The association of HER-2 expression with clinicopathological characteristics and clinical outcomes in patients with localized prostate cancer after radical prostatectomy

The association of HER-2 expression with clinicopathological characteristics and clinical outcomes in patients with localized prostate cancer after radical prostatectomy | 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 Research Article The association of HER-2 expression with clinicopathological characteristics and clinical outcomes in patients with localized prostate cancer after radical prostatectomy Shuo Wang, xiao yang, Ruijian You, Peng Du, Yiqiang Liu, Yongpeng Ji, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4153815/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 Purpose To investigate the association between HER-2 expression and clinicopathological characteristics, biochemical recurrence (BCR) rate and BCR free survival in localized prostate cancer (PCa) patients after radical prostatectomy (RP). Methods Between January 2014 and December 2019, 44 patients with pathological confirmed localized PCa who underwent RP were included into this study. According to the expressed level of HER-2 protein, patients were divided into 4 cohorts, cohort-1 (HER-2 0+), cohort-2 (HER-2 1 + or 2+), cohort-3 (HER-2 0 + or 1+) and cohort-4 (HER-2 2+), the clinicopathological and clinical outcomes were analyzed and compared between cohort-1 and cohort-2, cohort-3 and cohort-4, respectively. Univariable, multivariable COX regression model and Kaplan-Meier curves were used to determine the association between HER-2 expression and clinicopathological outcomes including Gleason Score (GS), pathological T (pT) stage, positive surgical margins (PSM) and BCR free survival, respectively. Results The median follow-up time was 43 months (IQR 35–49), 20 patients (45.45%) of tumors exhibited HER-2 immuno-reactivity, 14 (31.82%) had HER-2 1+, 6 (13.64%) had HER-2 2 + and 0 (0%) had HER-2 3 + immunostaining. The proportion of PSM in patients with HER-2 0 + was significant lower compared with 1 + or 2+ (41.7% vs 70%, P = 0.045). By using multivariable logistics regression models revealed that HER-2 1 + or 2 + was the independent risk factor strongly associated with higher proportion of PSM (HR, 2.691; 95% CI, 0.619–11.71, P = 0.042). 24 (54.55%) patients developed BCR after surgery, including 8 (33.3%) in cohort-1, 16 (80%) in cohort-2, P = 0.029 while 18 (47.4%) in cohort-3, 6 (100%) in cohort-4, P = 0.025. According to Kaplan-Meier analysis, results showed that in cohort-1, the BCR free survival was significantly longer than in cohort-2, P = 0.000; while in cohort-3, the BCR free survival was significantly longer than in cohort-4, P = 0.000. By using multivariable Cox regression model revealed that HER-2 1+, 2+ (HR, 17.002; 95% CI, 1.378-210.216, P < 0.001), HER-2 2+ (HR, 2.849; 95% CI, 1.234–3.246, P = 0.004) were all significant independent factors associated with BCR after surgery Conclusion HER-2 expression was a common phenomenon in PCa, nearly half proportion of localized PCa had HER-2 1 + or 2+, but the cases expressed HER-2 3 + were rare. Cases with HER-2 1 + or 2 + were more likely developed BCR compared with HER-2 0+. The HER-2 expression was closely associated with shorter BCR free survival and higher proportion of PSM, but not associated with GS and pT stage. HER-2 could be considered as a potential method predicting clinical outcomes in patients after RP. prostate cancer biochemical recurrence HER-2 radical prostatectomy Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Prostate cancer (PCa) is one of the most common malignant tumors in the world. Many factors may influence the clinicopathology characteristics and progression of PCa. In recent years, the pathways are increasingly understood, as a transmembrane tyrosine kinase receptor with high homology to the epidermal growth factor receptor, HER-2 protein overexpression is not common in normal tissue but has been found in a variety of epithelial malignancies, including breast, ovarian, bladder gastric and endometrial carcinoma [ 1 ]. Since Slamon et al first reported the association of HER-2 overexpression and poor outcome of breast cancer, it has been considered to be a factor predicting the poor outcome of the malignant tumor [ 2 ]. Most recently, several studies reported that HER-2 protein overexpression might be associated with the progression of PCa, by activating androgen receptor signal pathway HER-2 dependent signaling may promote the PCa developing to the castration resistant prostate cancer (CRPC) [ 3 ]. And in CRPC, HER-2 is amplified or overexpressed in up to 60% of patients and strongly correlated with the progression of the disease and shorter survival time [ 4 ]. Even so, most of the studies reported are focus on PCa with latent phase, researches detecting the role of HER-2 expression on localized PCa are rare. With these considerations, in this research we investigated whether expression of HER-2 is associated with poor clinicopathological outcome, high biochemical recurrence (BCR) rate and short BCR free survival with localized PCa treated by radical prostatectomy (RP). Material and Methods This is a retrospective study approved by the medical ethics review committee (protocol code 2019KT30). Patients 44 localized PCa cases who underwent laparoscopic RP between January 2018 and December 2019 were reviewed. Among these patients, no one received neo-adjuvant therapy before RP and adjuvant therapy after RP until the detection of BCR. Preoperative clinical characteristics including age, serum tPSA value, PSA f/t value, total prostate volume (TPV), body mass index (BMI) and biopsy positive cores (BPC) as well as postoperative pathological and clinical outcomes including Gleason Score (GS), pathological T (pT) stage, positive surgical margins (PSM) and BCR were collected and compared depending on the level of HER-2 expressed. Data of risk factors might relate to BCR including HER-2, GS, PSM and pT stage were collected, and their associations with BCR and BCR free survival time were analyzed. Procedure Ultrasound guided 13-core trans-rectal prostatic biopsy was performed in patients suspected PCa in our institute. Data of serum tPSA value, PSA f/t values were collected just 1–2 days before surgery and at least 3 weeks after prostatic biopsy. MRI, PSMA PET-CT were performed before surgery to confirm no bone, lymph nodes or distant organ metastasis. Laparoscopic RP was performed at least 25 days after biopsy. Through an extraperitoneal approach, extra-fascial radical prostatectomy was performed by skilled surgeons in our institute according to the technique of Walsh et al [ 5 ]. All specimens were assessed by sophisticated pathologist at our institute, tissues from patients were tested for HER-2 protein expression. HER-2 positive could be documented either on the original diagnostic biopsy or on the RP specimen. For every 1–3 months, serum tPSA and f/t values were detected. Variables The prostate was measured in 3-dimensional aspects, and its volume was estimated with the modified ellipsoid formulation in cm 3 (0.523 [ length × width × height]) after surgery, pathologic GS were recorded and patients were staged according to the 2010 American Joint Committee on Cancer system (AJCC, pathologic stage T1-T4) [ 6 ]. Tumors were classified into low (GS ≤ 6), intermediate (GS = 7), high grade (GS ≥ 8) group according to D’Amico risk classification [ 7 ]. Body Mass index (BMI) = weight (kg)/ height (meter) 2 . BCR was defined as at least two consecutive serum tPSA ≥ 0.2ng/mL according to the guidelines of the American Urological Association [ 8 ], and data of time free from BCR was collected. Sections of the surgical piece with prostate cancer were selected for the determination of HER-2 expression. This was evaluated using the FDA approved immunochemical kit HercepTest (DAKO, USA). The status of HER-2 immunostaining were catalogized into 4 types, HER-2 0: membrane stain absent; HER-2 1+: greater than 10% of tumors cells present with barely perceptible staining; HER-2 2+: greater than 10% of tumors cells present with weak to moderated staining; HER-2 3+: greater than 10% tumor cells present with strong staining [ 9 ]. Then patients were divided into 4 sub-cohorts according to the expression status of HER-2. Cohort-1, HER-2 0+, cohort-2, HER-2 1+, 2+, 3+; cohort-3, HER-2 0, 1+; cohort-4 HER-2 2+, 3+. The clinicopathological factors were analyzed and compared between cohort-1 and 2, cohort-3 and 4, respectively. Statistical analysis Measurement data confirming to normal distribution analyzed by Shapiro-Wilk test are presented as Mean ± SD, independent sample t test is used to evaluate the differences between continuous variables, while Chi-square tests were performed to examine categorical variables. The binary logistic regression model (univariate and multivariate analysis) was used to evaluate the association between HER-2 expression and adverse pathological events, which were all compared with reference group (Ref). Kaplan-Merier analyses were performed of BCR free survival according to level of HER-2 expressed using the log-rank test, and the survival curves were described. Univariable and multivariable Cox regression model was used to identify the co-variables that influence BCR. The software used to run the analysis was IBM-SPSS version 20. All tests were two-sided, P < 0.05 was considered to be the threshold for statistically meaningful differences. Result Clinicopathologic characteristics of the entire cohort. Totally 44 localized PCa patients were enrolled into this study. The median values of the factors was 67.95 ± 6.84 yeas for age, 25.60 ± 2.13kg/m 2 for BMI, 29.49 ± 40.59 ng/mL for tPSA, 0.129 ± 0.01 for f/t value, 34.77 ± 12.28 mL for TPV and 44.65 ± 22.48 for proportion of BCP. 2 (4.5%) patients were with GS ≤ 6, 22 (50%) patients were with GS = 7 and 20 (45.45%) patients were with GS ≥ 8; 26 (59.09%) patients were pT2, 18 patients (40.91%) were pT3. 24 patients (54.5%) were with PSM. The patients’ clinicopathologic demographics are summarized in Table 1 . Table 1 Clinicopathological characteristics of the entire cohort and sub-cohorts divided by HER-2 expression Entire cohort Cohort- 1 (HER-2 0+) Cohort-2 (HER-2 1+, 2+) P value Number 44 24 20 Age (years) 67.95 ± 6.89 68.33 ± 7.70 67.5 ± 5.93 0.694 BMI (kg/m 2 ) 25.60 ± 2.13 25.51 ± 2.25 25.70 ± 2.02 0.771 tPSA (ng/mL) 29.49 ± 40.59 36.66 ± 51.68 20.89 ± 18.80 0.203 f/t 0.129 ± 0.01 0.119 ± 0.047 0.148 ± 0.046 0.177 TPV (mL) 34.77 ± 12.28 32.82 ± 11.09 37.11 ± 13.48 0.254 BCP (%) 44.65 ± 22.48 49.03 ± 17.91 39.01 ± 26.93 0.216 GS (n, %) 0.40 ≤ 6 2 (4.5) 2 (8.3) 0 (0) 7 22 (50) 12 (50) 10 (50) ≥8 20 (45.45) 10 (41.7) 10 (50) pT stage (n, %) 0.911 pT2 26 (59.09) 14 (58.3) 12 (60) pT3 18 (40.91) 10 (41.7) 8 (40) PSM (n, %) 24 (54.5) 10 (41.7) 14 (70) 0.045 BCR (n, %) 24 (54.5) 8 (33.3) 16 (80) 0.029 BMI: body mass index; tPSA: total prostate cancer specific antigen; TPV: total prostate volume; BCP: biopsy core positive; GS: Gleason Score; pT: pathological stage; PSM: positive surgical margins; BCR: biochemical recurrence. Sub-cohorts divided by levels of HER-2 protein expression 20 cases (45.45%) of tumors exhibited HER-2 immuno-reactivity, 24 cases (54.55%) exhibited non- HER-2 immuno-reactivity. Of these HER-2 expressed tumors, 14 (31.82%) had HER-2 1+, 6 (13.64%) had HER-2 2 + and 0 (0%) had HER-2 3 + immunostaining. All patients were divided into 4 sub-cohorts according to the level of HER-2 protein expression. 24 (54.55%) cases with HER-2 0 and 20 cases (45.45%) with HER-2 1+, 2 + were catalogized into cohort-1 and cohort-2; 38 cases (86.36%) with HER-2 0 + or 1 + and 6 cases (13.64%) with HER-2 2 + were catalogized into cohort-3 and cohort-4. Initially, data were analyzed and compared between cohort-1 and cohort-2, cohort-3 and cohort-4, respectively. In cohort-1, the proportion of PSM was significant lower compared with cohort-2 (41.7% vs 70%, P = 0.045), but the distribution of age, BMI, tPSA, f/t, TPV, BCP, GS and pT stage did not show any significant differences; in cohort-3, the TPV (32.72 ± 11.57 vs 43.73 ± 8.49mL, P = 0.004) was significant lower compared with cohort-4, but the distribution of age, BMI, tPSA, f/t, BCP, GS, PSM and pT stage did not show any significant differences as shown in Table 1 and Table 2 . Table 2 Clinicopathological characteristics of patients divided by HER-2 expression Cohort-3 Cohort-4 P value (HER-2 0,1+) (HER-2 2+) Number 38 6 Age (years) 67.79 ± 7.14 69.00 ± 5.44 0.694 BMI (kg/m 2 ) 25.53 ± 2.12 26.04 ± 2.34 0.588 tPSA (ng/mL) 31.25 ± 43.36 12.46 ± 0.50 0.299 f/t 0.129 ± 0.048 0.113 ± 0.069 0.521 TPV (mL) 32.72 ± 11.57 43.73 ± 8.49 0.004 BCP (%) 49.84 ± 18.86 29.37 ± 32.58 0.043 GS (n, %) 0.499 ≤ 6 2 (5.3) 0 (0) 7 20 (52.6) 2 (33.3) ≥8 16 (42.1) 4 (66.7) pT stage (n, %) 1 pT2 22 (57.9) 4 (66.7) pT3 16 (42.1) 2 (33.3) PSM (n, %) 20 (52.6) 4 (66.7) 0.650 BCR (n, %) 18 (47.37) 6 (100) 0.025 BMI: body mass index; tPSA: total prostate cancer specific antigen; TPV: total prostate volume; BCP: biopsy core positive; GS: Gleason Score; pT: pathological stage; PSM: positive surgical margins; BCR: biochemical recurrence. Then the association of HER-2 1+, 2 + with PSM were analyzed according to univariable and multivariable logistics regression models. The result showed HER-2 expressed 1 + or 2 + was the independent risk factor strongly associated with the higher proportion of PSM (HR, 2.691; 95% CI, 0.619–11.71, P = 0.042) after surgery as shown in Table 3 . Table 3 Univariable and multivariable analysis of the impact of HER-2 expression on status of surgical margins Univariable analysis Multivariable analysis PSM vs NSM PSM vs NSM HR 95% CI P value HR 95% CI P value HER-2 0+ Ref Ref Ref Ref HER-2 1+,2+ 2.333 0.897–6.072 0.046 2.691 0.619–11.71 0.042 Ref: reference; PSM: positive surgical margins; NSM: negative surgical margins Factors associated with BCR and BCR free survival The median follow-up time was 43 months (IQR 35–49). Totally 24 (54.55%) patients developed BCR after surgery. Factors might associate with BCR including HER-2 expression, GS, pT stage and PSM were collected and analyzed. The data showed that 8 (33.3%) cases occurred BCR in cohort-1, 16 (80%) in cohort-2, P = 0.029 while 18 (47.4%) in cohort-3, 6 (100%) in cohort-4, P = 0.025, but there were no differences of the proportions of BCR occurred in patients divided by GS (P = 0.267), PSM (P = 0.402) and pT stage (P = 0.15) as shown in Table 4 . According to Kaplan-Meier analysis, results showed that in cohort-1, the BCR free survival was significantly longer than in cohort-2 as shown in Fig. 4 , P = 0.000; while in cohort-3, the BCR free survival was significantly longer than in cohort-4, P = 0.000 as shown in Fig. 5 , but the GS, pT stage and PSM were not associated with BCR free survival as shown in Fig. 1 – 3 . By using univariable and multivariable Cox regression model revealed that HER-2 1 + or 2+ (HR, 17.002; 95% CI, 1.378-210.216, P < 0.001), HER-2 2+ (HR, 2.849; 95% CI, 1.234–3.246, P = 0.004) were all significant independent factors associated with developed BCR after surgery, but GS, pT stage, PSM were not factors associated with BCR as shown in Table 5 . Table 4 Clinicopathological characteristics of the patients divided by status of BCR no BCR BCR P value HER-2 0+ (n, %) 16 (66.7) 8 (33.3) 0.029 HER-2 1+,2+ 4 (20) 16 (80) HER-2 0,1+ (n, %) 20 (52.6) 18 (47.4) 0.025 HER-2 2+ 0 (0) 6 (100) GS (n, %) 0.267 ≤6 2 (10) 0 (0) 7 10 (50) 12 (50) ≥8 8 (40) 12 (50) pT stage (n, %) 0.150 pT2 14 (70) 12 (50) pT3 6 (30) 12 (50) PSM (n, %) 10 (50) 14 (58.3) 0.402 NSM (n, %) 10 (50) 10 (41.7) PSM: positive surgical margins; NSM: negative surgical margins; GS: gleason Score; pT stage: pathological T stage. Table 5 Cox regression analysis of potential factors associated with development of BCR after RP. Univariable analysis Multivariable analysis HR 95% CI P value HR 95% CI P value HER-2 0 Ref Ref Ref Ref HER-2 1+,2+ 4 1.337–11.965 0.005 17.002 1.378-210.216 < 0.001 HER-2 0,1+ Ref Ref Ref Ref HER-2 2+ 1.615 0.825–2.424 0.015 2.849 1.234–3.246 0.004 GS ≤ 6 Ref Ref Ref Ref 7 1.5 0.613–3.670 0.374 8.745 0.535–2.822 0.151 ≥ 8 1.25 0.493–3.167 0.638 5.441 0.789–2.632 0.452 Surgical margin NSM Ref Ref Ref Ref PSM 1.4 0.424–4.623 0.416 2.956 0.437–19.984 0.266 pT stage T2 Ref Ref Ref Ref T3 1.167 0.540–2.522 0.334 17.022 0.678–2.216 0.327 GS: gleason score; PSM: positive surgical margins; pT stage: pathological T stage; Ref: reference. Discussion This trial was designed to examine the feasibility of molecular profiling in patients with localized PCa to determine the association between HER-2 protein expression and clinicopathological characters and BCR after surgery. HER-2 oncoprotein is 1 of the 4 transmembrane receptors of the erB family. It can form heterodimers with the other erbB family members after binding to specific ligands [ 10 ]. HER-2 overexpression has been seen in variable kinds of cancer. In breast cancer, about 30% of patients has been found with HER-2 overexpression. In patients with urothelial carcinoma of the bladder, HER-2 expression in circulating tumor cells was higher than in the tumor original [ 11 ]. These finding suggested that HER-2 positive cells in the original tumor have a higher capacity of vascular dissemination than HER-2 negative cells. In patients with prostate cancer, tumor progression to androgen independent growth eventually after treating with androgen ablation therapy. Androgen receptor pathway activation independent of androgen plays a key role in it [ 12 ]. However, the mechanism by which the pathway is activated in the absence of androgen is unknown. One important factor may induce the development of androgen independent is HER-2. Specific HER-2 overexpression may promote AR transactivation and phosphorylation, and by enhancing AR binding to androgen regulated gene promoters HER-2 may stimulate AR proteins [ 13 ]. In vivo experiments, HER-2 may be important for the survival of prostate cancer cells in androgen depleted environment [ 14 ]. In PCa patients, the HER-2 overexpression varies differently according to the reports of different experiments. It is reported that 70% of patients with localized PCa underwent radical prostatectomy were HER-2 overexpression [ 15 ]; Koeppen et al reported that among 61 PCa patients, only 5 had HER-2 overexpression classified as 2+, none classified as 3+ [ 16 ]; while another study found that among hormone refractory prostate carcinoma, HER-2 overexpression was seen in only 7% patients [ 17 ]. Yoshiaki et al, reported that in M1b prostate cancer patients, 19.2% of the subjects had HER-2 overexpression, and these patients had a significantly poorer outcome [ 18 ]. The findings of our study seemed accordance with the previous studies reported, in our study 45.45% of cases were with HER-2 expressed, but only 13.64% cases expressed HER-2 2+, none expressed HER-2 3+. Therefore, HER-2 expression seemed to be a common phenomenon in both early stage or latent stage prostate cancer patients. Several studies considered HER-2 overexpression may play an important role in the development of prostate cancer. One research obtained prostate cancer tissues from patients which were divided into three sub-cohorts including treated by surgery alone (UNT), treated with total androgen ablation therapy before surgery (TAA), and treated with total androgen ablation therapy failed and developed bone metastases (AI), found that HER-2 protein expression was significantly higher in TAA tumors than in UNT tumors, and proportion of HER-2 positive tumors increased from UNT to TAA to AI, concluded that HER-2 expression appears to increase with the progression to androgen independence [ 19 ]. Another study collected samples from PCa patients, found that levels of HER-2 expression are infrequent in the tumors among hormone-naïve patients, but significantly increased among patients treated with androgen blockage [ 20 ]. HER-2 overexpression might be associated with the development of the prostate cancer. In organ confined prostate cancer, rare studies detected the relationship between HER-2 expression and the clinicopathological characteristics. In 2008, one study investigated the expression of HER-2 and AR in organ confined prostate cancer patients who underwent RP to determine whether alterations in these signal pathways contributes to the progression of the diseases, the results showed that high HER-2 and AR expression were both closely associated with higher rate of PSA failure, and higher pathological stage [ 21 ]. Another study demonstrated that higher level of HER-2 expression was associated with higher prostate cancer stage and PSA progression in clinical localized PCa [ 22 ]. Our data seemed not very much accordance with the previous study, we found that HER-2 overexpression was associated with higher rates of BCR and PSM after RP, but it seemed not closely associated with higher GS and pT stage. For HER-2 overexpression is common in PCa patients and may related to the progression of the disease, the development of additional treatment strategies that target the HER-2 may provide a more effective approach for treating PCa patients. Antibody-drug conjugates (ADCs) might be a potential medicine for treating PCa with latent phase. The ADCs are novel medicines consisting of payload linked to specific antibodies which can recognize antigens expressed over cancer cell’s surfaces. Recently, studies are focusing on STEAP1, TROP2, PSMA and CD46 as potential antigens targeted by ADCs [ 23 , 24 ]. The studies detecting the ADCs targeted on the HER-2 antigen are rare, only few cases have been reported. Therefore, more research explorations are needed detecting the applications of ADCs targeting on HER-2 antigen. Our study still has some limitations. It was a single center, retrospective study, and the sample size was relatively small, more samples are needed in further studies. Conclusion The data indicated that nearly half proportion of localized PCa expressed HER-2 1 + or 2+, but the patients expressed HER-2 3 + were rare. The HER-2 expression was closely associated with higher proportion of BCR, PSM and shorter BCR free survival, but not associated with GS and pT stage. However, further well organized and large prospective studies are needed. Declarations Author’s contribution : Shuo Wang and Peng Du designed the study. Shuo Wang, Xiao Yang and Ruijian You made the same contribution in this study as the first coauthor. Peng Du, Yiqiang Liu made the same contribution in this study as the corresponding coauthor. Shuo Wang, Xiao Yang, Ruijian You, Peng Du, Yiqiang Liu, Yongpeng Ji, Qiang Zhao, Yudong Cao, Jinchao Ma, Ziyi Yu, Yong Yang performed the study and analyzed the data. Peng Du, Shuo Wang, Xiao Yang, Yiqiang Liu and Ruijian You wrote the manuscript draft and revised the manuscript. All authors have read and agreed to the published version of the manuscript. Funding : 1. Clinical Research Fund For Distinguished Young Scholars of Peking University Cancer Hospital, QNJJ2022004; 2. Beijing Hospitals Authority Youth Programme, QML20231114. Institutional Review Board Statement : This study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of Peking University Cancer Hospital & Institution in April 2021 (protocol code 2019KT30). Informal Consent Statement : Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. Data Availability : The data presented in this study are available on request from the corresponding author. Conflict of Interests : These authors declare no competing interests. References Ross JS, Nazeer T, Church K et al. Contribution of HER-2/neu oncogene expression to tumor grade and DNA content analysis in the prediction of prostatic carcinoma metastasis. Cancer. 1993, 3020–8. Press MF, Bernstein L, Thomas PA, et al. HER-2/neu gene amplification characterized by fluorescence in situ hybridization: poor prognosis in node-negative breast carcinomas. J Clin Oncol. 1997;15:2894–904. Craft N, Shostak Y, Carey M, et al. A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat Med. 1999;5:280–5. Signoretti S, Montironi R, Manola J, et al. HER-2/neu expression and progression toward androgen independence in human prostate cancer. J Natl Cancer Inst. 2000;92:1918–25. Walsh PC, Retik AB, Vaughan ED et al. Anatomic radical retropubic prostatectomy; in Campbell’s Urology (ed 8). Philadephia 2002, 4, 3107–3129. Frederick L, Page DL, Fleming ID, et al. AJCC Cancer Staging Manual. New York, NY, USA: Springer Science & Business Media; 2002. D’ Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280:969–74. Cookson MS, Aus G, Burnett AL, et al. Variation in the definition of biochemical recurrence in patients treated for localized prostate cancer: the American Urological Association Prostate Guidelines for localized prostate update panel report and recommendations for a standard in the reporting of surgical outcomes. J Urol. 2007;177:540–5. Osman I, Scher HI, Drobnjak M, et al. HER-2/neu (p185neu) protein expression in the natural or treated history of prostate cancer. Clin Cancer Res. 2001;7:2643–7. Beerli RR, Graus Porta D, Woods Cook K, et al. Neu differentiation factor activation of erbB-3 and erbB-4 is cell specific and displays a differential requirement for erbB-2. Mol Cell Biol. 1995;15:6496. Rink M, Chun FK, Dahlem R et al. Prognostic role and HER-2 expression of circulating tumor cells in peripheral blood of patients prior to radical cystectomy: a prospective study. Eur Urol, 61. 810–7. Veldscholte J, Berrevoets CA, Ris-Stalpers C, et al. The androgen receptor in LNCaP cells contains a mutation in the ligand binding domain which affects steroid binding characteristics and response to antiandrogens. J Steroid Biochem Mol Biol. 1992;41:665–9. Craft N, Shostak Y, Carey M, et al. A mechanism for hormone independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat Med. 1999;5:280–5. Berger R, Lin Di, Nieto M, et al. Androgen dependent regulation of HER-2/neu in prostate cancer cells. Cancer Res. 2006;66:5723. Ricciarde lli C, Jackson MV, Choong CS, et al. Elevated level s of HER-2/neu and androgen receptor in clinically localized prostate cancer identifies metastatic potential. Prostate. 2008;68:830–8. Koeppen HK, Wright BD, Burt AD, et al. Overexpression of HER2/neu in solid tumours: an immunohistochemical survey. Histopathology. 2001;38:96–104. Lara PN Jr, Longmate J, Ruel C, et al. Trastuzumab plus docetaxel in HER-2/neu positive prostate carcinoma: final results from the California Cancer Consortium Screening and Phase II trial. Cancer. 2004;100:2125–31. Yoshiaki Yamada K, Nakamura S, Aoki, et al. Lactate dehydrogenase, Gleason Score and HER-2 overexpression are significant prognostic factors for M1b prostate cancer. Oncol Rep. 2011;25:937–44. Sabina Signoretti R, Montironi J, Manola et al. HER-2 neu expression and progression toward androgen independence in human prostate cancer. J Natl Cancer Inst. 2000, 92. Murray NP, Badinez LV, Duenas R et al. Positive HER-2 protein expression in circulating prostate cells and micro-metastasis, resistant to androgen blockage but not diethylstilbestol. Indian J Urol. 2011, 200–7. Ricciarde lli C, Jackson MV, Choong CS, et al. Elevated level s of HER-2/neu and androgen receptor in clinically localized prostate cancer identifies metastatic potential. Prostate. 2008;68:830–8. Shahrokh FS, Karim B, Jose AK, et al. Preoperative plasma HER2 and epidermal growth factor receptor for staging and prognostication in patients with clinically localized prostate cancer. Clin Cancer Res. 2007;15:5377–84. Petrylak DP, Vogelzang NJ, Chatta K, et al. PSMA ADC monotherapy in patients with progressive metastatic castration resistant prostate cancer following abiraterone and/or enzalutamide: efficacy and safety in open-label single arm phase 2 study. Prostate. 2020;80:99–108. Milowsky MI, Galsky MD, Morris MJ, et al. Phase 1/2 multiple ascending dose trial of the prostate specific cancer. Urol Oncol. 2016;34:e53015–21. Additional Declarations No competing interests reported. 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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-4153815","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":286715255,"identity":"e2b101e4-5b8d-46ed-9849-20cf621061eb","order_by":0,"name":"Shuo Wang","email":"","orcid":"","institution":"Peking University Cancer Hospital \u0026 Institute","correspondingAuthor":false,"prefix":"","firstName":"Shuo","middleName":"","lastName":"Wang","suffix":""},{"id":286715256,"identity":"da66df80-d44d-4e77-bcb6-7fa787005e36","order_by":1,"name":"xiao yang","email":"","orcid":"","institution":"Peking University Cancer Hospital \u0026 Institute","correspondingAuthor":false,"prefix":"","firstName":"xiao","middleName":"","lastName":"yang","suffix":""},{"id":286715257,"identity":"688f94e2-6539-41c5-adba-df0801827b61","order_by":2,"name":"Ruijian You","email":"","orcid":"","institution":"Peking University Cancer Hospital \u0026 Institute","correspondingAuthor":false,"prefix":"","firstName":"Ruijian","middleName":"","lastName":"You","suffix":""},{"id":286715258,"identity":"282cf56d-e3ab-4fcd-8f32-13b37010128b","order_by":3,"name":"Peng Du","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1ElEQVRIiWNgGAWjYDCCA2DShoeNmfnAgQ8VxGtJk+Nnb0s8OOMM8VoOG0v2nDE+zNtChA6+G7kHHxf8Opy44UbOhwO8DQzy/GIH8GuRvJGXbDyzLx2oJXfDAckdDIYzZyfg12JwI8dMmrfHGqLF8AxDgsFtwlrMf/P2MIMc9uBAYhtxWsyYeX44g7zPcOAgMVokz7xLluZtAAeywcGGMxKE/cJ3PPfgZ54/4Kh8/PlPhY08vzQBLQwMPAwMjG1wngQh5VAtDH+IUTgKRsEoGAUjFgAAj9hPcOfzWH4AAAAASUVORK5CYII=","orcid":"","institution":"Peking University Cancer Hospital \u0026 Institute","correspondingAuthor":true,"prefix":"","firstName":"Peng","middleName":"","lastName":"Du","suffix":""},{"id":286715259,"identity":"505d55f0-85ef-4266-a3ef-6260973090ae","order_by":4,"name":"Yiqiang Liu","email":"","orcid":"","institution":"Peking University Cancer Hospital \u0026 Institute","correspondingAuthor":false,"prefix":"","firstName":"Yiqiang","middleName":"","lastName":"Liu","suffix":""},{"id":286715260,"identity":"e2f74b05-d6bb-47a4-aa5a-d089e1f0c3f6","order_by":5,"name":"Yongpeng Ji","email":"","orcid":"","institution":"Peking University Cancer Hospital \u0026 Institute","correspondingAuthor":false,"prefix":"","firstName":"Yongpeng","middleName":"","lastName":"Ji","suffix":""},{"id":286715261,"identity":"c1245b86-58c3-4068-b57f-0e03da18a26d","order_by":6,"name":"Qiang Zhao","email":"","orcid":"","institution":"Peking University Cancer Hospital \u0026 Institute","correspondingAuthor":false,"prefix":"","firstName":"Qiang","middleName":"","lastName":"Zhao","suffix":""},{"id":286715262,"identity":"08ffc5e1-a207-4727-a275-87ac278220a4","order_by":7,"name":"Yudong Cao","email":"","orcid":"","institution":"Peking University Cancer Hospital \u0026 Institute","correspondingAuthor":false,"prefix":"","firstName":"Yudong","middleName":"","lastName":"Cao","suffix":""},{"id":286715264,"identity":"975996ce-9d95-4860-9a51-0ca4603f797a","order_by":8,"name":"Jinchao Ma","email":"","orcid":"","institution":"Peking University Cancer Hospital \u0026 Institute","correspondingAuthor":false,"prefix":"","firstName":"Jinchao","middleName":"","lastName":"Ma","suffix":""},{"id":286715265,"identity":"4281e141-b55a-44e1-9ca6-12a98f496b77","order_by":9,"name":"Ziyi Yu","email":"","orcid":"","institution":"Peking University Cancer Hospital \u0026 Institute","correspondingAuthor":false,"prefix":"","firstName":"Ziyi","middleName":"","lastName":"Yu","suffix":""},{"id":286715267,"identity":"5913ad4a-db19-4b7c-819b-53b2185a3ee9","order_by":10,"name":"Yong Yang","email":"","orcid":"","institution":"Peking University Cancer Hospital \u0026 Institute","correspondingAuthor":false,"prefix":"","firstName":"Yong","middleName":"","lastName":"Yang","suffix":""}],"badges":[],"createdAt":"2024-03-23 09:59:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4153815/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4153815/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":54039403,"identity":"760e181c-8e5e-4f4d-a2ce-8d26a6609b0a","added_by":"auto","created_at":"2024-04-03 17:21:36","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":39822,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier curves for BCR free survival according to GS.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere were no significantly differences of BCR free survival between patients grading by GS. P=0.412 by log-rank test.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4153815/v1/f5ddc8e5c21dfa1ee8a33b2a.png"},{"id":54039404,"identity":"8e90a7cc-7cb3-4b74-9a72-23b03273e584","added_by":"auto","created_at":"2024-04-03 17:21:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":36364,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier curves for BCR free survival according to surgical margins.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere were no significantly differences of BCR free survival between patients with NSM and PSM. P=0.282 by log-rank test.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4153815/v1/91d1f5d3d8698b1d732e6f4c.png"},{"id":54039405,"identity":"3c5d65f3-75da-4662-b514-790dfd2385f3","added_by":"auto","created_at":"2024-04-03 17:21:36","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":35573,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier curves for BCR free survival according to pT stage.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere were no significantly differences of BCR free survival between patients with pT2 and pT3. P=0.067 by log-rank test.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4153815/v1/f14fa779e8244d6f4b3b3ba8.png"},{"id":54039402,"identity":"7010a78d-acb4-4406-9f52-d1222ddb7c96","added_by":"auto","created_at":"2024-04-03 17:21:36","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":37217,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier curves for BCR free survival according to expression level of HER-2.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBCR free survival of patients with HER-2 0+ (cohort-1) was significantly longer than patients with HER-2 1+ or 2+ (cohort-2), P = 0.000 by log-rank test.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4153815/v1/85b4778076afc7fc6332bc94.png"},{"id":54039406,"identity":"03496d98-b219-44ef-a8bb-a4a708aeae99","added_by":"auto","created_at":"2024-04-03 17:21:36","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":40976,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier curves for BCR free survival according to HER-2 expression level.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBCR free survival of patients with HER-2 0+ or 1+ (cohort-3) was significantly longer than patients with HER-2 2+ (cohort-4), P = 0.000 by log-rank test.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-4153815/v1/283988d0c734324c2698ec83.png"},{"id":57268698,"identity":"a61a48ef-df83-46ea-bcba-346e309d7d29","added_by":"auto","created_at":"2024-05-28 11:52:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":904012,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4153815/v1/63481502-1063-4664-a7d9-c8ac99f3d7ac.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The association of HER-2 expression with clinicopathological characteristics and clinical outcomes in patients with localized prostate cancer after radical prostatectomy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eProstate cancer (PCa) is one of the most common malignant tumors in the world. Many factors may influence the clinicopathology characteristics and progression of PCa. In recent years, the pathways are increasingly understood, as a transmembrane tyrosine kinase receptor with high homology to the epidermal growth factor receptor, HER-2 protein overexpression is not common in normal tissue but has been found in a variety of epithelial malignancies, including breast, ovarian, bladder gastric and endometrial carcinoma [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Since Slamon et al first reported the association of HER-2 overexpression and poor outcome of breast cancer, it has been considered to be a factor predicting the poor outcome of the malignant tumor [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Most recently, several studies reported that HER-2 protein overexpression might be associated with the progression of PCa, by activating androgen receptor signal pathway HER-2 dependent signaling may promote the PCa developing to the castration resistant prostate cancer (CRPC) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. And in CRPC, HER-2 is amplified or overexpressed in up to 60% of patients and strongly correlated with the progression of the disease and shorter survival time [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Even so, most of the studies reported are focus on PCa with latent phase, researches detecting the role of HER-2 expression on localized PCa are rare.\u003c/p\u003e \u003cp\u003eWith these considerations, in this research we investigated whether expression of HER-2 is associated with poor clinicopathological outcome, high biochemical recurrence (BCR) rate and short BCR free survival with localized PCa treated by radical prostatectomy (RP).\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cp\u003e This is a retrospective study approved by the medical ethics review committee (protocol code 2019KT30).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003e44 localized PCa cases who underwent laparoscopic RP between January 2018 and December 2019 were reviewed. Among these patients, no one received neo-adjuvant therapy before RP and adjuvant therapy after RP until the detection of BCR. Preoperative clinical characteristics including age, serum tPSA value, PSA f/t value, total prostate volume (TPV), body mass index (BMI) and biopsy positive cores (BPC) as well as postoperative pathological and clinical outcomes including Gleason Score (GS), pathological T (pT) stage, positive surgical margins (PSM) and BCR were collected and compared depending on the level of HER-2 expressed. Data of risk factors might relate to BCR including HER-2, GS, PSM and pT stage were collected, and their associations with BCR and BCR free survival time were analyzed.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eProcedure\u003c/h2\u003e \u003cp\u003eUltrasound guided 13-core trans-rectal prostatic biopsy was performed in patients suspected PCa in our institute. Data of serum tPSA value, PSA f/t values were collected just 1\u0026ndash;2 days before surgery and at least 3 weeks after prostatic biopsy. MRI, PSMA PET-CT were performed before surgery to confirm no bone, lymph nodes or distant organ metastasis. Laparoscopic RP was performed at least 25 days after biopsy. Through an extraperitoneal approach, extra-fascial radical prostatectomy was performed by skilled surgeons in our institute according to the technique of Walsh et al [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. All specimens were assessed by sophisticated pathologist at our institute, tissues from patients were tested for HER-2 protein expression. HER-2 positive could be documented either on the original diagnostic biopsy or on the RP specimen. For every 1\u0026ndash;3 months, serum tPSA and f/t values were detected.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eVariables\u003c/h2\u003e \u003cp\u003eThe prostate was measured in 3-dimensional aspects, and its volume was estimated with the modified ellipsoid formulation in cm\u003csup\u003e3\u003c/sup\u003e (0.523 [ length \u0026times; width \u0026times; height]) after surgery, pathologic GS were recorded and patients were staged according to the 2010 American Joint Committee on Cancer system (AJCC, pathologic stage T1-T4) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Tumors were classified into low (GS\u0026thinsp;\u0026le;\u0026thinsp;6), intermediate (GS\u0026thinsp;=\u0026thinsp;7), high grade (GS\u0026thinsp;\u0026ge;\u0026thinsp;8) group according to D\u0026rsquo;Amico risk classification [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Body Mass index (BMI)\u0026thinsp;=\u0026thinsp;weight (kg)/ height (meter)\u003csup\u003e2\u003c/sup\u003e. BCR was defined as at least two consecutive serum tPSA\u0026thinsp;\u0026ge;\u0026thinsp;0.2ng/mL according to the guidelines of the American Urological Association [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], and data of time free from BCR was collected. Sections of the surgical piece with prostate cancer were selected for the determination of HER-2 expression. This was evaluated using the FDA approved immunochemical kit HercepTest (DAKO, USA). The status of HER-2 immunostaining were catalogized into 4 types, HER-2 0: membrane stain absent; HER-2 1+: greater than 10% of tumors cells present with barely perceptible staining; HER-2 2+: greater than 10% of tumors cells present with weak to moderated staining; HER-2 3+: greater than 10% tumor cells present with strong staining [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Then patients were divided into 4 sub-cohorts according to the expression status of HER-2. Cohort-1, HER-2 0+, cohort-2, HER-2 1+, 2+, 3+; cohort-3, HER-2 0, 1+; cohort-4 HER-2 2+, 3+. The clinicopathological factors were analyzed and compared between cohort-1 and 2, cohort-3 and 4, respectively.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eMeasurement data confirming to normal distribution analyzed by Shapiro-Wilk test are presented as Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, independent sample t test is used to evaluate the differences between continuous variables, while Chi-square tests were performed to examine categorical variables. The binary logistic regression model (univariate and multivariate analysis) was used to evaluate the association between HER-2 expression and adverse pathological events, which were all compared with reference group (Ref). Kaplan-Merier analyses were performed of BCR free survival according to level of HER-2 expressed using the log-rank test, and the survival curves were described. Univariable and multivariable Cox regression model was used to identify the co-variables that influence BCR. The software used to run the analysis was IBM-SPSS version 20. All tests were two-sided, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered to be the threshold for statistically meaningful differences.\u003c/p\u003e \u003c/div\u003e"},{"header":"Result","content":"\u003cp\u003e \u003cb\u003eClinicopathologic characteristics of the entire cohort.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eTotally 44 localized PCa patients were enrolled into this study. The median values of the factors was 67.95\u0026thinsp;\u0026plusmn;\u0026thinsp;6.84 yeas for age, 25.60\u0026thinsp;\u0026plusmn;\u0026thinsp;2.13kg/m\u003csup\u003e2\u003c/sup\u003e for BMI, 29.49\u0026thinsp;\u0026plusmn;\u0026thinsp;40.59 ng/mL for tPSA, 0.129\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01 for f/t value, 34.77\u0026thinsp;\u0026plusmn;\u0026thinsp;12.28 mL for TPV and 44.65\u0026thinsp;\u0026plusmn;\u0026thinsp;22.48 for proportion of BCP. 2 (4.5%) patients were with GS\u0026thinsp;\u0026le;\u0026thinsp;6, 22 (50%) patients were with GS\u0026thinsp;=\u0026thinsp;7 and 20 (45.45%) patients were with GS\u0026thinsp;\u0026ge;\u0026thinsp;8; 26 (59.09%) patients were pT2, 18 patients (40.91%) were pT3. 24 patients (54.5%) were with PSM. The patients\u0026rsquo; clinicopathologic demographics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinicopathological characteristics of the entire cohort and sub-cohorts divided by HER-2 expression\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEntire cohort\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort- 1\u003c/p\u003e \u003cp\u003e(HER-2 0+)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCohort-2\u003c/p\u003e \u003cp\u003e(HER-2 1+, 2+)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67.95\u0026thinsp;\u0026plusmn;\u0026thinsp;6.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68.33\u0026thinsp;\u0026plusmn;\u0026thinsp;7.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e67.5\u0026thinsp;\u0026plusmn;\u0026thinsp;5.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.694\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25.60\u0026thinsp;\u0026plusmn;\u0026thinsp;2.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.51\u0026thinsp;\u0026plusmn;\u0026thinsp;2.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25.70\u0026thinsp;\u0026plusmn;\u0026thinsp;2.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.771\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003etPSA (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29.49\u0026thinsp;\u0026plusmn;\u0026thinsp;40.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36.66\u0026thinsp;\u0026plusmn;\u0026thinsp;51.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20.89\u0026thinsp;\u0026plusmn;\u0026thinsp;18.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.203\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ef/t\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.129\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.119\u0026thinsp;\u0026plusmn;\u0026thinsp;0.047\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.148\u0026thinsp;\u0026plusmn;\u0026thinsp;0.046\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.177\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTPV (mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34.77\u0026thinsp;\u0026plusmn;\u0026thinsp;12.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32.82\u0026thinsp;\u0026plusmn;\u0026thinsp;11.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37.11\u0026thinsp;\u0026plusmn;\u0026thinsp;13.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.254\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBCP (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44.65\u0026thinsp;\u0026plusmn;\u0026thinsp;22.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49.03\u0026thinsp;\u0026plusmn;\u0026thinsp;17.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39.01\u0026thinsp;\u0026plusmn;\u0026thinsp;26.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.216\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGS (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (8.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (45.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (41.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epT stage (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.911\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (59.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (58.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epT3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (40.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (41.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSM (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (54.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (41.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.045\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBCR (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (54.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.029\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eBMI: body mass index; tPSA: total prostate cancer specific antigen; TPV: total prostate volume; BCP: biopsy core positive; GS: Gleason Score; pT: pathological stage; PSM: positive surgical margins; BCR: biochemical recurrence.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eSub-cohorts divided by levels of HER-2 protein expression\u003c/h2\u003e \u003cp\u003e20 cases (45.45%) of tumors exhibited HER-2 immuno-reactivity, 24 cases (54.55%) exhibited non- HER-2 immuno-reactivity. Of these HER-2 expressed tumors, 14 (31.82%) had HER-2 1+, 6 (13.64%) had HER-2 2\u0026thinsp;+\u0026thinsp;and 0 (0%) had HER-2 3\u0026thinsp;+\u0026thinsp;immunostaining. All patients were divided into 4 sub-cohorts according to the level of HER-2 protein expression. 24 (54.55%) cases with HER-2 0 and 20 cases (45.45%) with HER-2 1+, 2\u0026thinsp;+\u0026thinsp;were catalogized into cohort-1 and cohort-2; 38 cases (86.36%) with HER-2 0\u0026thinsp;+\u0026thinsp;or 1\u0026thinsp;+\u0026thinsp;and 6 cases (13.64%) with HER-2 2\u0026thinsp;+\u0026thinsp;were catalogized into cohort-3 and cohort-4.\u003c/p\u003e \u003cp\u003eInitially, data were analyzed and compared between cohort-1 and cohort-2, cohort-3 and cohort-4, respectively. In cohort-1, the proportion of PSM was significant lower compared with cohort-2 (41.7% vs 70%, P\u0026thinsp;=\u0026thinsp;0.045), but the distribution of age, BMI, tPSA, f/t, TPV, BCP, GS and pT stage did not show any significant differences; in cohort-3, the TPV (32.72\u0026thinsp;\u0026plusmn;\u0026thinsp;11.57 vs 43.73\u0026thinsp;\u0026plusmn;\u0026thinsp;8.49mL, P\u0026thinsp;=\u0026thinsp;0.004) was significant lower compared with cohort-4, but the distribution of age, BMI, tPSA, f/t, BCP, GS, PSM and pT stage did not show any significant differences as shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e \u003cb\u003eand\u003c/b\u003e Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinicopathological characteristics of patients divided by HER-2 expression\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCohort-3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort-4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(HER-2 0,1+)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(HER-2 2+)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67.79\u0026thinsp;\u0026plusmn;\u0026thinsp;7.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69.00\u0026thinsp;\u0026plusmn;\u0026thinsp;5.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.694\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25.53\u0026thinsp;\u0026plusmn;\u0026thinsp;2.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26.04\u0026thinsp;\u0026plusmn;\u0026thinsp;2.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.588\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003etPSA (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31.25\u0026thinsp;\u0026plusmn;\u0026thinsp;43.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.46\u0026thinsp;\u0026plusmn;\u0026thinsp;0.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.299\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ef/t\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.129\u0026thinsp;\u0026plusmn;\u0026thinsp;0.048\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.113\u0026thinsp;\u0026plusmn;\u0026thinsp;0.069\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.521\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTPV (mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32.72\u0026thinsp;\u0026plusmn;\u0026thinsp;11.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43.73\u0026thinsp;\u0026plusmn;\u0026thinsp;8.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBCP (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49.84\u0026thinsp;\u0026plusmn;\u0026thinsp;18.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29.37\u0026thinsp;\u0026plusmn;\u0026thinsp;32.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.043\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGS (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.499\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (52.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (42.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epT stage (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (57.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epT3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (42.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSM (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (52.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.650\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBCR (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (47.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.025\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eBMI: body mass index; tPSA: total prostate cancer specific antigen; TPV: total prostate volume; BCP: biopsy core positive; GS: Gleason Score; pT: pathological stage; PSM: positive surgical margins; BCR: biochemical recurrence.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThen the association of HER-2 1+, 2\u0026thinsp;+\u0026thinsp;with PSM were analyzed according to univariable and multivariable logistics regression models. The result showed HER-2 expressed 1\u0026thinsp;+\u0026thinsp;or 2\u0026thinsp;+\u0026thinsp;was the independent risk factor strongly associated with the higher proportion of PSM (HR, 2.691; 95% CI, 0.619\u0026ndash;11.71, P\u0026thinsp;=\u0026thinsp;0.042) after surgery as shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariable and multivariable analysis of the impact of HER-2 expression on status of surgical margins\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eUnivariable analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eMultivariable analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003ePSM vs NSM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003ePSM vs NSM\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHER-2 0+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRef\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRef\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRef\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHER-2 1+,2+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.333\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.897\u0026ndash;6.072\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.046\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.691\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.619\u0026ndash;11.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.042\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eRef: reference; PSM: positive surgical margins; NSM: negative surgical margins\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eFactors associated with BCR and BCR free survival\u003c/h2\u003e \u003cp\u003eThe median follow-up time was 43 months (IQR 35\u0026ndash;49). Totally 24 (54.55%) patients developed BCR after surgery. Factors might associate with BCR including HER-2 expression, GS, pT stage and PSM were collected and analyzed. The data showed that 8 (33.3%) cases occurred BCR in cohort-1, 16 (80%) in cohort-2, P\u0026thinsp;=\u0026thinsp;0.029 while 18 (47.4%) in cohort-3, 6 (100%) in cohort-4, P\u0026thinsp;=\u0026thinsp;0.025, but there were no differences of the proportions of BCR occurred in patients divided by GS (P\u0026thinsp;=\u0026thinsp;0.267), PSM (P\u0026thinsp;=\u0026thinsp;0.402) and pT stage (P\u0026thinsp;=\u0026thinsp;0.15) as shown in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. According to Kaplan-Meier analysis, results showed that in cohort-1, the BCR free survival was significantly longer than in cohort-2 as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, P\u0026thinsp;=\u0026thinsp;0.000; while in cohort-3, the BCR free survival was significantly longer than in cohort-4, P\u0026thinsp;=\u0026thinsp;0.000 as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, but the GS, pT stage and PSM were not associated with BCR free survival as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. By using univariable and multivariable Cox regression model revealed that HER-2 1\u0026thinsp;+\u0026thinsp;or 2+ (HR, 17.002; 95% CI, 1.378-210.216, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), HER-2 2+ (HR, 2.849; 95% CI, 1.234\u0026ndash;3.246, P\u0026thinsp;=\u0026thinsp;0.004) were all significant independent factors associated with developed BCR after surgery, but GS, pT stage, PSM were not factors associated with BCR as shown in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinicopathological characteristics of the patients divided by status of BCR\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eno BCR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBCR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHER-2 0+ (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.029\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHER-2 1+,2+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHER-2 0,1+ (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (52.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (47.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.025\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHER-2 2+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGS (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.267\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epT stage (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.150\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epT3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSM (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (58.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.402\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNSM (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (41.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003ePSM: positive surgical margins; NSM: negative surgical margins; GS: gleason Score; pT stage: pathological T stage.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCox regression analysis of potential factors associated with development of BCR after RP.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eUnivariable analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eMultivariable analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHER-2 0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRef\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRef\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRef\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHER-2 1+,2+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.337\u0026ndash;11.965\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e17.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.378-210.216\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHER-2 0,1+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRef\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRef\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRef\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHER-2 2+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.615\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.825\u0026ndash;2.424\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.849\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.234\u0026ndash;3.246\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRef\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRef\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRef\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.613\u0026ndash;3.670\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.374\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.745\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.535\u0026ndash;2.822\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.151\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.493\u0026ndash;3.167\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.638\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.441\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.789\u0026ndash;2.632\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.452\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurgical margin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNSM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRef\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRef\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRef\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.424\u0026ndash;4.623\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.416\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.956\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.437\u0026ndash;19.984\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.266\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epT stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRef\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRef\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRef\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.167\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.540\u0026ndash;2.522\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.334\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e17.022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.678\u0026ndash;2.216\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.327\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eGS: gleason score; PSM: positive surgical margins; pT stage: pathological T stage; Ref: reference.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis trial was designed to examine the feasibility of molecular profiling in patients with localized PCa to determine the association between HER-2 protein expression and clinicopathological characters and BCR after surgery. HER-2 oncoprotein is 1 of the 4 transmembrane receptors of the erB family. It can form heterodimers with the other erbB family members after binding to specific ligands [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. HER-2 overexpression has been seen in variable kinds of cancer. In breast cancer, about 30% of patients has been found with HER-2 overexpression. In patients with urothelial carcinoma of the bladder, HER-2 expression in circulating tumor cells was higher than in the tumor original [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. These finding suggested that HER-2 positive cells in the original tumor have a higher capacity of vascular dissemination than HER-2 negative cells.\u003c/p\u003e \u003cp\u003eIn patients with prostate cancer, tumor progression to androgen independent growth eventually after treating with androgen ablation therapy. Androgen receptor pathway activation independent of androgen plays a key role in it [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, the mechanism by which the pathway is activated in the absence of androgen is unknown. One important factor may induce the development of androgen independent is HER-2. Specific HER-2 overexpression may promote AR transactivation and phosphorylation, and by enhancing AR binding to androgen regulated gene promoters HER-2 may stimulate AR proteins [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In vivo experiments, HER-2 may be important for the survival of prostate cancer cells in androgen depleted environment [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In PCa patients, the HER-2 overexpression varies differently according to the reports of different experiments. It is reported that 70% of patients with localized PCa underwent radical prostatectomy were HER-2 overexpression [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]; Koeppen et al reported that among 61 PCa patients, only 5 had HER-2 overexpression classified as 2+, none classified as 3+ [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]; while another study found that among hormone refractory prostate carcinoma, HER-2 overexpression was seen in only 7% patients [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Yoshiaki et al, reported that in M1b prostate cancer patients, 19.2% of the subjects had HER-2 overexpression, and these patients had a significantly poorer outcome [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The findings of our study seemed accordance with the previous studies reported, in our study 45.45% of cases were with HER-2 expressed, but only 13.64% cases expressed HER-2 2+, none expressed HER-2 3+. Therefore, HER-2 expression seemed to be a common phenomenon in both early stage or latent stage prostate cancer patients.\u003c/p\u003e \u003cp\u003eSeveral studies considered HER-2 overexpression may play an important role in the development of prostate cancer. One research obtained prostate cancer tissues from patients which were divided into three sub-cohorts including treated by surgery alone (UNT), treated with total androgen ablation therapy before surgery (TAA), and treated with total androgen ablation therapy failed and developed bone metastases (AI), found that HER-2 protein expression was significantly higher in TAA tumors than in UNT tumors, and proportion of HER-2 positive tumors increased from UNT to TAA to AI, concluded that HER-2 expression appears to increase with the progression to androgen independence [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Another study collected samples from PCa patients, found that levels of HER-2 expression are infrequent in the tumors among hormone-na\u0026iuml;ve patients, but significantly increased among patients treated with androgen blockage [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. HER-2 overexpression might be associated with the development of the prostate cancer. In organ confined prostate cancer, rare studies detected the relationship between HER-2 expression and the clinicopathological characteristics. In 2008, one study investigated the expression of HER-2 and AR in organ confined prostate cancer patients who underwent RP to determine whether alterations in these signal pathways contributes to the progression of the diseases, the results showed that high HER-2 and AR expression were both closely associated with higher rate of PSA failure, and higher pathological stage [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Another study demonstrated that higher level of HER-2 expression was associated with higher prostate cancer stage and PSA progression in clinical localized PCa [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Our data seemed not very much accordance with the previous study, we found that HER-2 overexpression was associated with higher rates of BCR and PSM after RP, but it seemed not closely associated with higher GS and pT stage. For HER-2 overexpression is common in PCa patients and may related to the progression of the disease, the development of additional treatment strategies that target the HER-2 may provide a more effective approach for treating PCa patients. Antibody-drug conjugates (ADCs) might be a potential medicine for treating PCa with latent phase. The ADCs are novel medicines consisting of payload linked to specific antibodies which can recognize antigens expressed over cancer cell\u0026rsquo;s surfaces. Recently, studies are focusing on STEAP1, TROP2, PSMA and CD46 as potential antigens targeted by ADCs [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. The studies detecting the ADCs targeted on the HER-2 antigen are rare, only few cases have been reported. Therefore, more research explorations are needed detecting the applications of ADCs targeting on HER-2 antigen.\u003c/p\u003e \u003cp\u003eOur study still has some limitations. It was a single center, retrospective study, and the sample size was relatively small, more samples are needed in further studies.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe data indicated that nearly half proportion of localized PCa expressed HER-2 1\u0026thinsp;+\u0026thinsp;or 2+, but the patients expressed HER-2 3\u0026thinsp;+\u0026thinsp;were rare. The HER-2 expression was closely associated with higher proportion of BCR, PSM and shorter BCR free survival, but not associated with GS and pT stage. However, further well organized and large prospective studies are needed.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s contribution\u003c/strong\u003e: Shuo Wang and Peng Du designed the study. Shuo Wang, Xiao Yang and Ruijian You made the same contribution in this study as the first coauthor. Peng Du, Yiqiang Liu made the same contribution in this study as the corresponding coauthor. Shuo Wang, Xiao Yang, Ruijian You, Peng Du, Yiqiang Liu, Yongpeng Ji, Qiang Zhao, Yudong Cao, Jinchao Ma, Ziyi Yu, Yong Yang performed the study and analyzed the data. Peng Du, Shuo Wang, Xiao Yang, Yiqiang Liu and Ruijian You wrote the manuscript draft and revised the manuscript. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: 1. Clinical Research Fund For Distinguished Young Scholars of Peking University Cancer Hospital, QNJJ2022004; 2. Beijing Hospitals Authority Youth Programme, QML20231114.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInstitutional Review Board Statement\u003c/strong\u003e: This study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of Peking University Cancer Hospital \u0026amp; Institution in April 2021 (protocol code 2019KT30).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformal Consent Statement\u003c/strong\u003e: Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e: The data presented in this study are available on request from the corresponding author.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interests\u003c/strong\u003e: These authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRoss JS, Nazeer T, Church K et al. Contribution of HER-2/neu oncogene expression to tumor grade and DNA content analysis in the prediction of prostatic carcinoma metastasis. Cancer. 1993, 3020\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePress MF, Bernstein L, Thomas PA, et al. HER-2/neu gene amplification characterized by fluorescence in situ hybridization: poor prognosis in node-negative breast carcinomas. J Clin Oncol. 1997;15:2894\u0026ndash;904.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCraft N, Shostak Y, Carey M, et al. A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat Med. 1999;5:280\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSignoretti S, Montironi R, Manola J, et al. HER-2/neu expression and progression toward androgen independence in human prostate cancer. J Natl Cancer Inst. 2000;92:1918\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWalsh PC, Retik AB, Vaughan ED et al. Anatomic radical retropubic prostatectomy; in Campbell\u0026rsquo;s Urology (ed 8). Philadephia 2002, 4, 3107\u0026ndash;3129.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFrederick L, Page DL, Fleming ID, et al. AJCC Cancer Staging Manual. New York, NY, USA: Springer Science \u0026amp; Business Media; 2002.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eD\u0026rsquo; Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280:969\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCookson MS, Aus G, Burnett AL, et al. Variation in the definition of biochemical recurrence in patients treated for localized prostate cancer: the American Urological Association Prostate Guidelines for localized prostate update panel report and recommendations for a standard in the reporting of surgical outcomes. J Urol. 2007;177:540\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOsman I, Scher HI, Drobnjak M, et al. HER-2/neu (p185neu) protein expression in the natural or treated history of prostate cancer. Clin Cancer Res. 2001;7:2643\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeerli RR, Graus Porta D, Woods Cook K, et al. Neu differentiation factor activation of erbB-3 and erbB-4 is cell specific and displays a differential requirement for erbB-2. Mol Cell Biol. 1995;15:6496.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRink M, Chun FK, Dahlem R et al. Prognostic role and HER-2 expression of circulating tumor cells in peripheral blood of patients prior to radical cystectomy: a prospective study. Eur Urol, 61. 810\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVeldscholte J, Berrevoets CA, Ris-Stalpers C, et al. The androgen receptor in LNCaP cells contains a mutation in the ligand binding domain which affects steroid binding characteristics and response to antiandrogens. J Steroid Biochem Mol Biol. 1992;41:665\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCraft N, Shostak Y, Carey M, et al. A mechanism for hormone independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat Med. 1999;5:280\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBerger R, Lin Di, Nieto M, et al. Androgen dependent regulation of HER-2/neu in prostate cancer cells. Cancer Res. 2006;66:5723.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRicciarde lli C, Jackson MV, Choong CS, et al. Elevated level s of HER-2/neu and androgen receptor in clinically localized prostate cancer identifies metastatic potential. Prostate. 2008;68:830\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKoeppen HK, Wright BD, Burt AD, et al. Overexpression of HER2/neu in solid tumours: an immunohistochemical survey. Histopathology. 2001;38:96\u0026ndash;104.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLara PN Jr, Longmate J, Ruel C, et al. Trastuzumab plus docetaxel in HER-2/neu positive prostate carcinoma: final results from the California Cancer Consortium Screening and Phase II trial. Cancer. 2004;100:2125\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoshiaki Yamada K, Nakamura S, Aoki, et al. Lactate dehydrogenase, Gleason Score and HER-2 overexpression are significant prognostic factors for M1b prostate cancer. Oncol Rep. 2011;25:937\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSabina Signoretti R, Montironi J, Manola et al. HER-2 neu expression and progression toward androgen independence in human prostate cancer. J Natl Cancer Inst. 2000, 92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMurray NP, Badinez LV, Duenas R et al. Positive HER-2 protein expression in circulating prostate cells and micro-metastasis, resistant to androgen blockage but not diethylstilbestol. Indian J Urol. 2011, 200\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRicciarde lli C, Jackson MV, Choong CS, et al. Elevated level s of HER-2/neu and androgen receptor in clinically localized prostate cancer identifies metastatic potential. Prostate. 2008;68:830\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShahrokh FS, Karim B, Jose AK, et al. Preoperative plasma HER2 and epidermal growth factor receptor for staging and prognostication in patients with clinically localized prostate cancer. Clin Cancer Res. 2007;15:5377\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePetrylak DP, Vogelzang NJ, Chatta K, et al. PSMA ADC monotherapy in patients with progressive metastatic castration resistant prostate cancer following abiraterone and/or enzalutamide: efficacy and safety in open-label single arm phase 2 study. Prostate. 2020;80:99\u0026ndash;108.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMilowsky MI, Galsky MD, Morris MJ, et al. Phase 1/2 multiple ascending dose trial of the prostate specific cancer. Urol Oncol. 2016;34:e53015\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e\u003c/ol\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":"[email protected]","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":"prostate cancer, biochemical recurrence, HER-2, radical prostatectomy","lastPublishedDoi":"10.21203/rs.3.rs-4153815/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4153815/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eTo investigate the association between HER-2 expression and clinicopathological characteristics, biochemical recurrence (BCR) rate and BCR free survival in localized prostate cancer (PCa) patients after radical prostatectomy (RP).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eBetween January 2014 and December 2019, 44 patients with pathological confirmed localized PCa who underwent RP were included into this study. According to the expressed level of HER-2 protein, patients were divided into 4 cohorts, cohort-1 (HER-2 0+), cohort-2 (HER-2 1\u0026thinsp;+\u0026thinsp;or 2+), cohort-3 (HER-2 0\u0026thinsp;+\u0026thinsp;or 1+) and cohort-4 (HER-2 2+), the clinicopathological and clinical outcomes were analyzed and compared between cohort-1 and cohort-2, cohort-3 and cohort-4, respectively. Univariable, multivariable COX regression model and Kaplan-Meier curves were used to determine the association between HER-2 expression and clinicopathological outcomes including Gleason Score (GS), pathological T (pT) stage, positive surgical margins (PSM) and BCR free survival, respectively.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe median follow-up time was 43 months (IQR 35\u0026ndash;49), 20 patients (45.45%) of tumors exhibited HER-2 immuno-reactivity, 14 (31.82%) had HER-2 1+, 6 (13.64%) had HER-2 2\u0026thinsp;+\u0026thinsp;and 0 (0%) had HER-2 3\u0026thinsp;+\u0026thinsp;immunostaining. The proportion of PSM in patients with HER-2 0\u0026thinsp;+\u0026thinsp;was significant lower compared with 1\u0026thinsp;+\u0026thinsp;or 2+ (41.7% vs 70%, P\u0026thinsp;=\u0026thinsp;0.045). By using multivariable logistics regression models revealed that HER-2 1\u0026thinsp;+\u0026thinsp;or 2\u0026thinsp;+\u0026thinsp;was the independent risk factor strongly associated with higher proportion of PSM (HR, 2.691; 95% CI, 0.619\u0026ndash;11.71, P\u0026thinsp;=\u0026thinsp;0.042). 24 (54.55%) patients developed BCR after surgery, including 8 (33.3%) in cohort-1, 16 (80%) in cohort-2, P\u0026thinsp;=\u0026thinsp;0.029 while 18 (47.4%) in cohort-3, 6 (100%) in cohort-4, P\u0026thinsp;=\u0026thinsp;0.025. According to Kaplan-Meier analysis, results showed that in cohort-1, the BCR free survival was significantly longer than in cohort-2, P\u0026thinsp;=\u0026thinsp;0.000; while in cohort-3, the BCR free survival was significantly longer than in cohort-4, P\u0026thinsp;=\u0026thinsp;0.000. By using multivariable Cox regression model revealed that HER-2 1+, 2+ (HR, 17.002; 95% CI, 1.378-210.216, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), HER-2 2+ (HR, 2.849; 95% CI, 1.234\u0026ndash;3.246, P\u0026thinsp;=\u0026thinsp;0.004) were all significant independent factors associated with BCR after surgery\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eHER-2 expression was a common phenomenon in PCa, nearly half proportion of localized PCa had HER-2 1\u0026thinsp;+\u0026thinsp;or 2+, but the cases expressed HER-2 3\u0026thinsp;+\u0026thinsp;were rare. Cases with HER-2 1\u0026thinsp;+\u0026thinsp;or 2\u0026thinsp;+\u0026thinsp;were more likely developed BCR compared with HER-2 0+. The HER-2 expression was closely associated with shorter BCR free survival and higher proportion of PSM, but not associated with GS and pT stage. HER-2 could be considered as a potential method predicting clinical outcomes in patients after RP.\u003c/p\u003e","manuscriptTitle":"The association of HER-2 expression with clinicopathological characteristics and clinical outcomes in patients with localized prostate cancer after radical prostatectomy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-03 17:21:31","doi":"10.21203/rs.3.rs-4153815/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","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":"fc74e9d3-b244-449a-ac90-d2b5b2f65572","owner":[],"postedDate":"April 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-03-03T16:11:04+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-03 17:21:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4153815","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4153815","identity":"rs-4153815","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}