{"paper_id":"4ba88e30-e710-43ad-b3aa-e956d9f553d4","body_text":"Correlation of NK cell activity and Clinical Parameters with Survival in Breast Cancer patients | 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 Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Correlation of NK cell activity and Clinical Parameters with Survival in Breast Cancer patients Ga-Young Lee, Jung-Hyo Cho, Chang-Gue Son, Chong-Kwan Cho, Nam-Hun Lee This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2800963/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Through analyzing a correlation between natural killer cell activity (NKA) and survival rate of patients with breast cancer, this study aims to assess the potential of NKA as a prognostic biomarker of breast cancer. We retrospectively analyzed the digital medical records of breast cancer patients treated at two traditional Korean medicine hospitals, located in Daejeon and Cheonan, South Korea, from April 1, 2016, to April 4, 2021. NKA levels were assessed by measuring interferon-γ released by stimulated- NK cells using commercial kit (NK Vue®; NKMAX, Seongnam, Korea). The patients were divided into two groups: A high NKA (≥ 500 pg/mL), and a low NKA (< 500 pg/mL) group, and compared in terms of tumor progression, physical status, overall survival (OS), and event-free survival (EFS). The high-NKA group exhibited significant longer OS (67.3 ± 1.5 vs 57.4 ± 3.7 months, p=0.002), longer EFS (62.9 ± 2.0 vs 49.2 ± 3.8 months, p=0.004) and better response rate (84.5% vs 69.8%, p=0.021). A relationship between NKA and prognosis in stage III and IV was more significant. Stage III and IV patients with high NKA had longer OS (38.9 ± 6.8 vs 56.7 ± 5.5 months, p = 0.039) and longer EFS (50.5 ± 6.2 months vs 31.4 ± 6.3 months, p = 0.053). NKA may serve as a prognostic biomarker for breast cancer patients. Further studies with more patients over a longer period are needed. Biological sciences/Cancer Biological sciences/Cancer/Breast cancer Biological sciences/Cancer/Cancer screening Figures Figure 1 Figure 2 Figure 3 Introduction Generally, the immune status is regarded as a hallmark of cancer development, recurrence and prognosis 1 . One of major components of innate immune system, natural killer (NK) cell is known to play a crucial role in primary cancer cells and metastasis by exerting natural cytotoxicity and activating the immune response by secreting cytokines such as interferon (IFN)-γ 2 . Since July 2016, an NKA test using a proprietary kit (NK Vue; ATGen Co., Seoul, South Korea) has been clinically adapted to gastric, prostate, pancreatic, and breast cancer patients, and partially covered by national health insurance. In 2020, 21,989 patients received NKA tests but no study was conducted analyzing NKA specifically in breast cancer ( http://opendata.hira.or.kr/ , accessed July 20, 2021). In Korea, breast cancer is the fifth most prevalent cancer (9.7%) and the most common cancer among females (20.5%) 3 . The number of patients newly diagnosed with it continues to rise, and, it is the third most common type across both sexes and the most common type in females among those treated at hospitals using traditional Korean medicine 4 . A number of NKA tests have been conducted in clinical settings at Korean medicine hospitals, but there are no studies analyzing their significance. Here, we retrospectively sought a relationship between the NKA level and breast cancer prognosis. Results Clinical Characteristics of the enrolled patients We analyzed a total of 179 patients in this study. In total, 23 patients died and 36 patients had documented progression. The patients’ clinical characteristics and NKA values are listed in Table 1. Most patients were in their 50s (mean age 54.1, range 37−76 years) and in an early stage of cancer, with 38.0% and 35.2% of patients in stages 0 and I, and stage II, respectively. Of the patients, 93.3% had ECOG 2 status, which is “ambulatory and capable of all self-care, but unable to carry out any work activities”. The median NKA values in patients with stages 0−I and stage II disease were higher than those of the stage III−IV group (1109.0 ± 96.4 vs. 1083.0 ± 95.7 vs. 833.2 ± 111.6 pg/mL, p = 0.13), but the differences were not significant. Patients who received preventative treatment tended to have a better NKA result than those who received combined treatment (1262.0 ± 101.4 vs. 942.3 ± 71.0 pg/mL, p = 0.048). The average NKA value of the ECOG 1 patient group was 1267.0 ± 274.8, which was higher than that of ECOG 3−4 patients (691.7 ± 357.9), but the difference was not significant. Correlation between NKA and Survival Patients were divided into two group, whose NKA level was over or below 500 pg/mL. 500pg/mL is a value which lies in the bottom 10% of NKA results from normal people according to the manufacturer’s instructions, and suggested as baseline of normal NKA in clinical practices. The clinical differences between the patients in the abnormal and normal NKA groups are listed in Table 2. The mean ages of the groups were similar (52.7 ± 8.5 vs. 54.9 ± 8.0 years, p = 0.321). The high NKA group had lower proportions of patients in a terminal stage ( p = 0.043), with metastasis ( p = 0.001), or with a history of receiving chemotherapy ( p = 0.039). The median OS values in patients with high and low NKA were 67.3 ± 1.5 and 57.4 ± 3.7 months, respectively ( p = 0.002, Figure 2A). The median EFS values were 62.9 ± 2.0 and 49.2 ± 3.8 months, respectively ( p = 0.004, Figure 2B). The proportions of patients responding were 84.5% and 69.8%, respectively, which is a significant difference ( p = 0.021, Table 2, Figure 2C). Correlation between NKA and Survival in stage III and IV Similarly, we observed a relationship between NKA and prognosis in terminal stages. Stage III and IV patients with high NKA had better OS than those with low NKA (38.9 ± 6.8 vs. 56.7 ± 5.5 months, p = 0.039, Figure 3A). Furthermore, the high NKA group had longer EFS (50.5 ± 6.2 months) than the low NKA group (31.4 ± 6.3 months, p = 0.053, Figure 3B). However, the RR was similar (87.2% vs. 90.2%, respectively) in patients below stage II (n = 131, p = 0.758). Prognostic factor for overall survival Table 3 shows the results of Cox regression for OS in all patients. Variables with p < 0.05 under simple analysis were included in a multiple analysis. NKA and stage have independent impacts on OS (p < 0.05). Under multiple analysis, terminal stage (stages III and IV) exhibited a hazard ratio (HR) of 23.774 (95% CI = 3.160−178.878, p = 0.002). high NKA levels exhibited low HR, but it lacked statistical significance. Discussion NK cell activity (NKA) has been reported as significantly lower in gastric 6 , prostate 7,8 , and colon 9 cancer patients than in healthy individuals. Regarding breast cancer, several studies in the 1980s reported that NKA is impaired when the stage of breast cancer is high and metastasis exists, regardless of hormone receptors 10,11 . In 2000, decreased function of NK cells in cancer patients compared to healthy people was reported in a prospective cohort study in which 3,625 people were followed for 11 years 12 . Furthermore, these findings made NKA a potential prognostic factor for predicting the effectiveness of antitumor treatment in several cancers 7,13–15 . This was the first retrospective study to examine the association of NKA and clinical outcome in breast cancer patients visiting Korean medicine hospitals. One finding is that patients who had high NKA tended to have longer OS and EFS than those who had low NKA. A higher RR to anticancer therapy was also found in patients with high NKA. We found better OS and EFS in terminal stages for patients with higher NKA, but the RR in early stages was not related to NKA. Similar results were obtained when we divided the patients into high and low groups based on the standard NKA level of 500 pg/mL. This study has a few limitations. The included cancer patients received NKA test at a random time point. Moreover, the follow-up period in this study was relatively short, given that the 5-year relative survival rate of Korean breast cancer patients was 93.2% in 2013−2017 3 . The prognostic value of NKA for longer survival requires further investigation. Nevertheless, increasing NKA may be crucial for improving the clinical outcomes for breast cancer patients, according to the results from the present study. Therefore, several suggestions for clinical applications are worth consideration. First, we recommend that KMAT be used because it improves NKA. This is supported by the fact that the patients in this study whose NKA increased had received KMAT the longest. Of course, it is impossible to analyze which KMAT treatment is related to the increase in NKA because patients received various treatments, including acupuncture, moxibustion, herbal medicine, and herbal acupuncture. However, we can infer from previous studies that KMAT would have helped, and that it can help to improve NKA. Acupuncture and electro-acupuncture stimulation induce β-endorphin release through the hypothalamic–pituitary–adrenal axis, enabling its binding to opioid receptors on NK cells, promoting their secretion of IFN-γ 16,17 . In particular, studies of acupuncture and moxibustion at the Zusanli acupoint (ST36) 17–20 support the inference that KMAT, according to the guidelines of two Korean medicine hospitals that recommend acupuncture at that acupoint, may enhance NKA. Several herbal medicines can also improve NKA. Panax ginseng , which enhances immunity and induces IFN-γ-mediated NK cell activation 21 , is frequently used in Korean medicine hospitals. Salvia miltiorrhiza and astragaloside III, a type of triterpenoid saponin from Astragalus membranaceus , are reported to increase NKA by increasing IFN-γ in vitro 22,23 . Myelophil, which is composed of extracts from S. miltiorrhiza and A. membranaceus , is frequently prescribed for chronic fatigue syndrome 24 , fatigue, and neutropenia after chemotherapy at both of the hospitals. We also recommend nutrition management, which enhances NK cell function, for breast cancer patients alongside therapy. Vitamins belonging to families A–E, polysaccharides, lectins, and a number of phytochemicals, including genistein, curcumin, garlic extract, ashwagandha extract, ingenol mebutate, kumquat pericarp extract, rostratins, lectins, and polysaccharides, have been reported as enhancing NKA 25 . Resveratrol 26 , white button mushroom powder 27 , vitamin E 28 , and selenium 29 have been reported to increase IFN-γ expression in in vivo and in vitro studies. Providing a diet enriched with nutrients will contribute to improving the clinical outcome of breast cancer patients. Emotional distress is reported to reduce NKA and dysregulate cytokines 30 , and fatigue or depression, and a lack of social support cause approximately 30% of NKA level variance 11 . Stress reduction therapy, such as mindfulness, has been used to restore the immune function of breast cancer patients 31 . Thus, regulating emotional stress should accompany other steps to improve NKA; this can be also be addressed by treatment with Korean medicine. It appears that the NKA level can be used to estimate the OS and EFS of breast cancer patients. This study can provide guidance for clinical settings, but further study is needed to strengthen the evidence. Methods Patients This study included breast cancer patients who were treated at two traditional Korean medicine hospitals, located in Daejeon and Cheonan, South Korea, from April 1, 2016, to April 4, 2021. The inclusion criteria were histologically confirmed breast cancer and at least one NKA test during the study period. The exclusion criteria were: patients with end-stage cancers whose life expectancy was less than three months, those who did not receive KMAT, and those with NKA results within two weeks of chemotherapy. The overall process of the study is summarized in Figure 1. Ethical Statement The study protocol was approved by the Institutional Review Board of Daejeon (DJDSKH‑20‑E‑31‑1) and Cheonan (DJUMC‑2020‑BM‑17) Korean Medicine Hospital, Daejeon University, Daejeon, South Korea. Since this is a retrospective study, the informed consent procedure was exempted according to the review regulations. Variables A retrospective review of registered patients was conducted based on digital medical records. We reviewed their records from the two hospitals, including pathologic features such as presence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2; tumor stage; metastasis; operations; chemotherapy; radiotherapy; and hormone therapy. We designated overall survival (OS), event-free survival (EFS), and response rate (RR) to anticancer therapy as indicators for evaluating clinical outcomes. OS was defined as the interval from the date when a patient had the first NKA test to their date of death. EFS was defined as the interval from the date of the first NKA test to the date of the first documented tumor progression or death. We analyzed OS, EFS, and RR for all patients, but because the survival rate is high in early disease stages, we used RR for patients below stage II, and OS and EFS for patients with stage III or IV disease. During the observation period, responding patients were defined as having a complete response, a partial response, or stable disease, and non-responding patients were defined as having progressive disease. NKA analysis Peripheral NKA was measured at the first or on a subsequent visit to the hospital. It was measured based on the stimulated level of IFN-γ in the plasma using a proprietary kit (NK Vue; ATGen Co., Seoul, South Korea) according to the manufacturer’s instructions 5 . Whole blood (1 mL) from a peripheral vein was collected in the kit tube containing a stimulatory cytokine, Promoca. Then, it was incubated at 37°C for 20−24 h, and the supernatants harvested. Plasma samples were completely thawed and centrifuged at 11,500 x g for 1 min at room temperature immediately before loading them into wells. NKA was measured through a sandwich enzyme immunoassay. Briefly, samples were incubated in anti-human IFN-γ-coated plates at room temperature for 2 h and washed with buffer (0.05% Tween 20 in phosphate-buffered saline, pH 7.4). IFN-γ conjugate was added to the wells, incubated for 1 h, and washed. Then, 100 μL of tetramethyl benzidine substrate solution was added and incubated at room temperature for 30 min in the dark. The absorbance was measured at 450 nm and the level of IFN-γ determined with a calibration curve. The measurement range was 0.1−2000 pg/mL. Statistical analysis Statistical analyses were performed using IBM SPSS statistics software (version 20; IBM Corp., Armonk, NY, USA). The Kruskal-Wallis test and an analysis of variance were used to compare continuous and independent variables. Differences between categorical variables were analyzed using chi-square and Fisher’s exact tests. Kaplan-Meier analysis and the log-rank test were used to evaluate the OS and EFS of each group. We report median values with 95% confidence intervals (CIs), and statistical significance was defined as p < 0.05. Declarations Acknowledgements This work was supported by grants from the National Research Foundation of Korea (NRF) (No.NRF-2020R1F1A1069711) Author contributions G-YL: wrote the main manuscript text, and conducted statistical analysis; J-HC: contributed to the data collection and manuscript preparation including revision process; C-GS, C-KC: supervised the manuscript; N-HL: supervised the manuscript, and directed final version of all contents. All authors reviewed and approved this manuscript. Data availability statement The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. References Hanahan, D. & Coussens, L. M. Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment. 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Effect on cytotoxic lymphocytes and natural killer cells. Biol. Trace Elem. Res. 41 , 115–127 (1994). Witek-Janusek, L., Gabram, S. & Mathews, H. L. Psychologic stress, reduced NK cell activity, and cytokine dysregulation in women experiencing diagnostic breast biopsy. Psychoneuroendocrinology 32 , 22 (2007). Witek Janusek, L., Tell, D. & Mathews, H. L. Mindfulness based stress reduction provides psychological benefit and restores immune function of women newly diagnosed with breast cancer: A randomized trial with active control. Brain. Behav. Immun. 80 , 358–373 (2019). Tables Table 1. Clinical Characteristics of the enrolled patients (n=179) Variables All patients Age 54.1 ± 8.2 NKA (pg/mL) 1025.0 ± 781.6 Numbers of NKA tests 2.1 ± 1.6 Stage 0, I II III,IV 68 (38.0%) 63 (35.2%) 48 (26.8%) Receptor ER positive (unknown 55) PR positive (unknown 56) HER2 positive (unknown 58) 82 (66.1%) 63 (51.2%) 34 (28.1%) Metastasis exist 78 (43.6%) Performance status ECOG 1 ECOG 2 ECOG 3,4 10 (5.6%) 167 (93.3%) 2 (0.6%) Conventional treatment Surgery Chemotherapy Radiotherapy Hormone therapy 168 (93.9%) 128 (71.5%) 105 (58.7%) 87 (48.6%) KMAT period (days) 73.0 ± 90.3 Response rate to therapy 142 (79.3%) Table 2. Clinical Characteristics according to NKA high and low group Variables Group p-value NKA < 500 (n= 63) NKA ≥ 500 (n=1 16 ) Age 52.7±8.5 54.9±8.0 0.321 NKA(pg/mL) 166.4±127.1 1491.3±560.1 0.000* Stage 0.043* 0,I 20 (31.7%) 48 (41.4%) II 19 (30.2%) 44 (37.9%) III,IV 24 (38.1%) 24 (20.7%) Receptor ER positive (unknown 55) 32 (50.8%) 50 (43.1%) 0.605 PR positive (unknown 56) 22 (34.9%) 41 (35.3%) 0.952 HER2 positive (unknown 58) 14 (22.2%) 20 (17.2%) 0.712 Metastasis exist 38 (60.3%) 40 (34.5%) 0.001* Performance status 0.475 ECOG 1 3 (4.8%) 7 (6.0%) ECOG 2 59 (93.7%) 108 (93.1%) ECOG 3,4 1 (1.6%) 1 (0.9%) Conventional treatment Surgery 59 (93.7%) 109 (94.0%) 0.933 Chemotherapy 51 (81.0%) 77 (66.4%) 0.039* Radiotherapy 36 (57.1%) 69 (59.5%) 0.710 Hormone therapy 26 (41.3%) 61 (52.6%) 0.148 KMAT period(days) 66.9±81.9 76.3±94.7 0.295 Response rate to therapy 44 (69.8%) 98 (84.5%) 0.021* Table 3 . Univariate and multivariate Cox regression analyses of OS using clinical parameters, n=1 79 Parameters Univariate analysis Multivariate analysis HR 95%CI p-value HR 95%CI p-value Age <54 1 ≥54 1.716 0.727-4.049 0.212 NKA <500 pg/mL 1 1 ≥500 pg/mL 0.286 0.123-0.662 0.004* 0.993 0.274-3.602 0.992 Stage 0,I 1 1 II 4.071 0.455-36.430 0.209 4.208 0.469-37.787 0.199 III,IV 29.636 3.955-222.100 0.001* 23.774 3.160-178.878 0.002* KMAT period <40 days 1 ≥40 days 0.557 0.241-1.289 0.172 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board 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-2800963\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Article\",\"associatedPublications\":[],\"authors\":[{\"id\":192983779,\"identity\":\"bdcf5b3f-2d76-4a90-8cb9-d33146b9a8e9\",\"order_by\":0,\"name\":\"Ga-Young Lee\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Daejeon University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Ga-Young\",\"middleName\":\"\",\"lastName\":\"Lee\",\"suffix\":\"\"},{\"id\":192983780,\"identity\":\"8674c08d-fb19-4de0-a97f-cb342ad1c1ea\",\"order_by\":1,\"name\":\"Jung-Hyo Cho\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Daejeon University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Jung-Hyo\",\"middleName\":\"\",\"lastName\":\"Cho\",\"suffix\":\"\"},{\"id\":192983781,\"identity\":\"95dcb469-b2a7-4f23-9b6d-6f44fa2e3581\",\"order_by\":2,\"name\":\"Chang-Gue Son\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Daejeon University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Chang-Gue\",\"middleName\":\"\",\"lastName\":\"Son\",\"suffix\":\"\"},{\"id\":192983782,\"identity\":\"d810f9ba-6dcf-49dc-b84a-a8f516a5cce7\",\"order_by\":3,\"name\":\"Chong-Kwan Cho\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Daejeon University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Chong-Kwan\",\"middleName\":\"\",\"lastName\":\"Cho\",\"suffix\":\"\"},{\"id\":192983783,\"identity\":\"423f93a1-054d-49a1-8418-dff5c2b1d57f\",\"order_by\":4,\"name\":\"Nam-Hun Lee\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAs0lEQVRIiWNgGAWjYDACCeYGBoYKZmYI7wBRWhiBWs6QrIWxDaqDKC3m0o2NDz7Os2Y3OMD88APDmXuEtVjOOdhsOHNbOrPBATZjCYYbxYS1GNxIbJPm3XYYqIXBjIHhQwJRWtp//50D0sL+jWgtbcyMDSAtPEBbbhCnpVmy51g6s+RhnmKJhDNEaUk++OFHjXUy3/H2jR8+HCNCCwwkM4CihgQNDAx2pCgeBaNgFIyCEQYA7jo7ItaO3pMAAAAASUVORK5CYII=\",\"orcid\":\"\",\"institution\":\"Daejeon University\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Nam-Hun\",\"middleName\":\"\",\"lastName\":\"Lee\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2023-04-11 08:29:25\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-2800963/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-2800963/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":36065803,\"identity\":\"8bdcab59-d80f-4e60-a091-722b6b16f872\",\"added_by\":\"auto\",\"created_at\":\"2023-04-20 13:45:44\",\"extension\":\"jpg\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":91716,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eThe flow chart of patients enrolled\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"1.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-2800963/v1/1fb1827266f4dc18aed21167.jpg\"},{\"id\":36065089,\"identity\":\"a3339716-b94d-4830-9204-8cfad6afd48a\",\"added_by\":\"auto\",\"created_at\":\"2023-04-20 13:37:44\",\"extension\":\"jpg\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":56878,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eClinical outcome according to NKA high and low group. (A) OS, (B) EFS and (C) RR according to NKA high and low patients.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"2.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-2800963/v1/2fb6c03b84f3e3aac40c070f.jpg\"},{\"id\":36065091,\"identity\":\"94e4d328-1ac5-4616-8bcc-a8451a24b84b\",\"added_by\":\"auto\",\"created_at\":\"2023-04-20 13:37:44\",\"extension\":\"jpg\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":38902,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eRelationship between normality of NKA and clinical outcomes in terminal stages. (A) OS and (B) EFS in stage III -IV.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"3.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-2800963/v1/2de258b18b695ba75d2dfb8e.jpg\"},{\"id\":60002932,\"identity\":\"c8e29e73-caa7-4d82-8ba9-8bfcc3205866\",\"added_by\":\"auto\",\"created_at\":\"2024-07-10 11:10:19\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":892052,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-2800963/v1/a90d2c1a-fab4-4ce2-a5d4-054d23547d42.pdf\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Correlation of NK cell activity and Clinical Parameters with Survival in Breast Cancer patients\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003eGenerally, the immune status is regarded as a hallmark of cancer development, recurrence and prognosis \\u003csup\\u003e\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e\\u003c/sup\\u003e. One of major components of innate immune system, natural killer (NK) cell is known to play a crucial role in primary cancer cells and metastasis by exerting natural cytotoxicity and activating the immune response by secreting cytokines such as interferon (IFN)-γ \\u003csup\\u003e\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e\\u003c/sup\\u003e. Since July 2016, an NKA test using a proprietary kit (NK Vue; ATGen Co., Seoul, South Korea) has been clinically adapted to gastric, prostate, pancreatic, and breast cancer patients, and partially covered by national health insurance. In 2020, 21,989 patients received NKA tests but no study was conducted analyzing NKA specifically in breast cancer (\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttp://opendata.hira.or.kr/\\u003c/span\\u003e\\u003cspan address=\\\"http://opendata.hira.or.kr/\\\" targettype=\\\"URL\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e, accessed July 20, 2021).\\u003c/p\\u003e \\u003cp\\u003eIn Korea, breast cancer is the fifth most prevalent cancer (9.7%) and the most common cancer among females (20.5%)\\u003csup\\u003e3\\u003c/sup\\u003e. The number of patients newly diagnosed with it continues to rise, and, it is the third most common type across both sexes and the most common type in females among those treated at hospitals using traditional Korean medicine \\u003csup\\u003e\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e\\u003c/sup\\u003e. A number of NKA tests have been conducted in clinical settings at Korean medicine hospitals, but there are no studies analyzing their significance.\\u003c/p\\u003e \\u003cp\\u003eHere, we retrospectively sought a relationship between the NKA level and breast cancer prognosis.\\u003c/p\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eClinical Characteristics of the enrolled patients\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eWe analyzed a total of 179 patients in this study. In total, 23\\u0026nbsp;patients died and\\u0026nbsp;36\\u0026nbsp;patients had documented progression.\\u0026nbsp;The patients\\u0026rsquo; clinical characteristics\\u0026nbsp;and NKA values are listed\\u0026nbsp;in Table\\u0026nbsp;1.\\u0026nbsp;Most patients were in their 50s\\u0026nbsp;(mean age 54.1, range 37\\u0026minus;76 years)\\u0026nbsp;and in an early stage of cancer, with 38.0% and 35.2% of patients in stages\\u0026nbsp;0 and I, and stage\\u0026nbsp;II, respectively. Of the patients, 93.3% had ECOG\\u0026nbsp;2 status, which is \\u0026ldquo;ambulatory and capable of all self-care, but unable to carry out any work activities\\u0026rdquo;.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eThe median NKA values in patients with stages 0\\u0026minus;I and stage II disease were higher than those of the stage III\\u0026minus;IV group (1109.0\\u0026nbsp;\\u0026plusmn; 96.4\\u0026nbsp;vs. 1083.0\\u0026nbsp;\\u0026plusmn;\\u0026nbsp;95.7\\u0026nbsp;vs. 833.2\\u0026nbsp;\\u0026plusmn;\\u0026nbsp;111.6\\u0026nbsp;pg/mL, \\u003cem\\u003ep\\u0026nbsp;\\u003c/em\\u003e= 0.13), but the differences were not significant. Patients who received preventative treatment tended to have a better NKA result than those who received combined treatment (1262.0\\u0026nbsp;\\u0026plusmn;\\u0026nbsp;101.4\\u0026nbsp;vs. 942.3\\u0026nbsp;\\u0026plusmn;\\u0026nbsp;71.0\\u0026nbsp;pg/mL, \\u003cem\\u003ep\\u003c/em\\u003e = 0.048). The average NKA value of the ECOG 1 patient group was 1267.0\\u0026nbsp;\\u0026plusmn;\\u0026nbsp;274.8, which was higher than that of ECOG 3\\u0026minus;4 patients (691.7\\u0026nbsp;\\u0026plusmn;\\u0026nbsp;357.9), but the difference was not significant.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eCorrelation between NKA and\\u0026nbsp;\\u003c/em\\u003e\\u003c/strong\\u003e\\u003cstrong\\u003e\\u003cem\\u003eSurvival\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003ePatients were divided into two group, whose NKA level was over or below 500 pg/mL. 500pg/mL is\\u0026nbsp;a value which lies in the bottom 10% of NKA results from normal people according to\\u0026nbsp;the manufacturer\\u0026rsquo;s instructions, and suggested as baseline of normal NKA in clinical practices.\\u0026nbsp;The clinical differences between the patients in the abnormal and normal NKA groups are listed in Table\\u0026nbsp;2. The mean ages\\u0026nbsp;of the groups were similar (52.7\\u0026nbsp;\\u0026plusmn;\\u0026nbsp;8.5\\u0026nbsp;vs.\\u0026nbsp;54.9\\u0026nbsp;\\u0026plusmn;\\u0026nbsp;8.0\\u0026nbsp;years,\\u0026nbsp;\\u003cem\\u003ep\\u0026nbsp;\\u003c/em\\u003e=\\u0026nbsp;0.321).\\u0026nbsp;The high NKA group had\\u0026nbsp;lower proportions of patients in a terminal stage\\u0026nbsp;(\\u003cem\\u003ep\\u0026nbsp;\\u003c/em\\u003e=\\u0026nbsp;0.043), with\\u0026nbsp;metastasis (\\u003cem\\u003ep\\u0026nbsp;\\u003c/em\\u003e=\\u0026nbsp;0.001), or with a\\u0026nbsp;history of receiving\\u0026nbsp;chemotherapy (\\u003cem\\u003ep\\u0026nbsp;\\u003c/em\\u003e=\\u0026nbsp;0.039).\\u003c/p\\u003e\\n\\u003cp\\u003eThe median OS values in patients with high and low NKA were 67.3\\u0026nbsp;\\u0026plusmn;\\u0026nbsp;1.5\\u0026nbsp;and\\u0026nbsp;57.4\\u0026nbsp;\\u0026plusmn;\\u0026nbsp;3.7\\u0026nbsp;months,\\u0026nbsp;respectively (\\u003cem\\u003ep\\u0026nbsp;\\u003c/em\\u003e=\\u0026nbsp;0.002,\\u0026nbsp;Figure 2A). The median EFS values were 62.9\\u0026nbsp;\\u0026plusmn;\\u0026nbsp;2.0\\u0026nbsp;and\\u0026nbsp;49.2\\u0026nbsp;\\u0026plusmn;\\u0026nbsp;3.8\\u0026nbsp;months, respectively\\u0026nbsp;(\\u003cem\\u003ep\\u0026nbsp;\\u003c/em\\u003e=\\u0026nbsp;0.004, Figure\\u0026nbsp;2B). The proportions of patients responding were\\u0026nbsp;84.5% and 69.8%, respectively,\\u0026nbsp;which is a significant difference\\u0026nbsp;(\\u003cem\\u003ep\\u0026nbsp;\\u003c/em\\u003e=\\u0026nbsp;0.021,\\u0026nbsp;Table\\u0026nbsp;2, Figure\\u0026nbsp;2C).\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eCorrelation between NKA and\\u0026nbsp;\\u003c/em\\u003e\\u003c/strong\\u003e\\u003cstrong\\u003e\\u003cem\\u003eSurvival in stage\\u003c/em\\u003e\\u003c/strong\\u003e\\u003cstrong\\u003e\\u003cem\\u003e\\u0026nbsp;III and IV\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eSimilarly, we observed a relationship between NKA and prognosis in terminal stages. Stage III and IV patients with high NKA had better\\u0026nbsp;OS\\u0026nbsp;than those with low NKA (38.9\\u0026nbsp;\\u0026plusmn;\\u0026nbsp;6.8 vs. 56.7\\u0026nbsp;\\u0026plusmn;\\u0026nbsp;5.5 months, \\u003cem\\u003ep\\u003c/em\\u003e = 0.039, Figure\\u0026nbsp;3A). Furthermore, the high NKA group had longer EFS (50.5\\u0026nbsp;\\u0026plusmn;\\u0026nbsp;6.2 months) than the low NKA group (31.4\\u0026nbsp;\\u0026plusmn;\\u0026nbsp;6.3 months, \\u003cem\\u003ep\\u003c/em\\u003e = 0.053, Figure\\u0026nbsp;3B). However, the RR\\u0026nbsp;was similar\\u0026nbsp;(87.2% vs. 90.2%, respectively) in patients below stage II (n = 131, p = 0.758).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003ePrognostic factor for overall survival\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eTable 3 shows the results of Cox regression for OS in all patients. Variables with p \\u0026lt; 0.05 under simple analysis were included in a multiple analysis. NKA and stage have independent impacts on OS (p \\u0026lt; 0.05). Under multiple analysis, terminal stage (stages III and IV) exhibited a hazard ratio (HR) of 23.774 (95% CI = 3.160\\u0026minus;178.878, p = 0.002). high NKA levels exhibited low HR, but it lacked statistical significance.\\u003c/p\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eNK cell activity (NKA) has been reported as significantly lower in gastric\\u003csup\\u003e6\\u003c/sup\\u003e, prostate\\u003csup\\u003e7,8\\u003c/sup\\u003e, and colon\\u003csup\\u003e9\\u003c/sup\\u003e cancer patients than in healthy individuals.\\u0026nbsp;Regarding breast cancer, several studies in the 1980s reported that NKA is impaired when the stage of breast cancer is high and metastasis exists, regardless of hormone receptors\\u003csup\\u003e10,11\\u003c/sup\\u003e.\\u0026nbsp;In 2000, decreased function of NK cells in cancer patients compared to healthy people was reported in a prospective cohort study in which 3,625 people were followed for 11\\u0026nbsp;years\\u003csup\\u003e12\\u003c/sup\\u003e.\\u0026nbsp;Furthermore, these findings made NKA a potential prognostic factor for predicting the effectiveness of antitumor treatment in several cancers\\u003csup\\u003e7,13\\u0026ndash;15\\u003c/sup\\u003e.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eThis was the first retrospective study to examine the association\\u0026nbsp;of\\u0026nbsp;NKA\\u0026nbsp;and clinical outcome\\u0026nbsp;in breast cancer patients\\u0026nbsp;visiting Korean medicine hospitals.\\u0026nbsp;One finding is that patients who had high NKA tended to have longer OS and EFS than those who had low NKA. A higher RR to anticancer therapy was also found in patients with high NKA. We found better OS and EFS in terminal stages for patients with higher NKA, but the RR in early stages was not related to NKA. Similar results were obtained when we divided the patients into high and low groups based on the standard NKA level of 500 pg/mL.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eThis study has a few limitations. The included cancer patients received NKA test at a random time point. Moreover, the follow-up period in this study was relatively short, given that the 5-year relative survival rate of Korean breast cancer patients was 93.2% in 2013\\u0026minus;2017\\u003csup\\u003e3\\u003c/sup\\u003e. The prognostic value of NKA for longer survival requires further investigation.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eNevertheless, increasing NKA may be crucial for improving the clinical outcomes for breast cancer patients, according to the results from the present study. Therefore, several suggestions for clinical applications are worth consideration. First, we recommend that KMAT be used because it improves NKA. This is supported by the fact that the patients in this study whose NKA increased had received KMAT the longest. Of course, it is impossible to analyze which KMAT treatment is related to the increase in NKA because patients received various treatments, including acupuncture, moxibustion, herbal medicine, and herbal acupuncture. However, we can infer from previous studies that KMAT would have helped, and that it can help to improve NKA. Acupuncture and electro-acupuncture stimulation induce \\u0026beta;-endorphin release through the hypothalamic\\u0026ndash;pituitary\\u0026ndash;adrenal axis, enabling its binding to opioid receptors on NK cells, promoting their secretion of IFN-\\u0026gamma;\\u003csup\\u003e16,17\\u003c/sup\\u003e. In particular, studies of acupuncture and moxibustion at the Zusanli acupoint (ST36)\\u003csup\\u003e17\\u0026ndash;20\\u003c/sup\\u003e support the inference that KMAT, according to the guidelines of two Korean medicine hospitals that recommend acupuncture at that acupoint, may enhance NKA.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eSeveral herbal medicines can also improve NKA. \\u003cem\\u003ePanax ginseng\\u003c/em\\u003e, which enhances immunity and induces IFN-\\u0026gamma;-mediated NK cell activation\\u003csup\\u003e21\\u003c/sup\\u003e, is frequently used in Korean medicine hospitals.\\u0026nbsp;\\u003cem\\u003eSalvia miltiorrhiza\\u0026nbsp;\\u003c/em\\u003eand\\u003cem\\u003e\\u0026nbsp;\\u003c/em\\u003eastragaloside III, a type of triterpenoid saponin from \\u003cem\\u003eAstragalus membranaceus\\u003c/em\\u003e,\\u003cem\\u003e\\u0026nbsp;\\u003c/em\\u003eare reported to increase NKA by increasing IFN-\\u0026gamma; \\u003cem\\u003ein vitro\\u003c/em\\u003e\\u003csup\\u003e22,23\\u003c/sup\\u003e.\\u0026nbsp;Myelophil,\\u0026nbsp;which is composed of extracts from \\u003cem\\u003eS.\\u0026nbsp;miltiorrhiza\\u003c/em\\u003e and \\u003cem\\u003eA.\\u0026nbsp;membranaceus\\u003c/em\\u003e, is frequently prescribed for chronic fatigue syndrome\\u003csup\\u003e24\\u003c/sup\\u003e, fatigue, and neutropenia after chemotherapy\\u0026nbsp;at both of the hospitals.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eWe also recommend nutrition management, which enhances NK cell function, for breast cancer patients alongside therapy. Vitamins belonging to families A\\u0026ndash;E, polysaccharides, lectins, and a number of phytochemicals, including genistein, curcumin, garlic extract, ashwagandha extract, ingenol mebutate, kumquat pericarp extract, rostratins, lectins, and polysaccharides, have been reported as enhancing NKA\\u003csup\\u003e25\\u003c/sup\\u003e. Resveratrol\\u003csup\\u003e26\\u003c/sup\\u003e, white button mushroom powder\\u003csup\\u003e27\\u003c/sup\\u003e, vitamin E\\u003csup\\u003e28\\u003c/sup\\u003e, and selenium\\u0026nbsp;\\u003csup\\u003e29\\u003c/sup\\u003e have been reported to increase\\u0026nbsp;IFN-\\u0026gamma; expression in \\u003cem\\u003ein vivo\\u003c/em\\u003e and \\u003cem\\u003ein vitro\\u003c/em\\u003e studies.\\u003cem\\u003e\\u0026nbsp;\\u003c/em\\u003eProviding a diet enriched with nutrients will contribute to improving the clinical outcome of breast cancer patients.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eEmotional distress is reported to reduce NKA and dysregulate cytokines\\u003csup\\u003e30\\u003c/sup\\u003e,\\u0026nbsp;and fatigue or depression, and a lack of social support cause approximately 30% of NKA level variance\\u003csup\\u003e11\\u003c/sup\\u003e. Stress reduction therapy, such as mindfulness, has been used to restore the immune function of breast cancer patients\\u003csup\\u003e31\\u003c/sup\\u003e. Thus, regulating emotional stress should accompany other steps to improve NKA; this can be also be addressed by treatment with Korean medicine.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eIt appears that the NKA level can be used to estimate the OS and EFS of breast cancer patients. \\u0026nbsp;This study can provide guidance for clinical settings, but further study is needed to strengthen the evidence.\\u0026nbsp;\\u003c/p\\u003e\"},{\"header\":\"Methods\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003ePatients\\u0026nbsp;\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis study included breast cancer patients who were treated at two traditional Korean medicine hospitals, located in Daejeon\\u0026nbsp;and Cheonan, South Korea, from April 1, 2016, to April 4, 2021.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eThe inclusion criteria were histologically confirmed breast cancer and at least one NKA test during the study period.\\u0026nbsp;The exclusion criteria were: patients with end-stage cancers whose\\u0026nbsp;life expectancy was less than three months, those who did not receive KMAT, and\\u0026nbsp;those with NKA results within two weeks of chemotherapy. The overall process of the study is summarized in\\u0026nbsp;Figure 1.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eEthical Statement\\u0026nbsp;\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe study protocol was approved by the Institutional Review Board of Daejeon\\u0026nbsp;(DJDSKH‑20‑E‑31‑1) and Cheonan (DJUMC‑2020‑BM‑17) Korean Medicine Hospital, Daejeon University, Daejeon, South Korea.\\u0026nbsp;Since this is a retrospective study, the informed consent procedure was exempted according to the review regulations.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eVariables\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eA retrospective review of registered patients was conducted based on digital medical records. We reviewed their records from the two hospitals, including pathologic features such as presence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2; tumor stage; metastasis; operations; chemotherapy; radiotherapy; and hormone therapy.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eWe designated overall survival (OS),\\u0026nbsp;event-free survival (EFS), and response rate (RR) to anticancer therapy as indicators for evaluating clinical outcomes.\\u0026nbsp;OS was defined as the interval from the date when a patient had the first NKA test to their date of death. EFS was defined as the interval from the date of the first NKA test to the date\\u0026nbsp;of the first documented tumor progression or death. We analyzed OS, EFS, and RR for all patients, but because the survival rate is high in early disease stages, we used RR for patients below stage II, and OS and EFS for patients with stage III or IV disease. During the observation period, responding patients were defined as having a complete response, a partial response, or stable disease, and non-responding patients were defined as having progressive disease.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eNKA analysis\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003ePeripheral NKA was measured at the first or on a subsequent visit to the hospital. It was measured based on the stimulated level of IFN-\\u0026gamma;\\u0026nbsp;in the plasma using a proprietary kit (NK Vue; ATGen Co., Seoul, South Korea) according to the manufacturer\\u0026rsquo;s instructions\\u003csup\\u003e5\\u003c/sup\\u003e.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eWhole blood (1 mL) from a peripheral vein was collected in the kit tube containing a stimulatory cytokine,\\u0026nbsp;Promoca. Then, it was incubated at 37\\u0026deg;C for 20\\u0026minus;24 h, and the supernatants harvested.\\u0026nbsp;Plasma samples were completely thawed and centrifuged at 11,500 x \\u003cem\\u003eg\\u003c/em\\u003e for 1 min at room temperature immediately before loading them into wells.\\u0026nbsp;NKA was measured through a sandwich enzyme immunoassay. Briefly, samples were incubated in anti-human\\u0026nbsp;IFN-\\u0026gamma;-coated plates at room temperature for 2\\u0026nbsp;h and washed with buffer (0.05% Tween 20 in phosphate-buffered saline, pH\\u0026nbsp;7.4). IFN-\\u0026gamma; conjugate was added to the wells, incubated for 1\\u0026nbsp;h, and washed. Then, 100\\u0026nbsp;\\u0026mu;L of tetramethyl benzidine substrate solution was added and incubated at room temperature for 30\\u0026nbsp;min in the dark. The absorbance was measured at 450\\u0026nbsp;nm and the level of IFN-\\u0026gamma; determined with a calibration curve. The measurement range was 0.1\\u0026minus;2000\\u0026nbsp;pg/mL.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eStatistical analysis\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eStatistical analyses were performed using IBM SPSS statistics software (version\\u0026nbsp;20; IBM Corp., Armonk, NY, USA). The Kruskal-Wallis test and an analysis of variance were used to compare continuous and independent variables. Differences between categorical variables were analyzed using chi-square and Fisher\\u0026rsquo;s exact tests. Kaplan-Meier analysis and the log-rank test were used to evaluate the OS and\\u0026nbsp;EFS of each group. We report median values with 95% confidence intervals (CIs), and statistical significance was defined as \\u003cem\\u003ep\\u003c/em\\u003e \\u0026lt; 0.05.\\u0026nbsp;\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgements\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis work was supported by grants from the National Research Foundation of Korea (NRF) (No.NRF-2020R1F1A1069711) \\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthor contributions\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eG-YL: wrote the main manuscript text, and conducted statistical analysis; J-HC: contributed to the data collection and manuscript preparation including revision process; C-GS, C-KC: supervised the manuscript; N-HL: supervised the manuscript, and directed final version of all contents. All authors reviewed and approved this manuscript.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eData availability statement\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConflict of interest\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n\\u003cli\\u003eHanahan, D. \\u0026amp; Coussens, L. M. 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V. \\u003cem\\u003eet al.\\u003c/em\\u003e A short-term dietary supplementation with high doses of vitamin E increases NK cell cytolytic activity in advanced colorectal cancer patients. \\u003cem\\u003eCancer Immunol. Immunother.\\u003c/em\\u003e \\u003cstrong\\u003e56\\u003c/strong\\u003e, 973\\u0026ndash;984 (2007).\\u003c/li\\u003e\\n\\u003cli\\u003eKiremidjian-Schumacher, L., Roy, M., Wishe, H. I., Cohen, M. W. \\u0026amp; Stotzky, G. Supplementation with selenium and human immune cell functions. II. Effect on cytotoxic lymphocytes and natural killer cells. \\u003cem\\u003eBiol. Trace Elem. Res.\\u003c/em\\u003e \\u003cstrong\\u003e41\\u003c/strong\\u003e, 115\\u0026ndash;127 (1994).\\u003c/li\\u003e\\n\\u003cli\\u003eWitek-Janusek, L., Gabram, S. \\u0026amp; Mathews, H. L. Psychologic stress, reduced NK cell activity, and cytokine dysregulation in women experiencing diagnostic breast biopsy. \\u003cem\\u003ePsychoneuroendocrinology\\u003c/em\\u003e \\u003cstrong\\u003e32\\u003c/strong\\u003e, 22 (2007).\\u003c/li\\u003e\\n\\u003cli\\u003eWitek Janusek, L., Tell, D. \\u0026amp; Mathews, H. L. Mindfulness based stress reduction provides psychological benefit and restores immune function of women newly diagnosed with breast cancer: A randomized trial with active control. \\u003cem\\u003eBrain. Behav. Immun.\\u003c/em\\u003e \\u003cstrong\\u003e80\\u003c/strong\\u003e, 358\\u0026ndash;373 (2019).\\u003c/li\\u003e\\n\\u003c/ol\\u003e\"},{\"header\":\"Tables\",\"content\":\"\\u003ctable border=\\\"1\\\" cellpadding=\\\"0\\\" cellspacing=\\\"0\\\" width=\\\"552\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 94.7368%;\\\" valign=\\\"top\\\" width=\\\"100%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eTable 1. Clinical Characteristics of the enrolled patients (n=179)\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 40.6275%;\\\" width=\\\"40.50632911392405%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eVariables\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 54.1093%;\\\" width=\\\"59.49367088607595%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eAll patients\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 40.6275%;\\\" valign=\\\"top\\\" width=\\\"40.50632911392405%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eAge\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 54.1093%;\\\" valign=\\\"top\\\" width=\\\"59.49367088607595%\\\"\\u003e\\n \\u003cp\\u003e54.1\\u0026nbsp;\\u0026plusmn;\\u0026nbsp;8.2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 40.6275%;\\\" valign=\\\"top\\\" width=\\\"40.50632911392405%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eNKA (pg/mL)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 54.1093%;\\\" valign=\\\"top\\\" width=\\\"59.49367088607595%\\\"\\u003e\\n \\u003cp\\u003e1025.0\\u0026nbsp;\\u0026plusmn;\\u0026nbsp;781.6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 40.6275%;\\\" valign=\\\"top\\\" width=\\\"40.50632911392405%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eNumbers of NKA tests\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 54.1093%;\\\" valign=\\\"top\\\" width=\\\"59.49367088607595%\\\"\\u003e\\n \\u003cp\\u003e2.1\\u0026nbsp;\\u0026plusmn;\\u0026nbsp;1.6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 40.6275%;\\\" valign=\\\"top\\\" width=\\\"40.50632911392405%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eStage\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 54.1093%;\\\" valign=\\\"top\\\" width=\\\"59.49367088607595%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 40.6275%;\\\" valign=\\\"top\\\" width=\\\"40.50632911392405%\\\"\\u003e\\n \\u003cp\\u003e0, I\\u003c/p\\u003e\\n \\u003cp\\u003eII\\u003c/p\\u003e\\n \\u003cp\\u003eIII,IV\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 54.1093%;\\\" valign=\\\"top\\\" width=\\\"59.49367088607595%\\\"\\u003e\\n \\u003cp\\u003e68\\u0026nbsp;(38.0%)\\u003c/p\\u003e\\n \\u003cp\\u003e63\\u0026nbsp;(35.2%)\\u003c/p\\u003e\\n \\u003cp\\u003e48\\u0026nbsp;(26.8%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 40.6275%;\\\" valign=\\\"top\\\" width=\\\"40.50632911392405%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eReceptor\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 54.1093%;\\\" valign=\\\"top\\\" width=\\\"59.49367088607595%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 40.6275%;\\\" valign=\\\"top\\\" width=\\\"40.50632911392405%\\\"\\u003e\\n \\u003cp\\u003eER\\u0026nbsp;positive\\u0026nbsp;(unknown 55)\\u003c/p\\u003e\\n \\u003cp\\u003ePR\\u0026nbsp;positive\\u0026nbsp;(unknown 56)\\u003c/p\\u003e\\n \\u003cp\\u003eHER2\\u0026nbsp;positive\\u0026nbsp;(unknown 58)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 54.1093%;\\\" valign=\\\"top\\\" width=\\\"59.49367088607595%\\\"\\u003e\\n \\u003cp\\u003e82\\u0026nbsp;(66.1%)\\u003c/p\\u003e\\n \\u003cp\\u003e63\\u0026nbsp;(51.2%)\\u003c/p\\u003e\\n \\u003cp\\u003e34\\u0026nbsp;(28.1%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 40.6275%;\\\" valign=\\\"top\\\" width=\\\"40.50632911392405%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eMetastasis exist\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 54.1093%;\\\" valign=\\\"top\\\" width=\\\"59.49367088607595%\\\"\\u003e\\n \\u003cp\\u003e78 (43.6%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 40.6275%;\\\" valign=\\\"top\\\" width=\\\"40.50632911392405%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003ePerformance status\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 54.1093%;\\\" valign=\\\"top\\\" width=\\\"59.49367088607595%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 40.6275%;\\\" valign=\\\"top\\\" width=\\\"40.50632911392405%\\\"\\u003e\\n \\u003cp\\u003eECOG 1\\u003c/p\\u003e\\n \\u003cp\\u003eECOG\\u0026nbsp;2\\u003c/p\\u003e\\n \\u003cp\\u003eECOG\\u0026nbsp;3,4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 54.1093%;\\\" valign=\\\"top\\\" width=\\\"59.49367088607595%\\\"\\u003e\\n \\u003cp\\u003e10\\u0026nbsp;(5.6%)\\u003c/p\\u003e\\n \\u003cp\\u003e167\\u0026nbsp;(93.3%)\\u003c/p\\u003e\\n \\u003cp\\u003e2\\u0026nbsp;(0.6%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 40.6275%;\\\" valign=\\\"top\\\" width=\\\"40.50632911392405%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eConventional treatment\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 54.1093%;\\\" valign=\\\"top\\\" width=\\\"59.49367088607595%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 40.6275%;\\\" valign=\\\"top\\\" width=\\\"40.50632911392405%\\\"\\u003e\\n \\u003cp\\u003eSurgery\\u003c/p\\u003e\\n \\u003cp\\u003eChemotherapy\\u003c/p\\u003e\\n \\u003cp\\u003eRadiotherapy\\u003c/p\\u003e\\n \\u003cp\\u003eHormone therapy\\u003cstrong\\u003e\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 54.1093%;\\\" valign=\\\"top\\\" width=\\\"59.49367088607595%\\\"\\u003e\\n \\u003cp\\u003e168\\u0026nbsp;(93.9%)\\u003c/p\\u003e\\n \\u003cp\\u003e128\\u0026nbsp;(71.5%)\\u003c/p\\u003e\\n \\u003cp\\u003e105\\u0026nbsp;(58.7%)\\u003c/p\\u003e\\n \\u003cp\\u003e87\\u0026nbsp;(48.6%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 40.6275%;\\\" valign=\\\"top\\\" width=\\\"40.50632911392405%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eKMAT period\\u003c/strong\\u003e\\u003cstrong\\u003e\\u0026nbsp;\\u003c/strong\\u003e\\u003cstrong\\u003e(days)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 54.1093%;\\\" valign=\\\"top\\\" width=\\\"59.49367088607595%\\\"\\u003e\\n \\u003cp\\u003e73.0\\u0026nbsp;\\u0026plusmn; 90.3\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 40.6275%;\\\" valign=\\\"top\\\" width=\\\"40.50632911392405%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eResponse rate to therapy\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 54.1093%;\\\" valign=\\\"top\\\" width=\\\"59.49367088607595%\\\"\\u003e\\n \\u003cp\\u003e142\\u0026nbsp;(79.3%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n\\u003ctable border=\\\"1\\\" cellpadding=\\\"0\\\" cellspacing=\\\"0\\\" width=\\\"564\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"4\\\" style=\\\"width: 75.4805%;\\\" valign=\\\"top\\\" width=\\\"100%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eTable 2. Clinical Characteristics according to NKA high and low group\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd rowspan=\\\"2\\\" style=\\\"width: 25.7242%;\\\" valign=\\\"top\\\" width=\\\"35.701598579040855%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eVariables\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 47.161%;\\\" valign=\\\"top\\\" width=\\\"47.42451154529307%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eGroup\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"2\\\" style=\\\"width: 6.574%;\\\" valign=\\\"top\\\" width=\\\"16.518650088809945%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003ep-value\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 34.2989%;\\\" valign=\\\"top\\\" width=\\\"51.301115241635685%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eNKA\\u003c/strong\\u003e\\u003cstrong\\u003e\\u0026nbsp;\\u003c/strong\\u003e\\u003cstrong\\u003e\\u0026lt;\\u003c/strong\\u003e\\u003cstrong\\u003e\\u0026nbsp;\\u003c/strong\\u003e\\u003cstrong\\u003e500\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e(n=\\u003c/strong\\u003e\\u003cstrong\\u003e63)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 13.005%;\\\" valign=\\\"top\\\" width=\\\"47.95539033457249%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eNKA\\u003c/strong\\u003e\\u003cstrong\\u003e\\u0026nbsp;\\u003c/strong\\u003e\\u003cstrong\\u003e\\u0026ge;\\u0026nbsp;\\u003c/strong\\u003e\\u003cstrong\\u003e500\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e(n=1\\u003c/strong\\u003e\\u003cstrong\\u003e16\\u003c/strong\\u003e\\u003cstrong\\u003e)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 25.7242%;\\\" valign=\\\"top\\\" width=\\\"35.701598579040855%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eAge\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34.2989%;\\\" valign=\\\"top\\\" width=\\\"24.511545293072825%\\\"\\u003e\\n \\u003cp\\u003e52.7\\u0026plusmn;8.5\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 13.005%;\\\" valign=\\\"top\\\" width=\\\"22.912966252220247%\\\"\\u003e\\n \\u003cp\\u003e54.9\\u0026plusmn;8.0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 6.574%;\\\" valign=\\\"top\\\" width=\\\"16.518650088809945%\\\"\\u003e\\n \\u003cp\\u003e0.321\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 25.7242%;\\\" valign=\\\"top\\\" width=\\\"35.701598579040855%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eNKA(pg/mL)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34.2989%;\\\" valign=\\\"top\\\" width=\\\"24.511545293072825%\\\"\\u003e\\n \\u003cp\\u003e166.4\\u0026plusmn;127.1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 13.005%;\\\" valign=\\\"top\\\" width=\\\"22.912966252220247%\\\"\\u003e\\n \\u003cp\\u003e1491.3\\u0026plusmn;560.1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 6.574%;\\\" valign=\\\"top\\\" width=\\\"16.518650088809945%\\\"\\u003e\\n \\u003cp\\u003e0.000*\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 25.7242%;\\\" valign=\\\"top\\\" width=\\\"35.701598579040855%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eStage\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34.2989%;\\\" valign=\\\"top\\\" width=\\\"24.511545293072825%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 13.005%;\\\" valign=\\\"top\\\" width=\\\"22.912966252220247%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 6.574%;\\\" valign=\\\"top\\\" width=\\\"16.518650088809945%\\\"\\u003e\\n \\u003cp\\u003e0.043*\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 25.7242%;\\\" valign=\\\"top\\\" width=\\\"35.701598579040855%\\\"\\u003e\\n \\u003cp\\u003e0,I\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34.2989%;\\\" valign=\\\"top\\\" width=\\\"24.511545293072825%\\\"\\u003e\\n \\u003cp\\u003e20 (31.7%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 13.005%;\\\" valign=\\\"top\\\" width=\\\"22.912966252220247%\\\"\\u003e\\n \\u003cp\\u003e48 (41.4%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 6.574%;\\\" valign=\\\"top\\\" width=\\\"16.518650088809945%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 25.7242%;\\\" valign=\\\"top\\\" width=\\\"35.701598579040855%\\\"\\u003e\\n \\u003cp\\u003eII\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34.2989%;\\\" valign=\\\"top\\\" width=\\\"24.511545293072825%\\\"\\u003e\\n \\u003cp\\u003e19 (30.2%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 13.005%;\\\" valign=\\\"top\\\" width=\\\"22.912966252220247%\\\"\\u003e\\n \\u003cp\\u003e44 (37.9%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 6.574%;\\\" valign=\\\"top\\\" width=\\\"16.518650088809945%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 25.7242%;\\\" valign=\\\"top\\\" width=\\\"35.701598579040855%\\\"\\u003e\\n \\u003cp\\u003eIII,IV\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34.2989%;\\\" valign=\\\"top\\\" width=\\\"24.511545293072825%\\\"\\u003e\\n \\u003cp\\u003e24 (38.1%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 13.005%;\\\" valign=\\\"top\\\" width=\\\"22.912966252220247%\\\"\\u003e\\n \\u003cp\\u003e24 (20.7%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 6.574%;\\\" valign=\\\"top\\\" width=\\\"16.518650088809945%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 25.7242%;\\\" valign=\\\"top\\\" width=\\\"35.701598579040855%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eReceptor\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34.2989%;\\\" valign=\\\"top\\\" width=\\\"24.511545293072825%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 13.005%;\\\" valign=\\\"top\\\" width=\\\"22.912966252220247%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 6.574%;\\\" valign=\\\"top\\\" width=\\\"16.518650088809945%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 25.7242%;\\\" valign=\\\"top\\\" width=\\\"35.701598579040855%\\\"\\u003e\\n \\u003cp\\u003eER positive (unknown 55)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34.2989%;\\\" valign=\\\"top\\\" width=\\\"24.511545293072825%\\\"\\u003e\\n \\u003cp\\u003e32 (50.8%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 13.005%;\\\" valign=\\\"top\\\" width=\\\"22.912966252220247%\\\"\\u003e\\n \\u003cp\\u003e50 (43.1%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 6.574%;\\\" valign=\\\"top\\\" width=\\\"16.518650088809945%\\\"\\u003e\\n \\u003cp\\u003e0.605\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 25.7242%;\\\" valign=\\\"top\\\" width=\\\"35.701598579040855%\\\"\\u003e\\n \\u003cp\\u003ePR positive (unknown 56)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34.2989%;\\\" valign=\\\"top\\\" width=\\\"24.511545293072825%\\\"\\u003e\\n \\u003cp\\u003e22 (34.9%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 13.005%;\\\" valign=\\\"top\\\" width=\\\"22.912966252220247%\\\"\\u003e\\n \\u003cp\\u003e41 (35.3%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 6.574%;\\\" valign=\\\"top\\\" width=\\\"16.518650088809945%\\\"\\u003e\\n \\u003cp\\u003e0.952\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 25.7242%;\\\" valign=\\\"top\\\" width=\\\"35.701598579040855%\\\"\\u003e\\n \\u003cp\\u003eHER2 positive (unknown 58)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34.2989%;\\\" valign=\\\"top\\\" width=\\\"24.511545293072825%\\\"\\u003e\\n \\u003cp\\u003e14 (22.2%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 13.005%;\\\" valign=\\\"top\\\" width=\\\"22.912966252220247%\\\"\\u003e\\n \\u003cp\\u003e20 (17.2%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 6.574%;\\\" valign=\\\"top\\\" width=\\\"16.518650088809945%\\\"\\u003e\\n \\u003cp\\u003e0.712\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 25.7242%;\\\" valign=\\\"top\\\" width=\\\"35.701598579040855%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eMetastasis exist\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34.2989%;\\\" valign=\\\"top\\\" width=\\\"24.511545293072825%\\\"\\u003e\\n \\u003cp\\u003e38 (60.3%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 13.005%;\\\" valign=\\\"top\\\" width=\\\"22.912966252220247%\\\"\\u003e\\n \\u003cp\\u003e40 (34.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 6.574%;\\\" valign=\\\"top\\\" width=\\\"16.518650088809945%\\\"\\u003e\\n \\u003cp\\u003e0.001*\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 25.7242%;\\\" valign=\\\"top\\\" width=\\\"35.701598579040855%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003ePerformance status\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34.2989%;\\\" valign=\\\"top\\\" width=\\\"24.511545293072825%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 13.005%;\\\" valign=\\\"top\\\" width=\\\"22.912966252220247%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 6.574%;\\\" valign=\\\"top\\\" width=\\\"16.518650088809945%\\\"\\u003e\\n \\u003cp\\u003e0.475\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 25.7242%;\\\" valign=\\\"top\\\" width=\\\"35.701598579040855%\\\"\\u003e\\n \\u003cp\\u003eECOG 1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34.2989%;\\\" valign=\\\"top\\\" width=\\\"24.511545293072825%\\\"\\u003e\\n \\u003cp\\u003e3 (4.8%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 13.005%;\\\" valign=\\\"top\\\" width=\\\"22.912966252220247%\\\"\\u003e\\n \\u003cp\\u003e7 (6.0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 6.574%;\\\" valign=\\\"top\\\" width=\\\"16.518650088809945%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 25.7242%;\\\" valign=\\\"top\\\" width=\\\"35.701598579040855%\\\"\\u003e\\n \\u003cp\\u003eECOG 2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34.2989%;\\\" valign=\\\"top\\\" width=\\\"24.511545293072825%\\\"\\u003e\\n \\u003cp\\u003e59 (93.7%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 13.005%;\\\" valign=\\\"top\\\" width=\\\"22.912966252220247%\\\"\\u003e\\n \\u003cp\\u003e108 (93.1%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 6.574%;\\\" valign=\\\"top\\\" width=\\\"16.518650088809945%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 25.7242%;\\\" valign=\\\"top\\\" width=\\\"35.701598579040855%\\\"\\u003e\\n \\u003cp\\u003eECOG 3,4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34.2989%;\\\" valign=\\\"top\\\" width=\\\"24.511545293072825%\\\"\\u003e\\n \\u003cp\\u003e1 (1.6%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 13.005%;\\\" valign=\\\"top\\\" width=\\\"22.912966252220247%\\\"\\u003e\\n \\u003cp\\u003e1 (0.9%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 6.574%;\\\" valign=\\\"top\\\" width=\\\"16.518650088809945%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 25.7242%;\\\" valign=\\\"top\\\" width=\\\"35.701598579040855%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eConventional treatment\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34.2989%;\\\" valign=\\\"top\\\" width=\\\"24.511545293072825%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 13.005%;\\\" valign=\\\"top\\\" width=\\\"22.912966252220247%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 6.574%;\\\" valign=\\\"top\\\" width=\\\"16.518650088809945%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 25.7242%;\\\" valign=\\\"top\\\" width=\\\"35.701598579040855%\\\"\\u003e\\n \\u003cp\\u003eSurgery\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34.2989%;\\\" valign=\\\"top\\\" width=\\\"24.511545293072825%\\\"\\u003e\\n \\u003cp\\u003e59 (93.7%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 13.005%;\\\" valign=\\\"top\\\" width=\\\"22.912966252220247%\\\"\\u003e\\n \\u003cp\\u003e109 (94.0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 6.574%;\\\" valign=\\\"top\\\" width=\\\"16.518650088809945%\\\"\\u003e\\n \\u003cp\\u003e0.933\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 25.7242%;\\\" valign=\\\"top\\\" width=\\\"35.701598579040855%\\\"\\u003e\\n \\u003cp\\u003eChemotherapy\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34.2989%;\\\" valign=\\\"top\\\" width=\\\"24.511545293072825%\\\"\\u003e\\n \\u003cp\\u003e51 (81.0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 13.005%;\\\" valign=\\\"top\\\" width=\\\"22.912966252220247%\\\"\\u003e\\n \\u003cp\\u003e77 (66.4%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 6.574%;\\\" valign=\\\"top\\\" width=\\\"16.518650088809945%\\\"\\u003e\\n \\u003cp\\u003e0.039*\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 25.7242%;\\\" valign=\\\"top\\\" width=\\\"35.701598579040855%\\\"\\u003e\\n \\u003cp\\u003eRadiotherapy\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34.2989%;\\\" valign=\\\"top\\\" width=\\\"24.511545293072825%\\\"\\u003e\\n \\u003cp\\u003e36 (57.1%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 13.005%;\\\" valign=\\\"top\\\" width=\\\"22.912966252220247%\\\"\\u003e\\n \\u003cp\\u003e69 (59.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 6.574%;\\\" valign=\\\"top\\\" width=\\\"16.518650088809945%\\\"\\u003e\\n \\u003cp\\u003e0.710\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 25.7242%;\\\" valign=\\\"top\\\" width=\\\"35.701598579040855%\\\"\\u003e\\n \\u003cp\\u003eHormone therapy\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34.2989%;\\\" valign=\\\"top\\\" width=\\\"24.511545293072825%\\\"\\u003e\\n \\u003cp\\u003e26 (41.3%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 13.005%;\\\" valign=\\\"top\\\" width=\\\"22.912966252220247%\\\"\\u003e\\n \\u003cp\\u003e61 (52.6%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 6.574%;\\\" valign=\\\"top\\\" width=\\\"16.518650088809945%\\\"\\u003e\\n \\u003cp\\u003e0.148\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 25.7242%;\\\" valign=\\\"top\\\" width=\\\"35.701598579040855%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eKMAT period(days)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34.2989%;\\\" valign=\\\"top\\\" width=\\\"24.511545293072825%\\\"\\u003e\\n \\u003cp\\u003e66.9\\u0026plusmn;81.9\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 13.005%;\\\" valign=\\\"top\\\" width=\\\"22.912966252220247%\\\"\\u003e\\n \\u003cp\\u003e76.3\\u0026plusmn;94.7\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 6.574%;\\\" valign=\\\"top\\\" width=\\\"16.518650088809945%\\\"\\u003e\\n \\u003cp\\u003e0.295\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 25.7242%;\\\" valign=\\\"top\\\" width=\\\"35.701598579040855%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eResponse\\u003c/strong\\u003e\\u003cstrong\\u003e\\u0026nbsp;rate\\u0026nbsp;\\u003c/strong\\u003e\\u003cstrong\\u003eto therapy\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 34.2989%;\\\" valign=\\\"top\\\" width=\\\"24.511545293072825%\\\"\\u003e\\n \\u003cp\\u003e44 (69.8%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 13.005%;\\\" valign=\\\"top\\\" width=\\\"22.912966252220247%\\\"\\u003e\\n \\u003cp\\u003e98 (84.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 6.574%;\\\" valign=\\\"top\\\" width=\\\"16.518650088809945%\\\"\\u003e\\n \\u003cp\\u003e0.021*\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n\\u003ctable border=\\\"1\\\" cellpadding=\\\"0\\\" cellspacing=\\\"0\\\" width=\\\"566\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"7\\\" valign=\\\"top\\\" width=\\\"100%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eTable\\u003c/strong\\u003e\\u003cstrong\\u003e\\u0026nbsp;3\\u003c/strong\\u003e\\u003cstrong\\u003e. Univariate and multivariate Cox regression analyses of OS using clinical parameters, n=1\\u003c/strong\\u003e\\u003cstrong\\u003e79\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd rowspan=\\\"2\\\" valign=\\\"top\\\" width=\\\"22.43816254416961%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eParameters\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"3\\\" valign=\\\"top\\\" width=\\\"39.57597173144876%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eUnivariate analysis\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"3\\\" valign=\\\"top\\\" width=\\\"37.985865724381625%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eMultivariate analysis\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"15.034168564920273%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eHR\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"21.64009111617312%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e95%CI\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"14.350797266514807%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003ep-value\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"13.66742596810934%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eHR\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"21.4123006833713%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e95%CI\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"13.895216400911162%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003ep-value\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"22.43816254416961%\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eAge\\u003c/strong\\u003e\\u003cstrong\\u003e\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"11.66077738515901%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"16.784452296819786%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"11.130742049469964%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"10.60070671378092%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"16.607773851590107%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"10.777385159010601%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"22.43816254416961%\\\"\\u003e\\n \\u003cp\\u003e\\u0026lt;54\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"11.66077738515901%\\\"\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"16.784452296819786%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"11.130742049469964%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"10.60070671378092%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"16.607773851590107%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"10.777385159010601%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"22.43816254416961%\\\"\\u003e\\n \\u003cp\\u003e\\u0026ge;54\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"11.66077738515901%\\\"\\u003e\\n \\u003cp\\u003e1.716\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"16.784452296819786%\\\"\\u003e\\n \\u003cp\\u003e0.727-4.049\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"11.130742049469964%\\\"\\u003e\\n \\u003cp\\u003e0.212\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"10.60070671378092%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" width=\\\"16.607773851590107%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n 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\\u003c/tbody\\u003e\\n\\u003c/table\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":true,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":false,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true},\"keywords\":\"\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-2800963/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-2800963/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003eThrough analyzing a correlation between natural killer cell activity (NKA) and survival rate of patients with breast cancer, this study aims to assess the potential of NKA as a prognostic biomarker of breast cancer. We retrospectively analyzed the digital medical records of breast cancer patients treated at two traditional Korean medicine hospitals, located in Daejeon and Cheonan, South Korea, from April 1, 2016, to April 4, 2021. NKA levels were assessed by measuring interferon-γ released by stimulated- NK cells using commercial kit (NK Vue®; NKMAX, Seongnam, Korea). The patients were divided into two groups: A high NKA (≥ 500 pg/mL), and a low NKA (\\u0026lt; 500 pg/mL) group, and compared in terms of tumor progression, physical status, overall survival (OS), and event-free survival (EFS). The high-NKA group exhibited significant longer OS (67.3 ± 1.5 vs 57.4 ± 3.7 months, p=0.002), longer EFS (62.9 ± 2.0 vs 49.2 ± 3.8 months, p=0.004) and better response rate (84.5% vs 69.8%, p=0.021). A relationship between NKA and prognosis in stage III and IV was more significant. Stage III and IV patients with high NKA had longer OS (38.9 ± 6.8 vs 56.7 ± 5.5 months, p = 0.039) and longer EFS (50.5 ± 6.2 months vs 31.4 ± 6.3 months, p = 0.053). NKA may serve as a prognostic biomarker for breast cancer patients. Further studies with more patients over a longer period are needed.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Correlation of NK cell activity and Clinical Parameters with Survival in Breast Cancer patients\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2023-04-20 13:37:39\",\"doi\":\"10.21203/rs.3.rs-2800963/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"289e0ba9-1db7-428a-b772-932332158716\",\"owner\":[],\"postedDate\":\"April 20th, 2023\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[{\"id\":20808411,\"name\":\"Biological sciences/Cancer\"},{\"id\":20808412,\"name\":\"Biological sciences/Cancer/Breast cancer\"},{\"id\":20808413,\"name\":\"Biological sciences/Cancer/Cancer screening\"}],\"tags\":[],\"updatedAt\":\"2024-07-10T11:02:12+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2023-04-20 13:37:39\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-2800963\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-2800963\",\"identity\":\"rs-2800963\",\"version\":[\"v1\"]},\"buildId\":\"J0_U0BvcaRcwD8yVFaRlm\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}