groups. Based on our results, pretreatment NLR seems to have no significant predictive value in Turkish women with breast cancer who received NAC. However, prospective studies will surely provide deeper insights into the prognostic significance of NLR in this clinical setting.\u003c/p\u003e","manuscriptTitle":"No impact of neutrophil-to-lymphocyte ratio on pathological response to neoadjuvant chemotherapy in Turkish women with breast cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-02-25 21:15:25","doi":"10.21203/rs.3.rs-156091/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2021-05-04T03:44:17+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-04-14T03:01:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"161d0894-f155-45f9-b837-e8470104353e","date":"2021-04-13T10:47:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"c388a1f1-3d65-4407-a497-3338f019dbfc","date":"2021-04-08T19:27:40+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2021-04-08T15:58:18+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2021-04-08T15:57:10+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2021-02-24T17:44:40+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2021-02-24T17:33:35+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2021-01-26T17:38:34+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ca7657f1-8a26-4bf2-8c28-c8b8bb6955da","owner":[],"postedDate":"February 25th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":2635053,"name":"Oncology"},{"id":2635054,"name":"Cancer Biology"}],"tags":[],"updatedAt":"2021-08-22T15:19:00+00:00","versionOfRecord":{"articleIdentity":"rs-156091","link":"https://doi.org/10.1038/s41598-021-94184-7","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2021-07-19 15:04:47","publishedOnDateReadable":"July 19th, 2021"},"versionCreatedAt":"2021-02-25 21:15:25","video":"","vorDoi":"10.1038/s41598-021-94184-7","vorDoiUrl":"https://doi.org/10.1038/s41598-021-94184-7","workflowStages":[]},"version":"v1","identity":"rs-156091","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-156091","identity":"rs-156091","version":["v1"]},"buildId":"oE6Zbj460LM0Up2FdVbMZ","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}